二氧化钛纳米材料对小鼠哺乳期的毒性研究以及噻唑烷酮组合物协同抑制耐药肺癌细胞机制研究
|
摘要
第一部分二氧化钛纳米材料对小鼠哺乳期的毒性研究
近年来,纳米技术逐渐成为推动世界各国经济发展的主要驱动力之一。在未来新型纳米材料和纳米技术有望广泛应用于信息、环保、能源、生物医学、制造等领域,为上述领域带来技术变革。因此,其重要程度受到了越来越广泛的关注,世界各国纷纷制定了符合本国利益的纳米科技发展计划。近年来,随着纳米技术从基础研究领域向应用研究领域和相关产业的转化,一些纳米商品已经投放市场。自2006年以来,世界范围内已经有1317种纳米产品出现在消费品市场。
纳米技术在环保、生物医学等与人们健康相关领域的应用日益广泛,如在环保领域,纳米技术用于清除水中有毒、难降解的有机污染物,治理空气污染,在生物医学方面实现重大疾病的早期诊断以及低毒高效的靶向治疗等。这就加大了人类接触不同种类纳米材料的可能性。然而,纳米材料对环境是否存在危害?与人体接触是否会产生难以预期的不良后果?在纳米尺度下,物质具有小尺寸效应、表面效应、量子尺寸效应和宏观量子隧道效应。这就使得纳米材料与人体接触后可能产生与常规大尺寸物质不同的生物效应。纳米材料的尺寸、化学组成、表面修饰以及暴露途径等都是影响纳米材料生物效应的重要因素。在这种背景下诞生的纳米毒理学为纳米材料的安全使用提供了依据,为纳米科技的发展起到指引作用。
根据已有报道,二氧化钛纳米材料可以对脑、肺、肝脏造成损伤,甚至有致癌的可能。二氧化钛纳米材料能够通过嗅神经突触进入嗅球并迁移至大脑,分布于大脑的不同部位,并且可以在脑部滞留,诱发脑部氧化应激和炎症反应水平增高,导致小鼠嗅球和海马神经元形态发生改变；还可以引起肝细胞坏死、凋亡和纤维化。
哺乳是生殖过程的延续。人类的哺乳期持续时间较长,母乳为婴儿提供其健康发育所需的营养素,并含有一些能保护婴儿免受儿童常见病侵袭的抗体。女性哺乳期间的用药可能会在母代、子代两方面产生影响。一方面药物本身对乳汁产生有影响；另外通过乳汁传递的药物对处于哺乳期的新生儿也会有毒副作用。近来随着人们接触纳米产品日益增多,纳米颗粒对哺乳期女性以及哺乳期婴儿有无毒性已引起学术界的关注和重视。有研究报道,C60和二氧化钛纳米材料随乳汁而传递给仔鼠,并且在仔鼠体内发生了吸收。但上述两项研究并未系统阐述纳米材料对处于哺乳期的母鼠有无毒性,以及纳米材料如何通过乳汁传递的机制。
由于二氧化钛纳米材料的良好应用前景以及纳米材料对哺乳期女性毒性的未知,本论文第一部分选取两种不同粒径的二氧化钛纳米材料(8nm和50nm)为研究对象,以哺乳期母鼠为模型,系统评价了二氧化钛纳米材料对处于哺乳期的母鼠及仔鼠哺乳期发育的毒性。并围绕乳腺展开研究,阐述了纳米材料通过乳汁传递给仔鼠的机制。研究结果揭示了纳米材料对哺乳期女性的潜在健康影响,另外对哺乳期女性的用药安全也具有指导意义。
实验首先通过尾静脉方式对处于哺乳期的母鼠暴露8nm和50nm的二氧化钛纳米材料,在随后的体内分布研究中发现二氧化钛纳米材料在乳腺中有分布。但在材料暴露期间以及暴露后对母鼠都没有引起明显的系统毒性。暴露组母鼠的主要脏器系数以及组织病理学与对照组相比无显著性差异。但聚集在乳腺中的二氧化钛纳米材料能引起乳腺组织发生氧化应激,病理学结果显示乳腺上皮细胞脱落,高剂量暴露组的母鼠乳腺组织出现脂肪化。其中高剂量暴露8nm二氧化钛纳米材料对乳腺组织损伤更严重,造成的上皮细胞脱落数更多,部分血管充血。类似的病理学变化也同样出现在50nm二氧化钛纳米材料暴露组,但相对而言其造成的病理学改变较轻微。同时,随暴露剂量增加,构成乳腺上皮细胞之间的紧密连接蛋白ZO-1和occludin下调,说明氧化应激也破坏了乳腺上皮细胞之间的紧密连接,这直接导致纳米材料经过上皮细胞之间松散的紧密连接通道随乳汁传递。上皮细胞脱落和脂肪化都可能造成乳腺组织中乳汁蛋白基因表达量下调或者乳汁中蛋白含量下降。对此我们选择了乳汁中4个有重要生理功能的蛋白,分别是p-酪蛋白,a-乳清蛋白,乳铁传递蛋白,表皮生长因子。经过乳腺组织实时荧光定量PCR和乳汁蛋白印迹实验的验证,这4个蛋白表达量、含量与对照组比都未发生改变,其原因可能是乳腺损伤程度较小。而仔鼠在哺乳期的发育指标以及生存率都未受到影响。
第二部分噻唑烷酮化合物组合协同抑制耐药肺癌细胞机制研究
肺癌是全世界发病率和死亡率最高的恶性肿瘤。据统计,肺癌的五年生存率只有16.3%。癌症治疗手段包括手术治疗、放射治疗和化学治疗,其中化学治疗占有非常重要的地位。肿瘤细胞耐药性的产生及化疗药物引发的毒副作用是肿瘤化疗失败的两个主要原因。近来,研发单一靶点的抗癌药物是减小药物毒副作用的策略之一,比如格列卫(Gleevec),特罗凯(Tarceva),易瑞沙(Iressa)皆是单靶点药物。然而,单一靶点的药物在化疗过程中逐渐显露出劣势,比如治疗效率逐渐下降、严重的副作用以及肿瘤细胞的耐药性。因此,多层次、多靶点的治疗策略在肿瘤治疗中显示出了较大的潜力。这种治疗策略优势为多组分药物或者多靶点药物能发挥协同作用,共同抑制与肿瘤生长相关的信号通路。同时作用于多个靶点的药物组合物在肿瘤缩小和肿瘤细胞抑制方面,能更高效的克服多药耐药性,且有较低的副作用。
噻唑烷酮类化合物能够选择性地有效杀死对紫杉醇产生耐药性的肺癌细胞,而对人正常的成纤维细胞无严重杀伤作用。我们前期筛选了一个含100种化合物组合的化合物库,获得了一个含有27,107,167和254四种化合物的组合物(命名为M4),与单个化合物相比较,M4能够明显抑制对紫杉醇有耐药性的非小细胞肺癌H460/TaxR细胞生长。实验表明,M4化合物能调控细胞周期检验点蛋白,包括p53,p21,磷酸化cdc25C(Ser216)的表达升高；组蛋白H4及a-tubulin高度乙酰化；Akt磷酸化；Caspase激活；细胞色素C释放,线粒体膜电粒降低。这些结果表明,通过靶向不同的靶点,组成M4的单个化合物发挥协同作用,共同抑制肿瘤细胞的生长。本课题在前期工作的基础上进一步研究,发现(1)M4所包含的27、107、167和254四种化合物之间具有协同抗癌作用；(2)联合使用HDAC抑制剂和微管聚合抑制剂是治疗癌症的有效方法之一。
In recent years, nanotechnology is becoming one of the main driving forces of promoting the economic development in the world. It has already significantly affected modern society in many areas, such as bio-medicine, energy, electronics, transportation, architecture and the environment. Therefore, the importance of nanotechnology has been acquired increasing attention. Countries around the world have developed their nanotechnology development plan in line with national interests. Acompanying a number of nano-products have already on the market, nanotechnology is being shifted from basic research to applied research and to industrial transformation. Since2006, there have been1317kinds of nano products appeared in worldwide consumer market.
Nanotechnology have increasingly wide application prospects which is health-related fields with people, such as environmental and biomedical field. For example, nanotechnology is used to clear the toxic and organic contaminants in water, control air pollution and achieve remedy of diseases which combines low toxicity and efficient targeted therapy. Therefore, there has been increased possibility that human exposed to different types of nanomaterials. However, the negative effects of nanomaterials on environment or human body is unknown. Materials, at nanoscale, show quantum size effect, small bulk effect, surface effect and macroscopic quantum tunneling effect. So nanomaterials may present unique effects after their expsoure to human body due to their unique physical/chemical properties. In this context, nanotoxicology was proposed as a new branch of toxicology to address the adverse health effects caused by nanomaterials and development of nanotechnology.
Titanium oxide nanoparticels (TNPs) have attracted widespread attention due to its broad application prospect, such as environment, cosmetics and food adititive. However, it has been reported that TNPs can cause injury to brain, lungs, liver and even cancer. TNPs may be taken up directly to the brain from olfactory epithelium to the various parts of brain via the olfactory nerves. It produced the sustained accumulation in the brain tissues which induces brain pathological changes and oxidative stress-mediated responses. TNPs could induce some neurons to turn into filamentous shapes and others into inflammatory cells. It also induces hepatocytes necrosis, apoptosis and fibrosis.
Breastfeeding is a continuation of the reproductive process. The lactation period of human lasts long. Milk provides babies the nutrients they need which is beneficial to their health and development. It also contains a number of antibodies that can protect infants from common childhood diseases attacks. Medication of women during lactation period may have negative impact on the parent and the offspring or both. The medication may transfer to pups through milk. Milk producing and the transferred medication may have a negative impact on women and newborns. Recently, people have increased contact opportunity to nano-products. So the safety of nanomaterials to lactating women and infants is worthy of concern and attention. It has been reported that C60and TNPs transfer to pups through milk, while it can also be absorbed by pups. However, the two studies did not systematically expounded whether the nanomaterials have negative impact on lactating dams or the transfer mechanism of nanomaterials.
Due to the large-scale application of TNPs as well as the unknown potential negative effects on lactating dams, we select two sizes of TNPs in order to study the toxicological effects on lactating dams and their pups. And we conducted research around the lactating mammary glands (MGs) to elaborate the mechanism of nanomaterials transfer to milk. This mechanism has guiding significance to safety of nanomaterials and medication applicaion during lactation period.
The biodistribution of two sizes of TNPs after i.v. exposure to lactating dams shows that TNPs accumulate in lactating MGs. However, the TNPs didn't cause systemic toxicity to dams during exposure period and postexposure period. The dams' organ index didn't show significant difference between the dams exposed to TNPs and the PBS control group. The accumulation of TNPs in MGs cause oxidative stress and mammary epithelium cell shedding. Hyperplasia and adipocytes was found both in TNP1and TNP2exposure group at dose of6and8mg/kg BW. What noteworthy is that quantification of numbers of shedding epithelial cells showed that8mg/kg BW dose exposure of TNP1induces more shedding epithelial cells than its larger-sized counterpart. It also demostrates that TNP induced milk blood barrier disruption manifested by both cell shedding and loss of tight junctions. Theredore, the accumulation of TNPs in lactating MG disturbs the oxidant/antioxidant equilibrium and subsequent epithelial cells shed with tight junction loss. These results indicate that there is correlation between epithelial cells shedding and tight junction loss of mammary gland and TNP transfer to milk. MG epithelial cell shedding has another consequence that whether nutrient quality of milk will be deteriorated. The four proteins, including β-casein, a-lactalbumin, lactoferrin and epidermal growth factor, were chosen in the reason of their important function in the three aspects. The levels of four proteins, both mRNA and protein, were not meaningfully decreased after exposure to TNPs at8mg/kg BW. These data also suggest that exposure of TNPs does not impair milk secretion of dam, or deteriorate the nutrient quality of milk. Our data also showed that there was no significant difference in the pups that displayed hair growth and eye opening between the TNPs treated group at dose of8mg/kg BW and PBS control group.
Part II
Lung cancer is one of the main causes of death among all diseases. The five-year survival rate of lung cancer is merely16.3%. Cancer treatments include surgery, radiotherapy and chemotherapy. However, drug resistance and the dose-limiting toxicity are key reasons to account for unsuccessful cancer chemotherapy. Discovery of single target-specific drugs has been the focus of cancer drug development. Research in this area has led to the successful drugs such as Gleevec, Tarceva and Iressa. Single-target drugs have gradually showed some disadvantages, such as lack of efficacy, serious side effects, and development of drug resistance. Recently, multi-level and multi-targeting therapies have shown potential applications in cancer treatment. Such therapies, including multi-component drugs or multi-targeting drugs, may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive the growth of tumors. Synergistic action of such drugs may overcome side effects that resulted from high doses of single-target drugs, increase drug selectivity, and offer an opportunity for more precise control of biological systems. Drug combinations that simultaneously impact multiple targets are more effective to overcome MDR and lower side-effects in cancer cell inhibition and tumor shrinkage.
The thiazolidinone derivatives are useful anticancer agents with P-gp-evading property and minimal side effects. By screening compound combinations prepared from a thiazolidinone compound library in a drug-resistant variant H460/TaxR NSCLC cell line, a four-compound combination was identified that synergistically inhibit the growth of cancer cells from both lines. We found that (1) thiazolidinone compound combinations that have synergistic inhibitory effects on P-gp overexpressing NSCLC;(2) individual compound in this combination act as either tubulin polymerizationinhibitors or histone deacetylase (HDAC) inhibitors.
近年来,纳米技术逐渐成为推动世界各国经济发展的主要驱动力之一。在未来新型纳米材料和纳米技术有望广泛应用于信息、环保、能源、生物医学、制造等领域,为上述领域带来技术变革。因此,其重要程度受到了越来越广泛的关注,世界各国纷纷制定了符合本国利益的纳米科技发展计划。近年来,随着纳米技术从基础研究领域向应用研究领域和相关产业的转化,一些纳米商品已经投放市场。自2006年以来,世界范围内已经有1317种纳米产品出现在消费品市场。
纳米技术在环保、生物医学等与人们健康相关领域的应用日益广泛,如在环保领域,纳米技术用于清除水中有毒、难降解的有机污染物,治理空气污染,在生物医学方面实现重大疾病的早期诊断以及低毒高效的靶向治疗等。这就加大了人类接触不同种类纳米材料的可能性。然而,纳米材料对环境是否存在危害?与人体接触是否会产生难以预期的不良后果?在纳米尺度下,物质具有小尺寸效应、表面效应、量子尺寸效应和宏观量子隧道效应。这就使得纳米材料与人体接触后可能产生与常规大尺寸物质不同的生物效应。纳米材料的尺寸、化学组成、表面修饰以及暴露途径等都是影响纳米材料生物效应的重要因素。在这种背景下诞生的纳米毒理学为纳米材料的安全使用提供了依据,为纳米科技的发展起到指引作用。
根据已有报道,二氧化钛纳米材料可以对脑、肺、肝脏造成损伤,甚至有致癌的可能。二氧化钛纳米材料能够通过嗅神经突触进入嗅球并迁移至大脑,分布于大脑的不同部位,并且可以在脑部滞留,诱发脑部氧化应激和炎症反应水平增高,导致小鼠嗅球和海马神经元形态发生改变；还可以引起肝细胞坏死、凋亡和纤维化。
哺乳是生殖过程的延续。人类的哺乳期持续时间较长,母乳为婴儿提供其健康发育所需的营养素,并含有一些能保护婴儿免受儿童常见病侵袭的抗体。女性哺乳期间的用药可能会在母代、子代两方面产生影响。一方面药物本身对乳汁产生有影响；另外通过乳汁传递的药物对处于哺乳期的新生儿也会有毒副作用。近来随着人们接触纳米产品日益增多,纳米颗粒对哺乳期女性以及哺乳期婴儿有无毒性已引起学术界的关注和重视。有研究报道,C60和二氧化钛纳米材料随乳汁而传递给仔鼠,并且在仔鼠体内发生了吸收。但上述两项研究并未系统阐述纳米材料对处于哺乳期的母鼠有无毒性,以及纳米材料如何通过乳汁传递的机制。
由于二氧化钛纳米材料的良好应用前景以及纳米材料对哺乳期女性毒性的未知,本论文第一部分选取两种不同粒径的二氧化钛纳米材料(8nm和50nm)为研究对象,以哺乳期母鼠为模型,系统评价了二氧化钛纳米材料对处于哺乳期的母鼠及仔鼠哺乳期发育的毒性。并围绕乳腺展开研究,阐述了纳米材料通过乳汁传递给仔鼠的机制。研究结果揭示了纳米材料对哺乳期女性的潜在健康影响,另外对哺乳期女性的用药安全也具有指导意义。
实验首先通过尾静脉方式对处于哺乳期的母鼠暴露8nm和50nm的二氧化钛纳米材料,在随后的体内分布研究中发现二氧化钛纳米材料在乳腺中有分布。但在材料暴露期间以及暴露后对母鼠都没有引起明显的系统毒性。暴露组母鼠的主要脏器系数以及组织病理学与对照组相比无显著性差异。但聚集在乳腺中的二氧化钛纳米材料能引起乳腺组织发生氧化应激,病理学结果显示乳腺上皮细胞脱落,高剂量暴露组的母鼠乳腺组织出现脂肪化。其中高剂量暴露8nm二氧化钛纳米材料对乳腺组织损伤更严重,造成的上皮细胞脱落数更多,部分血管充血。类似的病理学变化也同样出现在50nm二氧化钛纳米材料暴露组,但相对而言其造成的病理学改变较轻微。同时,随暴露剂量增加,构成乳腺上皮细胞之间的紧密连接蛋白ZO-1和occludin下调,说明氧化应激也破坏了乳腺上皮细胞之间的紧密连接,这直接导致纳米材料经过上皮细胞之间松散的紧密连接通道随乳汁传递。上皮细胞脱落和脂肪化都可能造成乳腺组织中乳汁蛋白基因表达量下调或者乳汁中蛋白含量下降。对此我们选择了乳汁中4个有重要生理功能的蛋白,分别是p-酪蛋白,a-乳清蛋白,乳铁传递蛋白,表皮生长因子。经过乳腺组织实时荧光定量PCR和乳汁蛋白印迹实验的验证,这4个蛋白表达量、含量与对照组比都未发生改变,其原因可能是乳腺损伤程度较小。而仔鼠在哺乳期的发育指标以及生存率都未受到影响。
第二部分噻唑烷酮化合物组合协同抑制耐药肺癌细胞机制研究
肺癌是全世界发病率和死亡率最高的恶性肿瘤。据统计,肺癌的五年生存率只有16.3%。癌症治疗手段包括手术治疗、放射治疗和化学治疗,其中化学治疗占有非常重要的地位。肿瘤细胞耐药性的产生及化疗药物引发的毒副作用是肿瘤化疗失败的两个主要原因。近来,研发单一靶点的抗癌药物是减小药物毒副作用的策略之一,比如格列卫(Gleevec),特罗凯(Tarceva),易瑞沙(Iressa)皆是单靶点药物。然而,单一靶点的药物在化疗过程中逐渐显露出劣势,比如治疗效率逐渐下降、严重的副作用以及肿瘤细胞的耐药性。因此,多层次、多靶点的治疗策略在肿瘤治疗中显示出了较大的潜力。这种治疗策略优势为多组分药物或者多靶点药物能发挥协同作用,共同抑制与肿瘤生长相关的信号通路。同时作用于多个靶点的药物组合物在肿瘤缩小和肿瘤细胞抑制方面,能更高效的克服多药耐药性,且有较低的副作用。
噻唑烷酮类化合物能够选择性地有效杀死对紫杉醇产生耐药性的肺癌细胞,而对人正常的成纤维细胞无严重杀伤作用。我们前期筛选了一个含100种化合物组合的化合物库,获得了一个含有27,107,167和254四种化合物的组合物(命名为M4),与单个化合物相比较,M4能够明显抑制对紫杉醇有耐药性的非小细胞肺癌H460/TaxR细胞生长。实验表明,M4化合物能调控细胞周期检验点蛋白,包括p53,p21,磷酸化cdc25C(Ser216)的表达升高；组蛋白H4及a-tubulin高度乙酰化；Akt磷酸化；Caspase激活；细胞色素C释放,线粒体膜电粒降低。这些结果表明,通过靶向不同的靶点,组成M4的单个化合物发挥协同作用,共同抑制肿瘤细胞的生长。本课题在前期工作的基础上进一步研究,发现(1)M4所包含的27、107、167和254四种化合物之间具有协同抗癌作用；(2)联合使用HDAC抑制剂和微管聚合抑制剂是治疗癌症的有效方法之一。
In recent years, nanotechnology is becoming one of the main driving forces of promoting the economic development in the world. It has already significantly affected modern society in many areas, such as bio-medicine, energy, electronics, transportation, architecture and the environment. Therefore, the importance of nanotechnology has been acquired increasing attention. Countries around the world have developed their nanotechnology development plan in line with national interests. Acompanying a number of nano-products have already on the market, nanotechnology is being shifted from basic research to applied research and to industrial transformation. Since2006, there have been1317kinds of nano products appeared in worldwide consumer market.
Nanotechnology have increasingly wide application prospects which is health-related fields with people, such as environmental and biomedical field. For example, nanotechnology is used to clear the toxic and organic contaminants in water, control air pollution and achieve remedy of diseases which combines low toxicity and efficient targeted therapy. Therefore, there has been increased possibility that human exposed to different types of nanomaterials. However, the negative effects of nanomaterials on environment or human body is unknown. Materials, at nanoscale, show quantum size effect, small bulk effect, surface effect and macroscopic quantum tunneling effect. So nanomaterials may present unique effects after their expsoure to human body due to their unique physical/chemical properties. In this context, nanotoxicology was proposed as a new branch of toxicology to address the adverse health effects caused by nanomaterials and development of nanotechnology.
Titanium oxide nanoparticels (TNPs) have attracted widespread attention due to its broad application prospect, such as environment, cosmetics and food adititive. However, it has been reported that TNPs can cause injury to brain, lungs, liver and even cancer. TNPs may be taken up directly to the brain from olfactory epithelium to the various parts of brain via the olfactory nerves. It produced the sustained accumulation in the brain tissues which induces brain pathological changes and oxidative stress-mediated responses. TNPs could induce some neurons to turn into filamentous shapes and others into inflammatory cells. It also induces hepatocytes necrosis, apoptosis and fibrosis.
Breastfeeding is a continuation of the reproductive process. The lactation period of human lasts long. Milk provides babies the nutrients they need which is beneficial to their health and development. It also contains a number of antibodies that can protect infants from common childhood diseases attacks. Medication of women during lactation period may have negative impact on the parent and the offspring or both. The medication may transfer to pups through milk. Milk producing and the transferred medication may have a negative impact on women and newborns. Recently, people have increased contact opportunity to nano-products. So the safety of nanomaterials to lactating women and infants is worthy of concern and attention. It has been reported that C60and TNPs transfer to pups through milk, while it can also be absorbed by pups. However, the two studies did not systematically expounded whether the nanomaterials have negative impact on lactating dams or the transfer mechanism of nanomaterials.
Due to the large-scale application of TNPs as well as the unknown potential negative effects on lactating dams, we select two sizes of TNPs in order to study the toxicological effects on lactating dams and their pups. And we conducted research around the lactating mammary glands (MGs) to elaborate the mechanism of nanomaterials transfer to milk. This mechanism has guiding significance to safety of nanomaterials and medication applicaion during lactation period.
The biodistribution of two sizes of TNPs after i.v. exposure to lactating dams shows that TNPs accumulate in lactating MGs. However, the TNPs didn't cause systemic toxicity to dams during exposure period and postexposure period. The dams' organ index didn't show significant difference between the dams exposed to TNPs and the PBS control group. The accumulation of TNPs in MGs cause oxidative stress and mammary epithelium cell shedding. Hyperplasia and adipocytes was found both in TNP1and TNP2exposure group at dose of6and8mg/kg BW. What noteworthy is that quantification of numbers of shedding epithelial cells showed that8mg/kg BW dose exposure of TNP1induces more shedding epithelial cells than its larger-sized counterpart. It also demostrates that TNP induced milk blood barrier disruption manifested by both cell shedding and loss of tight junctions. Theredore, the accumulation of TNPs in lactating MG disturbs the oxidant/antioxidant equilibrium and subsequent epithelial cells shed with tight junction loss. These results indicate that there is correlation between epithelial cells shedding and tight junction loss of mammary gland and TNP transfer to milk. MG epithelial cell shedding has another consequence that whether nutrient quality of milk will be deteriorated. The four proteins, including β-casein, a-lactalbumin, lactoferrin and epidermal growth factor, were chosen in the reason of their important function in the three aspects. The levels of four proteins, both mRNA and protein, were not meaningfully decreased after exposure to TNPs at8mg/kg BW. These data also suggest that exposure of TNPs does not impair milk secretion of dam, or deteriorate the nutrient quality of milk. Our data also showed that there was no significant difference in the pups that displayed hair growth and eye opening between the TNPs treated group at dose of8mg/kg BW and PBS control group.
Part II
Lung cancer is one of the main causes of death among all diseases. The five-year survival rate of lung cancer is merely16.3%. Cancer treatments include surgery, radiotherapy and chemotherapy. However, drug resistance and the dose-limiting toxicity are key reasons to account for unsuccessful cancer chemotherapy. Discovery of single target-specific drugs has been the focus of cancer drug development. Research in this area has led to the successful drugs such as Gleevec, Tarceva and Iressa. Single-target drugs have gradually showed some disadvantages, such as lack of efficacy, serious side effects, and development of drug resistance. Recently, multi-level and multi-targeting therapies have shown potential applications in cancer treatment. Such therapies, including multi-component drugs or multi-targeting drugs, may produce concerted pharmacological intervention of multiple targets and signaling pathways that drive the growth of tumors. Synergistic action of such drugs may overcome side effects that resulted from high doses of single-target drugs, increase drug selectivity, and offer an opportunity for more precise control of biological systems. Drug combinations that simultaneously impact multiple targets are more effective to overcome MDR and lower side-effects in cancer cell inhibition and tumor shrinkage.
The thiazolidinone derivatives are useful anticancer agents with P-gp-evading property and minimal side effects. By screening compound combinations prepared from a thiazolidinone compound library in a drug-resistant variant H460/TaxR NSCLC cell line, a four-compound combination was identified that synergistically inhibit the growth of cancer cells from both lines. We found that (1) thiazolidinone compound combinations that have synergistic inhibitory effects on P-gp overexpressing NSCLC;(2) individual compound in this combination act as either tubulin polymerizationinhibitors or histone deacetylase (HDAC) inhibitors.
引文
1. 高春华.纳米材料的基本效应及其应用.江苏理工大学学报(自然科学版2001,22,45-49.
2.杜仕国；施冬梅；邓辉.纳米材料的特异效应及其应用.自然杂志2000,22,101-106.
3. Nel, A.; Xia, T.; Madler, L.; Li, N. Toxic potential of materials at the nanolevel. Science 2006,311,622-627.
4. Maynard, A. D.; Aitken, R. J.; Butz, T.; Colvin, V.; Donaldson, K.; Oberdoerster, G.; Philbert, M. A.; Ryan, J.; Seaton, A.; Stone, V.; Tinkle, S. S.; Tran, L.; Walker, N. J.; Warheit, D. B. Safe handling of nanotechnology. Nature 2006,444, 267-269.
5. Service, R. F. Nanotoxicology:Nanotechnology grows up. Science 2004,304, 1732-1734.
6. Zhao, Y.; Xing, G.; Chai, Z. Nanotoxicology:Are carbon nanotubes safe? Nat. Nanotechnol.2008,3,191-192.
7. http://ec.europa.eu/environment/chemicals/nanotech/.
8. http://www.nanotechproiect.org/inventories/consumer/analysis_draft/.
9. Service, R. F. Nanomaterials Show Signs of Toxicity. Science 2003,300,243.
10. Donaldson, K.; Stone, V.; Tran, C. L.; Kreyling, W.; Borm, P. J. A. Nanotoxicology. Occup. Environ. Med.2004,61,727-728.
11. Oberdorster, G.; Oberdorster, E.; Oberdorster, J. Nanotoxicology:an emerging discipline evolving from studies of ultrafine particles. Environmental health perspectives 2005,113,823.
12.柴之芳,赵.纳米毒理学：纳米材料安全应用的基础.科学出版社：北京,2010.
13.刘元方；陈欣欣；王海芳；.纳米材料生物效应研究和安全性评价前沿.自然杂志2011,44,193-197.
14. Oberdorster, G.; Maynard, A.; Donaldson, K.; Castranova, V.; Fitzpatrick, J.; Ausman, K.; Carter, J.; Karn, B.; Kreyling, W.; Lai, D.; Olin, S.; Monteiro-Riviere, N.; Warheit, D.; Yang, H.; Toxicity, I. R. F. R. S. I. N.; Screening Working, G. Principles for characterizing the potential human health effects from exposure to nanomaterials:elements of a screening strategy. Particle and fibre toxicology 2005,2,8-8.
15. Gao, N. N.; Zhang, Q.; Mu, Q. X.; Bai, Y. H.; Li, L. W.; Zhou, H. Y.; Butch, E. R.; Powell, T. B.; Snyder, S. E.; Jiang, G. B.; Yan, B. Steering Carbon Nanotubes to Scavenger Receptor Recognition by Nanotube Surface Chemistry Modification Partially Alleviates NF kappa B Activation and Reduces Its Immunotoxicity. ACS Nano 2011,5,4581-4591.
16. Choi, H. S.; Liu, W.; Misra, P.; Tanaka, E.; Zimmer, J. P.; Ipe, B. I.; Bawendi, M. G.; Frangioni, J. V. Renal clearance of quantum dots. Nat. Biotechnol.2007,25, 1165-1170.
17. Buzea, C.; Pacheco, I.; Robbie, K. Nanomaterials and nanoparticles:Sources and toxicity. Biointerphases 2007,2, MR17-MR71.
18. Gao, X.; Zhu, H.; Pan, G.; Ye, S.; Lan, Y.; Wu, F.; Song, D. Preparation and Electrochemical Characterization of Anatase Nanorods for Lithium-Inserting Electrode Material. The Journal of Physical Chemistry B 2004,108,2868-2872.
19. Kasuga, T.; Hiramatsu, M.; Hoson, A.; Sekino, T.; Niihara, K. Formation of Titanium Oxide Nanotube. Langmuir 1998,14,3160-3163.
20. Sasaki, T.; Watanabe, M.; Hashizume, H.; Yamada, H.; Nakazawa, H. Macromolecule-like Aspects for a Colloidal Suspension of an Exfoliated Titanate. Pairwise Association of Nanosheets and Dynamic Reassembling Process Initiated from It. Journal of the American Chemical Society 1996,118, 8329-8335.
21. Sukpirom, N.; Lerner, M. M. Preparation of Organic-Inorganic Nanocomposites with a Layered Titanate. Chem. Mater.2001,13,2179-2185.
22. Tang, J.; Wu, Y Y.; McFarland, E. W.; Stucky, G. D. Synthesis and photocatalytic properties of highly crystalline and ordered mesoporous TiO2 thin films. Chem. Commun.2004,1670-1671.
23. Fujishima, A.; Rao, T. N.; Tryk, D. A. Titanium dioxide photocatalysis. Journal of Photochemistry and Photobiology C:Photochemistry Reviews 2000,1,1-21.
24. Asahi, R.; Morikawa, T.; Ohwaki, T.; Aoki, K.; Taga, Y. Visible-light photocatalysis in nitrogen-doped titanium oxides. Science 2001,293,269-271.
25. Mills, A.; Le Hunte, S. An overview of semiconductor photocatalysis. Journal of Photochemistry and Photobiology A:Chemistry 1997,108,1-35.
26. Fu, G. F.; Vary, P. S.; Lin, C. T. Anatase TiO2 nanocomposites for antimicrobial coatings. J. Phys. Chem.B 2005,109,8889-8898.
27. Cho, M.; Chung, H.; Choi, W.; Yoon, J. Linear correlation between inactivation of E-coli and OH radical concentration in TiO2 photocatalytic disinfection. Water Res.2004,38,1069-1077.
28. Han, S. J.; Choi, S. H.; Kim, S. S.; Cho, M.; Jang, B.; Kim, D. Y.; Yoon, J.; Hyeon, T. Low-temperature synthesis of highly crystalline TiO2 nanocrystals and their application to photocatalysis. Small 2005,1,812-816.
29. Xu, M. H.; Ma, J. M.; Gu, J. H.; Lu, Z. H. Photocatalytic TiO2 nanoparticles damage to cellular membranes and genetic supramolecules. Supramolecular Science 1998,5,511-513.
30. Linnainmaa, K.; Kivipensas, P.; Vainio, H. Toxicity and cytogenetic studies of ultrafine titanium dioxide in cultured rat liver epithelial cells. Toxicol. In Vitro 1997,11,329-335.
31. Seo, J. W.; Chung, H.; Kim, M. Y.; Lee, J.; Choi, I. H.; Cheon, J. Development of water-soluble single-crystalline TiO2 nanoparticles for photocatalytic cancer-cell treatment. Small 2007,3,850-853.
32. Zhu, Y. F.; Shi, J. J.; Zhang, Z. Y.; Zhang, C.; Zhang, X. R. Development of a gas sensor utilizing chemiluminescence on nanosized titanium dioxide. Analytical Chemistry 2002,74,120-124.
33. Stergiopoulos, T.; Arabatzis, I. M.; Katsaros, G.; Falaras, P. Binary polyethylene oxide/titania solid-state redox electrolyte for highly efficient nanocrystalline TiO2 photoelectrochemical cells. Nano Letters 2002,2,1259-1261.
34. Nakade, S.; Saito, Y.; Kubo, W.; Kitamura, T.; Wada, Y.; Yanagida, S. Influence of TiO2 nanoparticle size on electron diffusion and recombination in dye-sensitized TiO2 solar cells. J. Phys. Chem. B 2003,107,8607-8611.
35. Ohko, Y.; Tatsuma, T.; Fujii, T.; Naoi, K.; Niwa, C.; Kubota, Y.; Fujishima, A. Multicolour photochromism of TiO2 films loaded with silver nanoparticles. Nat. Mater.2003,2,29-31.
36. Naoi, K.; Ohko, Y.; Tatsuma, T. TiO2 films loaded with silver nanoparticles: Control of multicolor photochromic behavior. Journal of the American Chemical Society 2004,126,3664-3668.
37. Donaldson, K.; Tran, C. L. Inflammation caused by particles and fibers. Inhalation Toxicology 2002,14,5-27.
38. Wang, J.; Chen, C.; Liu, Y.; Jiao, F.; Li, W.; Lao, F.; Li, Y.; Li, B.; Ge, C.; Zhou, G.; Gao, Y; Zhao, Y.; Chai, Z. Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicology Letters 2008,183,72-80.
39. Zhang, L.; Bai, R.; Li, B.; Ge, C.; Du, J.; Liu, Y.; Le Guyader, L.; Zhao, Y.; Wu, Y.; He, S.; Ma, Y.; Chen, C. Rutile TiO2 particles exert size and surface coating dependent retention and lesions on the murine brain. Toxicology Letters 2011, 207,73-81.
40. Wang, J.-X.; Fan, Y.-B.; Gao, Y.; Hu, Q.-H.; Wang, T.-C. TiO2 nanoparticles translocation and potential toxicological effect in rats after intraarticular injection. Biomaterials 2009,30,4590-4600.
41. Kreyling, W. G.; Semmler, M.; Erbe, F.; Mayer, P.; Takenaka, S.; Schulz, H.; Oberdorster, G.; Ziesenis, A. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. Journal of Toxicology and Environmental Health-Part A 2002,65, 1513-1530.
42. Kwon, J.-T.; Hwang, S.-K.; Jin, H.; Kim, D.-S.; Minai-Tehrani, A.; Yoon, H.-J.; Choi, M.; Yoon, T.-J.; Han, D.-Y.; Kang, Y-W.; Yoon, B.-I.; Lee, J.-K.; Cho, M.-H. Body Distribution of Inhaled Fluorescent Magnetic Nanoparticles in the Mice. J. Occup. Health 2008,50,1-6.
43. Chen, J.; Dong, X.; Zhao, J.; Tang, G. In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection. J. Appl. Toxicol.2009,29, 330-337.
44. Olmedo, D.; Tasat, D.; Guglielmotti, M.; Cabrini, R. Biodistribution of titanium dioxide from biologic compartments. J. Mater. Sci.:Mater. Med.2008,19, 3049-3056.
45. Wang, J.; Zhou, G.; Chen, C.; Yu, H.; Wang, T.; Ma, Y.; Jia, G.; Gao, Y.; Li, B.; Sun, J.; Li, Y.; Jiao, F.; Zhao, Y.; Chai, Z. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicology Letters 2007,168,176-185.
46. Pflucker, F.; Wendel, V.; Hohenberg, H.; Gartner, E.; Will, T.; Pfeiffer, S.; Wepf, R.; Gers-Barlag, H. The human stratum corneum layer:An effective barrier against dermal uptake of different forms of topically applied micronised titanium dioxide. Skin Pharmacol. Appl. Skin Physiol.2001,14,92-97.
47. Kiss, B.; Biro, T.; Czifra, G.; Toth, B. I.; Kertesz, Z.; Szikszai, Z.; Kiss, A. Z.; Juhasz, I.; Zouboulis, C. C.; Hunyadi, J. Investigation of micronized titanium dioxide penetration in human skin xenografts and its effect on cellular functions of human skin-derived cells. Experimental Dermatology 2008,17,659-667.
48. Gamer, A. O.; Leibold, E.; van Ravenzwaay, B. The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin. Toxicol. In Vitro 2006,20,301-307.
49. Sadrieh, N.; Wokovich, A. M.; Gopee, N. V.; Zheng, J. W.; Haines, D.; Parmiter, D.; Siitonen, P. H.; Cozart, C. R.; Patri, A. K.; McNeil, S. E.; Howard, P. C.; Doub, W. H.; Buhse, L. F. Lack of Significant Dermal Penetration of Titanium Dioxide from Sunscreen Formulations Containing Nano-and Submicron-Size TiO2 Particles. Toxicological Sciences 2010,115,156-166.
50. Gopee, N. V.; Roberts, D. W.; Webb, P.; Cozart, C. R.; Siitonen, P. H.; Latendresse, J. R.; Warbitton, A. R.; Yu, W. W.; Colvin, V. L.; Walker, N. J.; Howard, P. C. Quantitative Determination of Skin Penetration of PEG-Coated CdSe Quantum Dots in Dermabraded but not Intact SKH-1 Hairless Mouse Skin. Toxicological Sciences 2009,111,37-48.
51. Mortensen, L. J.; Oberdorster, G.; Pentland, A. P.; DeLouise, L. A. In Vivo Skin Penetration of Quantum Dot Nanoparticles in the Murine Model:The Effect of UVR. Nano Letters 2008,8,2779-2787.
52. Xie, G.; Wang, C.; Sun, J.; Zhong, G. Tissue distribution and excretion of intravenously administered titanium dioxide nanoparticles. Toxicology Letters 2011,205,55-61.
53. Wang, J.; Liu, Y.; Jiao, F.; Lao, F.; Li, W.; Gu, Y.; Li, Y.; Ge, C.; Zhou, G.; Li, B.; Zhao, Y.; Chai, Z.; Chen, C. Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles. Toxicology 2008,254,82-90.
54.汪冰,丰.,王萌,等.鼻腔滴入Fe203细颗粒在小鼠嗅球中的微区分布及对其他微量元素的影响.府能物理与核物理29,71-75.
55.陈春英等.二氧化钛纳米材料生物效应与安全应用.科学出版社：2010.
56. Emerit, J.; Edeas, M.; Bricaire, F. Neurodegenerative diseases and oxidative stress. Biomed. Pharmacother.2004,58,39-46.
57. Renwick, L. C.; Brown, D.; Clouter, A.; Donaldson, K. Increased inflammation and altered macrophage chemotactic responses caused by two ultrafine particle types. Occup. Environ. Med.2004,61,442-447.
58. Kobayashi, N.; Naya, M.; Endoh, S.; Maru, J.; Yamamoto, K.; Nakanishi, J. Comparative pulmonary toxicity study of nano-TiO2 particles of different sizes and agglomerations in rats:Different short-and long-term post-instillation results. Toxicology 2009,264,110-118.
59. Oberdorster, G.; Ferin, J.; Lehnert, B. E. Correlation between particle size, in vivo particle persistence, and lung injury. Environmental health perspectives 1994,102 Suppl 5,173-9.
60. Donaldson, K.; Li, X. Y.; MacNee, W. Ultrafine (nanometre) particle mediated lung injury. J. Aerosol Sci. 1998,29,553-560.
61. Ma, L.; Zhao, J.; Wang, J.; Liu, J.; Duan, Y.; Liu, H.; Li, N.; Yan, J.; Ruan, J.; Wang, H.; Hong, F. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2. Nanoscale Research Letters 2009,4,1275-1285.
62. Duan, Y.; Liu, J.; Ma, L.; Li, N.; Liu, H.; Wang, J.; Zheng, L.; Liu, C.; Wang, X.; Zhao, X.; Yan, J.; Wang, S.; Wang, H.; Zhang, X.; Hong, F. Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice. Biomaterials 2010,31,894-899.
63. Jaeger, A.; Weiss, D. G.; Jonas, L.; Kriehuber, R. Oxidative stress-induced cytotoxic and genotoxic effects of nano-sized titanium dioxide particles in human HaCaT keratinocytes. Toxicology 2012,296,27-36.
64. Chengbin, X.; Jianhong, W.; Fengli, L.; Wei, L.; Xiangliang, Y.; Fandian, Z.; Huibi, X. Nano Titanium Dioxide Induces the Generation of ROS and Potential Damage in HaCaT Cells Under UVA Irradiation. J. Nanosci. Nanotechnol.2010, 10,8500-7.
65. Tu, M.; Huang, Y.; Li, H.-L.; Gao, Z.-H. The stress caused by nitrite with titanium dioxide nanoparticles under UVA irradiation in human keratinocyte cell. Toxicology 2012,299,60-68.
66. Tyner, K. M.; Wokovich, A. M.; Godar, D. E.; Doub, W. H.; Sadrieh, N. The state of nano-sized titanium dioxide (TiO2) may affect sunscreen performance. Int. J. Cosmet. Sci.2011,33,234-244.
67. Kambara, T.; Aihara, M.; Matsukura, S.; Sato, I.; Kubota, Y.; Hirasawa, T.; Ikezawa, Z. Effects of photocatalytic agent on DS-Nh mice, developing atopic dermatitis-like eruption with an increase of Staphylococcus aureus. Int. Arch. Allergy Appl. Immunol.2006,141,151-157.
68. Boffetta, P.; Soutar, A.; Cherrie, J. W.; Granath, F.; Andersen, A.; Anttila, A.; Blettner, M.; Gaborieau, V.; Klug, S. J.; Langard, S.; Luce, D.; Merletti, F.; Miller, B.; Mirabelli, D.; Pukkala, E.; Adami, H. O.; Weiderpass, E. Mortality among workers employed in the titanium dioxide production industry in Europe. Cancer Causes Control 2004,15,697-706.
69. Hext, P. M.; Tomenson, J. A.; Thompson, P. Titanium dioxide:Inhalation toxicology and epidemiology. Ann. Occup. Hyg.2005,49,461-472.
70. Fryzek, J. P.; Chadda, B.; Marano, D.; White, K.; Schweitzer, S.; McLaughlin, J. K.; Blot, W. J. A cohort mortality study among titanium dioxide manufacturing workers in the United States. J. Occup. Environ. Med.2003,45,400-409.
71. Borm, P. J. A.; Schins, R. P. F.; Albrecht, C. Inhaled particles and lung cancer, part B:Paradigms and risk assessment. Int. J. Cancer 2004,110,3-14.
72. Dankovic, D.; Kuempel, E.; Wheeler, M. An approach to risk assessment for TiO2. Inhalation Toxicology 2007,19,205-212.
73. http://monographs.iarc.fr/ENG/Monographs/vol93/.
74. Trouiller, B.; Reliene, R.; Westbrook, A.; Solaimani, P.; Schiestl, R. H. Titanium Dioxide Nanoparticles Induce DNA Damage and Genetic Instability In vivo in Mice. Cancer Research 2009,69,8784-8789.
75.屈云芳等,王.郭.Cu对中国林蛙蝌蚪的急性毒性.应用生态学报1998,9,309-312.
76. Donaldson, K.; Duffin, R.; Langrish, J. P.; Miller, M. R.; Mills, N. L.; Poland, C. A.; Raftis, J.; Shah, A.; Shaw, C. A.; Newby, D. E. Nanoparticles and the cardiovascular system:a critical review. Nanomedicine 2013,8,403-423.
77. Sarnat, J. A.; Schwartz, J.; Suh, H. H. Fine particulate air pollution and mortality in 20 US cities. New England Journal of Medicine 2001,344,1253-1254.
78. Pope, C. A.; Dockery, D. W. Health effects of fine particulate air pollution:Lines that connect. J. Air Waste Manage. Assoc.2006,56,709-742.
79. Pope, C. A. Epidemiology of fine particulate air pollution and human health: Biologic mechanisms and who's at risk? Environmental Health Perspectives 2000,108,713-723.
80. Chen, Z.; Meng, H.; Xing, G.; Yuan, H.; Zhao, F.; Liu, R.; Chang, X.; Gao, X.; Wang, T.; Jia, G.; Ye, C.; Chai, Z.; Zhao, Y. Age-Related Differences in Pulmonary and Cardiovascular Responses to SiO(2) Nanoparticle Inhalation: Nanotoxicity Has Susceptible Population. Environmental Science & Technology 2008,42,8985-8992.
81. Wang, Y.; Chen, Z.; Ba, T.; Pu, J.; Chen, T.; Song, Y.; Gu, Y.; Qian, Q.; Xu, Y.; Xiang, K.; Wang, H.; Jia, G. Susceptibility of Young and Adult Rats to the Oral Toxicity of Titanium Dioxide Nanoparticles. Small 2013,9,1742-1752.
82. Lanphear, B. P.; Vorhees, C. V.; Bellinger, D. C. Protecting Children from Environmental Toxins. PLoS Med.2005,2, e61.
83. Bobak, M. Outdoor air pollution, low birth weight, and prematurity. Environmental health perspectives 2000,108,173.
84. Woodruff, T. J.; Grillo, J.; Schoendorf, K. C. The relationship between selected causes of postneonatal infant mortality and particulate air pollution in the United States. Environmental health perspectives 1997,105,608.
85. Yang, H.; Sun, C.; Fan, Z.; Tian, X.; Yan, L.; Du, L.; Liu, Y.; Chen, C.; Liang, X.-j.; Anderson, G. J.; Keelan, J. A.; Zhao, Y.; Nie, G. Effects of gestational age and surface modification on materno-fetal transfer of nanoparticles in murine pregnancy. Scientific Reports 2012,2.
86. Tian, X.; Zhu, M.; Du, L.; Wang, J.; Fan, Z.; Liu, J.; Zhao, Y.; Nie, G. Intrauterine Inflammation Increases Materno-Fetal Transfer of Gold Nanoparticles in a Size-Dependent Manner in Murine Pregnancy. Small 2013,9, 2432-2439.
87. Yamashita, K.; Yoshioka, Y.; Higashisaka, K.; Mimura, K.; Morishita, Y.; Nozaki, M.; Yoshida, T.; Ogura, T.; Nabeshi, H.; Nagano, K. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat. Nanotechnol.2011.
88. Myllynen, P. K.; Loughran, M. J.; Howard, C. V.; Sormunen, R.; Walsh, A. A.; Vahakangas, K. H. Kinetics of gold nanoparticles in the human placenta. Reproductive Toxicology 2008,26,130-137.
89. Sumner, S. C. J.; Fennell, T. R.; Snyder, R. W.; Taylor, G. F.; Lewin, A. H. Distribution of carbon-14 labeled C60 (C-14 C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine. J. Appl. Toxicol.2010,30,354-360.
90. Takeda, K.; Suzuki, K.-I.; Ishihara, A.; Kubo-Irie, M.; Fujimoto, R.; Tabata, M.; Oshio, S.; Nihei, Y.; Ihara, T.; Sugamata, M. Nanoparticles Transferred from Pregnant Mice to Their Offspring Can Damage the Genital and Cranial Nerve Systems. J. Health Sci.2009,55,95-102.
91. Tian, F.; Razansky, D.; Estrada, G. G.; Semmler-Behnke, M.; Beyerle, A.; Kreyling, W.; Ntziachristos, V.; Stoeger, T. Surface modification and size dependence in particle translocation during early embryonic development. Inhalation toxicology 2009,21 Suppl 1,92-6.
92. Chu, M.; Wu, Q.; Yang, H.; Yuan, R.; Hou, S.; Yang, Y.; Zou, Y.; Xu, S.; Xu, K.; Ji, A.; Sheng, L. Transfer of Quantum Dots from Pregnant Mice to Pups Across the Placental Barrier. Small 2010,6,670-678.
93. Pietroiusti, A.; Massimiani, M.; Fenoglio, I.; Colonna, M.; Valentini, F.; Palleschi, G.; Camaioni, A.; Magrini, A.; Siracusa, G.; Bergamaschi, A.; Sgambato, A.; Campagnolo, L. Low Doses of Pristine and Oxidized Single-Wall Carbon Nanotubes Affect Mammalian Embryonic Development. ACS Nano 2011,5, 4624-4633.
94. Refuerzo, J. S.; Godin, B.; Bishop, K.; Srinivasan, S.; Shah, S. K.; Amra, S.; Ramin, S. M.; Ferrari, M. Size of the nano vectors determines the transplacental passage in pregnancy:study in rats. Am. J. Obstet. Gynecol.2011,204, 546.e5-546.e9.
95. http://www.who.int/mediacentre/news/notes/2010/breastfeeding_20100730/zh/.
96. Anderson, P. O. Drug use during breast-feeding. Clin. Pharm.1991,10,594-624.
97.苗丽；邓万俊.妊娠及哺乳期应用抗生素的研究现状.国外医药：抗生素分册2008,29,248-254.
98. Tankeyoon, M.; Dusitsin, N.; Chalapati, S.; Koetsawang, S.; Saibiang, S.; Sas, M.; Gellen, J.; Ayeni, O.; Gray, R.; Pinol, A. Effects of hormonal contraceptives on milk volume and infant growth:WHO Special Programme of Research and Development and Research Training in Human Reproduction. Contraception 1984,30,505-522.
99.朱斌.哺乳期用药的安全性.中国医院用药评价与分析 2001,1,251.
100. Neville, M. C.; McFadden, T. B.; Forsyth, I. Hormonal regulation of mammary differentiation and milk secretion. J. Mammary Gland Biol. Neoplasia 2002,7, 49-66.
101. Tsukita, S.; Furuse, M. The structure and function of claudins, cell adhesion molecules at tight junctions. In Epithelial Transport and Barrier Function: Pathomechanisms in Gastrointestinal Disorders, Schulzke, J. D.; Fromm, M.; Riecken, E. O.; Binder, H. J., Eds.2000; Vol.915, pp 129-135.
102. Baumgart, D. C.; Dignass, A. U. Intestinal barrier function. Current Opinion in Clinical Nutrition & Metabolic Care 2002,5,685-694.
103.McManaman, J. L.; Neville, M. C. Mammary physiology and milk secretion. Adv. Drug Deliv. Rev.2003,55,629-641.
104. Gao, X.; Yin, S.; Tang, M.; Chen, J.; Yang, Z.; Zhang, W.; Chen, L.; Yang, B.; Li, Z.; Zha, Y.; Ruan, D.; Wang, M. Effects of Developmental Exposure to TiO2 Nanoparticles on Synaptic Plasticity in Hippocampal Dentate Gyrus Area:an In Vivo Study in Anesthetized Rats. Biol. Trace Elem. Res.2011,143,1616-1628.
105. Yeo, M.-K.; Kang, M. The biological toxicities of two crystalline phases and differential sizes of TiO2 nanoparticles during zebrafish embryogenesis development. Mol. Cell. Toxicol.2012,8,317-326.
106.Wang, J. X.; Liu, Y.; Jiao, F.; Lao, F.; Li, W.; Gu, Y. Q.; Li, Y. F.; Ge, C. C.; Zhou, G. Q.; Li, B.; Zhao, Y. L.; Chai, Z. F.; Chen, C. Y. Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles. Toxicology 2008,254,82-90.
107. Bai, Y. H.; Zhang, Y.; Zhang, J. P.; Mu, Q. X.; Zhang, W. D.; Butch, E. R.; Snyder, S. E.; Yan, B. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nat. Nanotechnol. 2010,5,683-689.
108. White, S. S.; Calafat, A. M.; Kuklenyik, Z.; Villanueva, L.; Zehr, R. D.; Helfant, L.; Strynar, M. J.; Lindstrom, A. B.; Thibodeaux, J. R.; Wood, C. Gestational PFOA exposure of mice is associated with altered mammary gland development in dams and female offspring. Toxicological sciences 2007,96,133-144.
109. Sonavane, G.; Tomoda, K.; Makino, K. Biodistribution of colloidal gold nanoparticles after intravenous administration:Effect of particle size. Colloids and Surfaces B:Biointerfaces 2008,66,274-280.
110. De Jong, W. H.; Hagens, W. I.; Krystek, P.; Burger, M. C.; Sips, A. J. A. M.; Geertsma, R. E. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 2008,29,1912-1919.
111. Williamson, D. H.; Lund, P.; Evans, R. D. Substrate selection and oxygen uptake by the lactating mammary gland. Proc. Nutr. Soc.1995,54,165-175.
112. Couto-Moraes, R.; Felicio, L. F.; Bernardi, M. M. Post-partum testosterone administration does not reverse the effects of perinatal exposure to cadmium on rat offspring development. J. Appl. Toxicol.2010,30,233-241.
113. Klaassen, C. D.; Watkins, J. B. Casarett and Doull's toxicology:the basic science of poisons. McGraw-Hill:1999.
114. Ma, L.; Liu, J.; Li, N.; Wang, J.; Duan, Y.; Yan, J.; Liu, H.; Wang, H.; Hong, F. Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 2010,31,99-105.
115. Yang, S.-T.; Wang, X.; Jia, G.; Gu, Y.; Wang, T.; Nie, H.; Ge, C.; Wang, H.; Liu, Y Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed mice. Toxicology Letters 2008,181,182-189.
116. Liu, H.; Ma, L.; Liu, J.; Zhao, J.; Yan, J.; Hong, F. Toxicity of nano-anatase TiO2 to mice:Liver injury, oxidative stress. Toxicol. Environ. Chem.2010,92, 175-186.
117.Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002,82,47-95.
118. Thannickal, V. J.; Fanburg, B. L. Reactive oxygen species in cell signaling. American Journal of Physiology-Lung Cellular and Molecular Physiology 2000, 279, L1005-L1028.
119. Nguyen, D. A. D.; Neville, M. C. Tight junction regulation in the mammary gland. J. Mammary Gland Biol. Neoplasia 1998,3,233-246.
120. Wang, B.; Feng, W. Y.; Wang, T. C.; Guang, J.; Wang, M.; Shi, J. W.; Zhang, F.; Zhao, Y L.; Chai, Z. F. Acute toxicity of nano- and micro-scale zinc powder in healthy adult mice. Toxicology Letters 2006,161,115-123.
121. Bonazzi, M.; Cossart, P. Impenetrable barriers or entry portals? The role of cell-cell adhesion during infection. J. Cell Biol.2011,195,349-58.
122. Uskokovic, V.; Lee, P. P.; Walsh, L. A.; Fischer, K. E.; Desai, T. A. PEGylated silicon nanowire coated silica microparticles for drug delivery across intestinal epithelium. Biomaterials 2012,33,1663-1672.
123. Brun, E.; Carriere, M.; Mabondzo, A. In vitro evidence of dysregulation of blood-brain barrier function after acute and repeated/long-term exposure to TiO2 nanoparticles. Biomaterials 2012,33,886-896.
124. Kobayashi, K.; Oyama, S.; Numata, A.; Rahman, M. M.; Kumura, H. Lipopolysaccharide Disrupts the Milk-Blood Barrier by Modulating Claudins in Mammary Alveolar Tight Junctions. PLoS One 2013,8.
125. Musch, M. W.; Walsh-Reitz, M. M.; Chang, E. B. Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption. American Journal of Physiology-Gastrointestinal and Liver Physiology 2006,290, G222-G231.
126. Singh, A.; Ramnath, R. D.; Foster, R. R.; Wylie, E, C.; Friden, V.; Dasgupta, I.; Haraldsson, B.; Welsh, G. I.; Mathieson, P. W.; Satchell, S. C. Reactive Oxygen Species Modulate the Barrier Function of the Human Glomerular Endothelial Glycocalyx. PLoS One 2013,8, e55852.
127. Ullen, A.; Singewald, E.; Konya, V.; Fauler, G.; Reicher, H.; Nusshold, C.; Hammer, A.; Kratky, D.; Heinemann, A.; Holzer, P.; Malle, E.; Sattler, W. Myeloperoxidase-Derived Oxidants Induce Blood-Brain Barrier DysfunctionIn Vitro andIn Vivo . PLoS One 2013,8, e64034.
128. Stull, M. A.; Pai, V.; Vomachka, A. J.; Marshall, A. M.; Jacob, G. A.; Horseman, N. D. Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions. Proc. Natl. Acad. Sci. U. S. A.2007,104,16708-16713.
129. Svennersten-Sjaunja, K.; Olsson, K. Endocrinology of milk production. Domest. Anim. Endocrinol.2005,29,241-258.
130. Li, C.; Taneda, S.; Taya, K.; Watanabe, G.; Li, X.; Fujitani, Y.; Ito, Y.; Nakajima, T.; Suzuki, A. K. Effects of inhaled nanoparticle-rich diesel exhaust on regulation of testicular function in adult male rats. Inhalation Toxicology 2009,21,803-811.
131.Ramdhan, D. H.; Ito, Y.; Yanagiba, Y.; Yamagishi, N.; Hayashi, Y.; Li, C.; Taneda, S.; Suzuki, A. K.; Watanabe, G.; Taya, K.; Kamijima, M.; Nakajima, T. Nanoparticle-rich diesel exhaust may disrupt testosterone biosynthesis and metabolism via growth hormone. Toxicology Letters 2009,191,103-108.
132. Burgoyne, R.; Duncan, J. Secretion of Milk Proteins. J. Mammary Gland Biol. Neoplasia 1998,3,275-286.
133. Lonnerdal, B. Nutritional and physiologic significance of human milk proteins. Am. J. Clin. Nutr.2003,77,1537S-1543S.
134. Wheeler, T. T.; Callaghan, M. R.; Davis, S. R.; Prosser, C. G.; Wilkins, R. J. Milk Protein Synthesis, Gene Expression, and Hormonal Responsiveness in Primary Cultures of Mammary Cells from Lactating Sheep. Exp. Cell Res.1995,217, 346-354.
135. Lonnerdal, B.; Lien, E. L. Nutritional and Physiologic Significance of a-Lactalbumin in Infants. Nutr. Rev.2003,61,295-305.
136. Ohrvik, H.; Yoshioka, M.; Oskarsson, A.; Tallkvist, J. Cadmium-induced disturbances in lactating mammary glands of mice. Toxicology Lettens 2006,164, 207-213.
1. Gottesman, M. M.; Fojo, T.; Bates, S. E. Multidrug resistance in cancer:role of ATP-dependent transporters. Nat. Rev. Cancer 2002,2,48-58.
2. 高冬冬;孙宏新.肿瘤多药耐药治疗的研究进展.第三届国际中医,中西医结合肿瘤学术交流大会暨第十二届全国中西医结合种瘤学术大会论文汇编2010.
3. http://www.who.int/mediacentre/factsheets/fs297/zh/.
4.NCLC. http://www.lung.org/lunng-disease/lung-cancer/resources/facts-figures /lung-cancer-fact-sheet.html.
5. NCCN guideline. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site
6.丁国钰；刘晓.乳腺癌患者对曲妥珠单抗的耐药机制与治疗策略.国际肿瘤学杂志2012,39,274-277.
7.王敏;刘荣玉.非小细胞肺癌分子靶向治疗的现状及进展.国际呼吸杂志2011,31,637-640.
8. Biedler, J. L.; Riehm, H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro:cross-resistance, radioautographic, and cytogenetic studies. Cancer research 1970,30,1174-84.
9. Robert, J. Resistance to cytotoxic agents. Curr. Opin. Pharmacol.2001,1, 353-357.
10.孙志勇；余宏字；刘会敏；李玉莉；何金；孙静.P-gP, MRP, LRP, P53及c-erbB一2在非小细胞肺癌中的表达.第二军医大学学报2006,27,474.
11.戴春岭；符立梧.肿瘤多药耐药逆转剂的研究进展.中国药理学通报2005,21,513-518.
12. Kartner, N.; Ling, V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 1983,221,1285-1288.
13. Ambudkar, S. V.; Kimchi-Sarfaty, C.; Sauna, Z. E.; Gottesman, M. M. P-glycoprotein:from genomics to mechanism. Oncogene 2003,22,7468-7485.
14. Eckford, P. D.; Sharom, F. J. ABC efflux pump-based resistance to chemotherapy drugs. Chemical reviews 2009,109,2989-3011.
15. Fletcher, J. I.; Haber, M.; Henderson, M. J.; Norris, M. D. ABC transporters in cancer:more than just drug efflux pumps. Nat. Rev. Cancer 2010,10,147-156.
16. Fojo, A.; Ueda, K.; Slamon, D.; Poplack, D.; Gottesman, M.; Pastan, I. Expression of a multidrug-resistance gene in human tumors and tissues. Proceedings of the National Academy of Sciences 1987,84,265-269.
17. Juliano, R. L.; Ling, V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 1976,455,152-62.
18. Leonard, G. D.; Fojo, T.; Bates, S. E. The role of ABC transporters in clinical practice. The oncologist 2003,8,411-424.
19. Jin, M. S.; Oldham, M. L.; Zhang, Q.; Chen, J. Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature 2012,490, 566-+.
20. Aller, S. G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P. M.; Trinh, Y. T.; Zhang, Q.; Urbatsch, I. L.; Chang, G. Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science 2009,323, 1718-1722.
21. Ambudkar, S. V.; Kim, I.-W.; Sauna, Z. E. The power of the pump:Mechanisms of action of P-glycoprotein (ABCB1). Eur. J. Pharm. Sci.2006,27,392-400.
22. Cordon-Cardo, C.; O'Brien, J. P.; Boccia, J.; Casals, D.; Bertino, J. R.; Melamed, M. R. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. The journal of histochemistry and cytochemistry:official journal of the Histochemistry Society 1990,38,1277-87.
23. Thiebaut, F.; Tsuruo, T.; Hamada, H.; Gottesman, M. M.; Pastan, I.; Willingham, M. C. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170:evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. The journal of histochemistry and cytochemistry:official journal of the Histochemistry Society 1989,37,159-64.
24. Szakacs, G.; Paterson, J. K.; Ludwig, J. A.; Booth-Genthe, C.; Gottesman, M. M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov.2006,5, 219-234.
25. Tsuruo, T.; Iida, H.; Tsukagoshi, S.; Sakurai, Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer research 1981,41,1967-72.
26. Thomas, H.; Coley, H. M. Overcoming multidrug resistance in cancer:an update on the clinical strategy of inhibiting p-glycoprotein. Cancer control:journal of the Moffitt Cancer Center 2003,10,159-65.
27. Krishna, R.; Mayer, L. D. Multidrug resistance (MDR) in cancer-Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur. J. Pharm. Sci.2000, 11,265-283.
28. Abolhoda, A.; Wilson, A. E.; Ross, H.; Danenberg, P. V.; Burt, M.; Scotto, K. W. Rapid activation of MDR 1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clin. Cancer Res.1999,5,3352-3356.
29. te Boekhorst, P. A.; van Kapel, J.; Schoester, M.; Sonneveld, P. Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive analogue SDZ PSC 833 in Chinese hamster ovary cells expressing the mdrl phenotype. Cancer Chemother. Pharmacol.1992,30,238-42.
30. Wandel, C.; Kim, R. B.; Kajiji, S.; Guengerich, F. P.; Wilkinson, G. R.; Wood, A. J. J. P-glycoprotein and cytochrome P-450 3A inhibition:Dissociation of inhibitory potencies. Cancer Research 1999,59,3944-3948.
31. Shepard, R. L.; Cao, J.; Starling, J. J.; Dantzig, A. H. Modulation of P-glycoprotein but not MRPI-or BCRP-mediated drug resistance by LY335979. Int. J. Cancer 2003,103,121-125.
32. Dantzig, A. H.; Shepard, R. L.; Cao, J.; Law, K. L.; Ehlhardt, W. J.; Baughman, T. M.; Bumol, T. F.; Starling, J. J. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Research 1996,56,4171-4179.
33. Mistry, P.; Stewart, A. J.; Dangerfield, W.; Okiji, S.; Liddle, C.; Bootle, D.; Plumb, J. A.; Templeton, D.; Charlton, P. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Research 2001,61,749-758.
34. Balayssac, D.; Cayre, A.; Ling, B.; Maublant, J.; Penault-Llorca, F.; Eschalier, A.; Coudore, F.; Authier, N. Increase in morphine antinociceptive activity by a P-glycoprotein inhibitor in cisplatin-induced neuropathy. Neurosci. Lett.2009, 465,108-112.
35. Wouters, W.; Janssens, F.; Van Dun, J.; Krekels, M.; Smets, G. R101933 is an antagonist of PgP and modulates resistance to different chemotherapy agents. Proc. Am. Assoc. Cancer Res. Annu. Meet.1999,40,663-663.
36. Mistry, P.; Folkes, A. ONT-093 (Ontogen). Current opinion in investigational drugs (London, England:2000) 2002,3,1666-71.
37. Pusztai, L.; Wagner, P.; Ibrahim, N.; Rivera, E.; Theriault, R.; Booser, D.; Symmans, F. W.; Wong, F.; Blumenschein, G.; Fleming, D. R.; Rouzier, R.; Boniface, G.; Hortobagyi, G. N. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 2005,104,682-691.
38. Scagliotti, G. V.; Novello, S.; Selvaggi, G. Multidrug resistance in non-small-cell lung cancer. Ann. Oncol.1999,10, S83-S86.
39. Borisy, A. A.; Elliott, P. J.; Hurst, N. W.; Lee, M. S.; Lehar, J.; Price, E. R.; Serbedzija, G.; Zimmermann, G. R.; Foley, M. A.; Stockwell, B. R. Systematic discovery of multicomponent therapeutics. Proceedings of the National Academy of Sciences 2003,100,7977-7982.
40. Fitzgerald, J. B.; Schoeberl, B.; Nielsen, U. B.; Sorger, P. K. Systems biology and combination therapy in the quest for clinical efficacy. Nat. Chem. Biol.2006, 2,458-466.
41.刘彦斌.组合药物数据库构建及药物协同作用机理分析.浙江大学,2011.
42. Chou, T.-C. Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method. Cancer Research 2010,70,440-446.
43. Druker, B. J.; Talpaz, M.; Resta, D. J.; Peng, B.; Buchdunger, E.; Ford, J. M.; Lydon, N. B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; Sawyers, C. L. Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. New England Journal of Medicine 2001,344, 1031-1037.
44. Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I.; Singh, B.; Heelan, R.; Rusch, V.; Fulton, L. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Nat1. Acad. Sci. U. S. A.2004,101,13306-13311.
45. Sams-Dodd, F. Target-based drug discovery:is something wrong? Drug Discov. Today 2005,10,139-147.
46. Pao, W.; Miller, V. A.; Politi, K. A.; Riely, G. J.; Somwar, R.; Zakowski, M. F.; Kris, M. G.; Varmus, H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med.2005,2, e73.
47. Bean, J.; Brennan, C.; Shih, J.-Y.; Riely, G.; Viale, A.; Wang, L.; Chitale, D.; Motoi, N.; Szoke, J.; Broderick, S. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences 2007, 104,20932-20937.
48. Teodori, E.; Dei, S.; Martelli, C.; Scapecchi, S.; Gualtieri, F. The functions and structure of ABC transporters:implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR). Curr. Drug Targets 2006, 7,893-909.
49. Georges, E.; Sharom, J. Multidrug Resistance and Chemosensitization: Therapeutic Implications for. Adv. Pharmacol.1990,21,185.
50. Ford, J. Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur, J. Cancer 1996,32,991-1001.
51. van Zuylen, L.; Nooter, K.; Sparreboom, A.; Verweij, J. Development of multidrug-resistance convertors:sense or nonsense? Invest. New Drugs 2000,18, 205-220.
52. Zhou, H.; Wu, S.; Zhai, S.; Liu, A.; Sun, Y.; Li, R.; Zhang, Y.; Ekins, S.; Swaan, P. W.; Fang, B. Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells. J. Med. Chem.2008,51,1242-1251.
53. Mayer, L. D.; Harasym, T. O.; Tardi, P. G.; Harasym, N. L.; Shew, C. R.; Johnstone, S. A.; Ramsay, E. C.; Bally, M. B.; Janoff, A. S. Ratiometric dosing of anticancer drug combinations:controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Molecular cancer therapeutics 2006,5,1854-1863.
54. Hopkins, A. L. Network pharmacology:the next paradigm in drug discovery. Nat. Chem. Biol.2008,4,682-690.
55. Lehar, J.; Krueger, A. S.; Avery, W.; Heilbut, A. M.; Johansen, L. M.; Price, E. R.; Rickles, R. J.; Short Iii, G. F.; Staunton, J. E.; Jin, X. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol.2009,27,659-666.
56. Raben, D.; Helfrich, B.; Chan, D. C.; Ciardiello, F.; Zhao, L.; Franklin, W.; Baron, A. E.; Zeng, C.; Johnson, T. K.; Bunn, P. A. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin. Cancer Res.2005,11,795-805.
57. Chou, T.-C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev.2006, 58.621-681.
58. Regales, L.; Gong, Y.; Shen, R.; de Stanchina, E.; Vivanco, I.; Goel, A.; Koutcher, J. A.; Spassova, M.; Ouerfelli, O.; Mellinghoff, I. K. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. The Journal of clinical investigation 2009,119,3000.
59. Soriano, A. F.; Helfrich, B.; Chan, D. C.; Heasley, L. E.; Bunn, P. A.; Chou, T.-C. Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines. Cancer research 1999,59, 6178-6184.
60. Dent, P.; Curiel, D. T.; Fisher, P. B.; Grant, S. Synergistic combinations of signaling pathway inhibitors:mechanisms for improved cancer therapy. Drug Resist. Updat.2009,12,65-73.
61. DiDiodato, G.; Sharom, F. J. Interaction of combinations of drugs, chemosensitizers, and peptides with the P-glycoprotein multidrug transporter. Biochemical pharmacology 1997,53,1789-1797.
62. Teraishi, F.; Wu, S.; Sasaki, J.; Zhang, L.; Zhu, H.-B.; Davis, J. J.; Fang, B. P-glycoprotein-independent apoptosis induction by a novel synthetic compound, MMPT [5-[(4-methylphenyl) methylene]-2-(phenylamino)-4 (5H)-thiazolone]. J. Pharmacol. Exp. Ther.2005,314,355-362.
63. Teraishi, F.; Wu, S.; Sasaki, J.; Zhang, L.; Davis, J. J.; Guo, W.; Dong, F.; Fang, B. JNK1-dependent antimitotic activity of thiazolidin compounds in human non-small-cell lung and colon cancer cells. Cellular and Molecular Life Sciences CMLS 2005,62,2382-2389.
64. Li, L.; Zhang, Q.; Liu, A.; Li, X.; Zhou, H.; Liu, Y.; Yan, B. Proteome Interrogation Using Nanoprobes To Identify Targets of a Cancer-Killing Molecule. Journal of the American Chemical Society 2011,133,6886-6889.
65. Zhang, Q.; Zhai, S.; Li, L.; Li, X.; Zhou, H.; Liu, A.; Su, G.; Mu, Q.; Du, Y.; Yan, B. Anti-tumor selectivity of a novel Tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models. Biochemical Pharmacology 2013,86, 351-360.
66. Hubbert, C.; Guardiola, A.; Shao, R.; Kawaguchi, Y.; Ito, A.; Nixon, A.; Yoshida, M.; Wang, X. F.; Yao, T. P. HDAC6 is a microtubule-associated deacetylase. Nature 2002,417,455-458.
67. Li, F. Z.; Ambrosini, G.; Chu, E. Y.; Plescia, J.; Tognin, S.; Marchisio, P. C.; Altieri, D. C. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998,396,580-584.
68. Harper, J. W.; Adami, G. R.; Wei, N.; Keyomarsi, K.; Elledge, S. J. The p21 Cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993,75,805-16.
69. Singh, S. V.; Herman-Antosiewicz, A.; Singh, A. V.; Lew, K. L.; Srivastava, S. K.; Kamath, R.; Brown, K. D.; Zhang, L.; Baskaran, R. Sulforaphane-induced G(2)/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. J. Biol. Chem.2004,279, 25813-25822.
70. Elmore, S. Apoptosis:A review of programmed cell death. Toxicol. Pathol.2007, 35,495-516.
71. Breckenridge, D. G.; Germain, M.; Mathai, J. F.; Nguyen, M.; Shore, G. C. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003,22, 8608-8618.
72. Rao, R. V.; Ellerby, H. M.; Bredesen, D. E. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ.2004,11,372-380.
73. Janicke, R. U.; Sprengart, M. L.; Wati, M. R.; Porter, A. G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem.1998,273,9357-9360.
74. Chen, C.-S.; Weng, S.-C.; Tseng, P.-H.; Lin, H.-P.; Chen, C.-S. Histone Acetylation-independent Effect of Histone Deacetylase Inhibitors on Akt through the Reshuffling of Protein Phosphatase 1 Complexes. J. Biol. Chem.2005,280, 38879-38887.
75. Chang, L.; Karin, M. Mammalian MAP kinase signalling cascades. Nature 2001, 410,37-40.
76. Martindale, J. L.; Holbrook, N. J. Cellular response to oxidative stress:Signaling for suicide and survival*. J. Cell. Physiol.2002,192,1-15.
77. Vijayaraghavalu, S.; Dermawan, J. K.; Cheriyath, V.; Labhasetwar, V. Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest. Molecular pharmaceutics 2012, 10,337-352.
78. Kawase, T.; Ichikawa, H.; Ohta, T.; Nozaki, N.; Tashiro, F.; Ohki, R.; Taya, Y. p53 target gene AEN is a nuclear exonuclease required for p53-dependent apoptosis. Oncogene 2008,27,3797-3810.
79. Yakovlev, A. G.; Di Giovanni, S.; Wang, G.; Liu, W.; Stoica, B.; Faden, A. I. BOK and NOXA are essential mediators of p53-dependent apoptosis. J. Biol. Chem.2004,279,28367-28374.
80. Carvajal, L. A.; Hamard, P.-J.; Tonnessen, C.; Manfredi, J. J. E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression. Genes Dev.2012,26,1533-1545.
81. Kawase, T.; Ohki, R.; Shibata, T.; Tsutsumi, S.; Kamimura, N.; Inazawa, J.; Ohta, T.; Ichikawa, H.; Aburatani, H.; Tashiro, F. PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell 2009,136,535-550.
82. Zuco, V.; De Cesare, M.; Cincinelli, R.; Nannei, R.; Pisano, C.; Zaffaroni, N.; Zunino, F. Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo. PLoS One 2011,6, e29085.
83. Dokmanovic, M.; Clarke, C.; Marks, P. A. Histone deacetylase inhibitors: overview and perspectives. Mol. Cancer Res.2007,5,981-989.
84. Rosato, R. R.; Almenara, J. A.; Dai, Y.; Grant, S. Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Molecular Cancer Therapeutics 2003,2,1273-1284.
85. Carew, J. S.; Giles, F. J.; Nawrocki, S. T. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett.2008,269,7-17.
86. Lee, J.-H.; Choy, M.; Ngo, L.; Foster, S.; Marks, P. A. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proceedings of the National Academy of Sciences 2010,107, 14639-14644.
87. Xu, W.; Parmigiani, R.; Marks, P. Histone deacetylase inhibitors:molecular mechanisms of action. Oncogene 2007,26,5541-5552.
88. Hubbert, C.; Guardiola, A.; Shao, R.; Kawaguchi, Y.; Ito, A.; Nixon, A.; Yoshida, M.; Wang, X.-F.; Yao, T.-P. HDAC6 is a microtubule-associated deacetylase. Nature 2002,417,455-458.
89. Bali, P.; Pranpat, M.; Bradner, J.; Balasis, M.; Fiskus, W.; Guo, F.; Rocha, K.; Kumaraswamy, S.; Boyapalle, S.; Atadja, P. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 A novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 2005,280,26729-26734.
90. Kim, M. S.; Blake, M.; Baek, J. H.; Kohlhagen, G.; Pommier, Y.; Carrier, F. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer research 2003,63,7291-7300.
91. Dowdy, S. C.; Jiang, S.; Zhou, X. C.; Hou, X.; Jin, F.; Podratz, K. C.; Jiang, S.-W. Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells. Molecular cancer therapeutics 2006,5,2767-2776.
92. Arnold, N. B.; Arkus, N.; Gunn, J.; Korc, M. The histone deacetylase'inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances gemcitabine-induced cell death in pancreatic cancer. Clin. Cancer Res.2007,13, 18-26.
93. Jane, E. P.; Premkumar, D. R.; Addo-Yobo, S. O.; Pollack, I. F. Abrogation of mitogen-activated protein kinase and Akt signaling by vandetanib synergistically potentiates histone deacetylase inhibitor-induced apoptosis in human glioma cells. J. Pharmacol. Exp. Ther.2009,331,327-337.
94. Yu, C.; Friday, B. B.; Lai, J.-P.; McCollum, A.; Atadja, P.; Roberts, L. R.; Adjei, A. A. Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin. Cancer Res.2007,13,1140-1148.
95. Rahmani, M.; Reese, E.; Dai, Y.; Bauer, C.; Payne, S. G.; Dent, P.; Spiegel, S.; Grant, S. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Research 2005,65,2422-2432.
96. Giommarelli, C.; Zuco, V.; Favini, E.; Pisano, C.; Dal Piaz, F.; De Tommasi, N.; Zunino, F. The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition. Cell. Mol. Life Sci.2010,67,995-1004.
2.杜仕国；施冬梅；邓辉.纳米材料的特异效应及其应用.自然杂志2000,22,101-106.
3. Nel, A.; Xia, T.; Madler, L.; Li, N. Toxic potential of materials at the nanolevel. Science 2006,311,622-627.
4. Maynard, A. D.; Aitken, R. J.; Butz, T.; Colvin, V.; Donaldson, K.; Oberdoerster, G.; Philbert, M. A.; Ryan, J.; Seaton, A.; Stone, V.; Tinkle, S. S.; Tran, L.; Walker, N. J.; Warheit, D. B. Safe handling of nanotechnology. Nature 2006,444, 267-269.
5. Service, R. F. Nanotoxicology:Nanotechnology grows up. Science 2004,304, 1732-1734.
6. Zhao, Y.; Xing, G.; Chai, Z. Nanotoxicology:Are carbon nanotubes safe? Nat. Nanotechnol.2008,3,191-192.
7. http://ec.europa.eu/environment/chemicals/nanotech/.
8. http://www.nanotechproiect.org/inventories/consumer/analysis_draft/.
9. Service, R. F. Nanomaterials Show Signs of Toxicity. Science 2003,300,243.
10. Donaldson, K.; Stone, V.; Tran, C. L.; Kreyling, W.; Borm, P. J. A. Nanotoxicology. Occup. Environ. Med.2004,61,727-728.
11. Oberdorster, G.; Oberdorster, E.; Oberdorster, J. Nanotoxicology:an emerging discipline evolving from studies of ultrafine particles. Environmental health perspectives 2005,113,823.
12.柴之芳,赵.纳米毒理学：纳米材料安全应用的基础.科学出版社：北京,2010.
13.刘元方；陈欣欣；王海芳；.纳米材料生物效应研究和安全性评价前沿.自然杂志2011,44,193-197.
14. Oberdorster, G.; Maynard, A.; Donaldson, K.; Castranova, V.; Fitzpatrick, J.; Ausman, K.; Carter, J.; Karn, B.; Kreyling, W.; Lai, D.; Olin, S.; Monteiro-Riviere, N.; Warheit, D.; Yang, H.; Toxicity, I. R. F. R. S. I. N.; Screening Working, G. Principles for characterizing the potential human health effects from exposure to nanomaterials:elements of a screening strategy. Particle and fibre toxicology 2005,2,8-8.
15. Gao, N. N.; Zhang, Q.; Mu, Q. X.; Bai, Y. H.; Li, L. W.; Zhou, H. Y.; Butch, E. R.; Powell, T. B.; Snyder, S. E.; Jiang, G. B.; Yan, B. Steering Carbon Nanotubes to Scavenger Receptor Recognition by Nanotube Surface Chemistry Modification Partially Alleviates NF kappa B Activation and Reduces Its Immunotoxicity. ACS Nano 2011,5,4581-4591.
16. Choi, H. S.; Liu, W.; Misra, P.; Tanaka, E.; Zimmer, J. P.; Ipe, B. I.; Bawendi, M. G.; Frangioni, J. V. Renal clearance of quantum dots. Nat. Biotechnol.2007,25, 1165-1170.
17. Buzea, C.; Pacheco, I.; Robbie, K. Nanomaterials and nanoparticles:Sources and toxicity. Biointerphases 2007,2, MR17-MR71.
18. Gao, X.; Zhu, H.; Pan, G.; Ye, S.; Lan, Y.; Wu, F.; Song, D. Preparation and Electrochemical Characterization of Anatase Nanorods for Lithium-Inserting Electrode Material. The Journal of Physical Chemistry B 2004,108,2868-2872.
19. Kasuga, T.; Hiramatsu, M.; Hoson, A.; Sekino, T.; Niihara, K. Formation of Titanium Oxide Nanotube. Langmuir 1998,14,3160-3163.
20. Sasaki, T.; Watanabe, M.; Hashizume, H.; Yamada, H.; Nakazawa, H. Macromolecule-like Aspects for a Colloidal Suspension of an Exfoliated Titanate. Pairwise Association of Nanosheets and Dynamic Reassembling Process Initiated from It. Journal of the American Chemical Society 1996,118, 8329-8335.
21. Sukpirom, N.; Lerner, M. M. Preparation of Organic-Inorganic Nanocomposites with a Layered Titanate. Chem. Mater.2001,13,2179-2185.
22. Tang, J.; Wu, Y Y.; McFarland, E. W.; Stucky, G. D. Synthesis and photocatalytic properties of highly crystalline and ordered mesoporous TiO2 thin films. Chem. Commun.2004,1670-1671.
23. Fujishima, A.; Rao, T. N.; Tryk, D. A. Titanium dioxide photocatalysis. Journal of Photochemistry and Photobiology C:Photochemistry Reviews 2000,1,1-21.
24. Asahi, R.; Morikawa, T.; Ohwaki, T.; Aoki, K.; Taga, Y. Visible-light photocatalysis in nitrogen-doped titanium oxides. Science 2001,293,269-271.
25. Mills, A.; Le Hunte, S. An overview of semiconductor photocatalysis. Journal of Photochemistry and Photobiology A:Chemistry 1997,108,1-35.
26. Fu, G. F.; Vary, P. S.; Lin, C. T. Anatase TiO2 nanocomposites for antimicrobial coatings. J. Phys. Chem.B 2005,109,8889-8898.
27. Cho, M.; Chung, H.; Choi, W.; Yoon, J. Linear correlation between inactivation of E-coli and OH radical concentration in TiO2 photocatalytic disinfection. Water Res.2004,38,1069-1077.
28. Han, S. J.; Choi, S. H.; Kim, S. S.; Cho, M.; Jang, B.; Kim, D. Y.; Yoon, J.; Hyeon, T. Low-temperature synthesis of highly crystalline TiO2 nanocrystals and their application to photocatalysis. Small 2005,1,812-816.
29. Xu, M. H.; Ma, J. M.; Gu, J. H.; Lu, Z. H. Photocatalytic TiO2 nanoparticles damage to cellular membranes and genetic supramolecules. Supramolecular Science 1998,5,511-513.
30. Linnainmaa, K.; Kivipensas, P.; Vainio, H. Toxicity and cytogenetic studies of ultrafine titanium dioxide in cultured rat liver epithelial cells. Toxicol. In Vitro 1997,11,329-335.
31. Seo, J. W.; Chung, H.; Kim, M. Y.; Lee, J.; Choi, I. H.; Cheon, J. Development of water-soluble single-crystalline TiO2 nanoparticles for photocatalytic cancer-cell treatment. Small 2007,3,850-853.
32. Zhu, Y. F.; Shi, J. J.; Zhang, Z. Y.; Zhang, C.; Zhang, X. R. Development of a gas sensor utilizing chemiluminescence on nanosized titanium dioxide. Analytical Chemistry 2002,74,120-124.
33. Stergiopoulos, T.; Arabatzis, I. M.; Katsaros, G.; Falaras, P. Binary polyethylene oxide/titania solid-state redox electrolyte for highly efficient nanocrystalline TiO2 photoelectrochemical cells. Nano Letters 2002,2,1259-1261.
34. Nakade, S.; Saito, Y.; Kubo, W.; Kitamura, T.; Wada, Y.; Yanagida, S. Influence of TiO2 nanoparticle size on electron diffusion and recombination in dye-sensitized TiO2 solar cells. J. Phys. Chem. B 2003,107,8607-8611.
35. Ohko, Y.; Tatsuma, T.; Fujii, T.; Naoi, K.; Niwa, C.; Kubota, Y.; Fujishima, A. Multicolour photochromism of TiO2 films loaded with silver nanoparticles. Nat. Mater.2003,2,29-31.
36. Naoi, K.; Ohko, Y.; Tatsuma, T. TiO2 films loaded with silver nanoparticles: Control of multicolor photochromic behavior. Journal of the American Chemical Society 2004,126,3664-3668.
37. Donaldson, K.; Tran, C. L. Inflammation caused by particles and fibers. Inhalation Toxicology 2002,14,5-27.
38. Wang, J.; Chen, C.; Liu, Y.; Jiao, F.; Li, W.; Lao, F.; Li, Y.; Li, B.; Ge, C.; Zhou, G.; Gao, Y; Zhao, Y.; Chai, Z. Potential neurological lesion after nasal instillation of TiO2 nanoparticles in the anatase and rutile crystal phases. Toxicology Letters 2008,183,72-80.
39. Zhang, L.; Bai, R.; Li, B.; Ge, C.; Du, J.; Liu, Y.; Le Guyader, L.; Zhao, Y.; Wu, Y.; He, S.; Ma, Y.; Chen, C. Rutile TiO2 particles exert size and surface coating dependent retention and lesions on the murine brain. Toxicology Letters 2011, 207,73-81.
40. Wang, J.-X.; Fan, Y.-B.; Gao, Y.; Hu, Q.-H.; Wang, T.-C. TiO2 nanoparticles translocation and potential toxicological effect in rats after intraarticular injection. Biomaterials 2009,30,4590-4600.
41. Kreyling, W. G.; Semmler, M.; Erbe, F.; Mayer, P.; Takenaka, S.; Schulz, H.; Oberdorster, G.; Ziesenis, A. Translocation of ultrafine insoluble iridium particles from lung epithelium to extrapulmonary organs is size dependent but very low. Journal of Toxicology and Environmental Health-Part A 2002,65, 1513-1530.
42. Kwon, J.-T.; Hwang, S.-K.; Jin, H.; Kim, D.-S.; Minai-Tehrani, A.; Yoon, H.-J.; Choi, M.; Yoon, T.-J.; Han, D.-Y.; Kang, Y-W.; Yoon, B.-I.; Lee, J.-K.; Cho, M.-H. Body Distribution of Inhaled Fluorescent Magnetic Nanoparticles in the Mice. J. Occup. Health 2008,50,1-6.
43. Chen, J.; Dong, X.; Zhao, J.; Tang, G. In vivo acute toxicity of titanium dioxide nanoparticles to mice after intraperitioneal injection. J. Appl. Toxicol.2009,29, 330-337.
44. Olmedo, D.; Tasat, D.; Guglielmotti, M.; Cabrini, R. Biodistribution of titanium dioxide from biologic compartments. J. Mater. Sci.:Mater. Med.2008,19, 3049-3056.
45. Wang, J.; Zhou, G.; Chen, C.; Yu, H.; Wang, T.; Ma, Y.; Jia, G.; Gao, Y.; Li, B.; Sun, J.; Li, Y.; Jiao, F.; Zhao, Y.; Chai, Z. Acute toxicity and biodistribution of different sized titanium dioxide particles in mice after oral administration. Toxicology Letters 2007,168,176-185.
46. Pflucker, F.; Wendel, V.; Hohenberg, H.; Gartner, E.; Will, T.; Pfeiffer, S.; Wepf, R.; Gers-Barlag, H. The human stratum corneum layer:An effective barrier against dermal uptake of different forms of topically applied micronised titanium dioxide. Skin Pharmacol. Appl. Skin Physiol.2001,14,92-97.
47. Kiss, B.; Biro, T.; Czifra, G.; Toth, B. I.; Kertesz, Z.; Szikszai, Z.; Kiss, A. Z.; Juhasz, I.; Zouboulis, C. C.; Hunyadi, J. Investigation of micronized titanium dioxide penetration in human skin xenografts and its effect on cellular functions of human skin-derived cells. Experimental Dermatology 2008,17,659-667.
48. Gamer, A. O.; Leibold, E.; van Ravenzwaay, B. The in vitro absorption of microfine zinc oxide and titanium dioxide through porcine skin. Toxicol. In Vitro 2006,20,301-307.
49. Sadrieh, N.; Wokovich, A. M.; Gopee, N. V.; Zheng, J. W.; Haines, D.; Parmiter, D.; Siitonen, P. H.; Cozart, C. R.; Patri, A. K.; McNeil, S. E.; Howard, P. C.; Doub, W. H.; Buhse, L. F. Lack of Significant Dermal Penetration of Titanium Dioxide from Sunscreen Formulations Containing Nano-and Submicron-Size TiO2 Particles. Toxicological Sciences 2010,115,156-166.
50. Gopee, N. V.; Roberts, D. W.; Webb, P.; Cozart, C. R.; Siitonen, P. H.; Latendresse, J. R.; Warbitton, A. R.; Yu, W. W.; Colvin, V. L.; Walker, N. J.; Howard, P. C. Quantitative Determination of Skin Penetration of PEG-Coated CdSe Quantum Dots in Dermabraded but not Intact SKH-1 Hairless Mouse Skin. Toxicological Sciences 2009,111,37-48.
51. Mortensen, L. J.; Oberdorster, G.; Pentland, A. P.; DeLouise, L. A. In Vivo Skin Penetration of Quantum Dot Nanoparticles in the Murine Model:The Effect of UVR. Nano Letters 2008,8,2779-2787.
52. Xie, G.; Wang, C.; Sun, J.; Zhong, G. Tissue distribution and excretion of intravenously administered titanium dioxide nanoparticles. Toxicology Letters 2011,205,55-61.
53. Wang, J.; Liu, Y.; Jiao, F.; Lao, F.; Li, W.; Gu, Y.; Li, Y.; Ge, C.; Zhou, G.; Li, B.; Zhao, Y.; Chai, Z.; Chen, C. Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles. Toxicology 2008,254,82-90.
54.汪冰,丰.,王萌,等.鼻腔滴入Fe203细颗粒在小鼠嗅球中的微区分布及对其他微量元素的影响.府能物理与核物理29,71-75.
55.陈春英等.二氧化钛纳米材料生物效应与安全应用.科学出版社：2010.
56. Emerit, J.; Edeas, M.; Bricaire, F. Neurodegenerative diseases and oxidative stress. Biomed. Pharmacother.2004,58,39-46.
57. Renwick, L. C.; Brown, D.; Clouter, A.; Donaldson, K. Increased inflammation and altered macrophage chemotactic responses caused by two ultrafine particle types. Occup. Environ. Med.2004,61,442-447.
58. Kobayashi, N.; Naya, M.; Endoh, S.; Maru, J.; Yamamoto, K.; Nakanishi, J. Comparative pulmonary toxicity study of nano-TiO2 particles of different sizes and agglomerations in rats:Different short-and long-term post-instillation results. Toxicology 2009,264,110-118.
59. Oberdorster, G.; Ferin, J.; Lehnert, B. E. Correlation between particle size, in vivo particle persistence, and lung injury. Environmental health perspectives 1994,102 Suppl 5,173-9.
60. Donaldson, K.; Li, X. Y.; MacNee, W. Ultrafine (nanometre) particle mediated lung injury. J. Aerosol Sci. 1998,29,553-560.
61. Ma, L.; Zhao, J.; Wang, J.; Liu, J.; Duan, Y.; Liu, H.; Li, N.; Yan, J.; Ruan, J.; Wang, H.; Hong, F. The Acute Liver Injury in Mice Caused by Nano-Anatase TiO2. Nanoscale Research Letters 2009,4,1275-1285.
62. Duan, Y.; Liu, J.; Ma, L.; Li, N.; Liu, H.; Wang, J.; Zheng, L.; Liu, C.; Wang, X.; Zhao, X.; Yan, J.; Wang, S.; Wang, H.; Zhang, X.; Hong, F. Toxicological characteristics of nanoparticulate anatase titanium dioxide in mice. Biomaterials 2010,31,894-899.
63. Jaeger, A.; Weiss, D. G.; Jonas, L.; Kriehuber, R. Oxidative stress-induced cytotoxic and genotoxic effects of nano-sized titanium dioxide particles in human HaCaT keratinocytes. Toxicology 2012,296,27-36.
64. Chengbin, X.; Jianhong, W.; Fengli, L.; Wei, L.; Xiangliang, Y.; Fandian, Z.; Huibi, X. Nano Titanium Dioxide Induces the Generation of ROS and Potential Damage in HaCaT Cells Under UVA Irradiation. J. Nanosci. Nanotechnol.2010, 10,8500-7.
65. Tu, M.; Huang, Y.; Li, H.-L.; Gao, Z.-H. The stress caused by nitrite with titanium dioxide nanoparticles under UVA irradiation in human keratinocyte cell. Toxicology 2012,299,60-68.
66. Tyner, K. M.; Wokovich, A. M.; Godar, D. E.; Doub, W. H.; Sadrieh, N. The state of nano-sized titanium dioxide (TiO2) may affect sunscreen performance. Int. J. Cosmet. Sci.2011,33,234-244.
67. Kambara, T.; Aihara, M.; Matsukura, S.; Sato, I.; Kubota, Y.; Hirasawa, T.; Ikezawa, Z. Effects of photocatalytic agent on DS-Nh mice, developing atopic dermatitis-like eruption with an increase of Staphylococcus aureus. Int. Arch. Allergy Appl. Immunol.2006,141,151-157.
68. Boffetta, P.; Soutar, A.; Cherrie, J. W.; Granath, F.; Andersen, A.; Anttila, A.; Blettner, M.; Gaborieau, V.; Klug, S. J.; Langard, S.; Luce, D.; Merletti, F.; Miller, B.; Mirabelli, D.; Pukkala, E.; Adami, H. O.; Weiderpass, E. Mortality among workers employed in the titanium dioxide production industry in Europe. Cancer Causes Control 2004,15,697-706.
69. Hext, P. M.; Tomenson, J. A.; Thompson, P. Titanium dioxide:Inhalation toxicology and epidemiology. Ann. Occup. Hyg.2005,49,461-472.
70. Fryzek, J. P.; Chadda, B.; Marano, D.; White, K.; Schweitzer, S.; McLaughlin, J. K.; Blot, W. J. A cohort mortality study among titanium dioxide manufacturing workers in the United States. J. Occup. Environ. Med.2003,45,400-409.
71. Borm, P. J. A.; Schins, R. P. F.; Albrecht, C. Inhaled particles and lung cancer, part B:Paradigms and risk assessment. Int. J. Cancer 2004,110,3-14.
72. Dankovic, D.; Kuempel, E.; Wheeler, M. An approach to risk assessment for TiO2. Inhalation Toxicology 2007,19,205-212.
73. http://monographs.iarc.fr/ENG/Monographs/vol93/.
74. Trouiller, B.; Reliene, R.; Westbrook, A.; Solaimani, P.; Schiestl, R. H. Titanium Dioxide Nanoparticles Induce DNA Damage and Genetic Instability In vivo in Mice. Cancer Research 2009,69,8784-8789.
75.屈云芳等,王.郭.Cu对中国林蛙蝌蚪的急性毒性.应用生态学报1998,9,309-312.
76. Donaldson, K.; Duffin, R.; Langrish, J. P.; Miller, M. R.; Mills, N. L.; Poland, C. A.; Raftis, J.; Shah, A.; Shaw, C. A.; Newby, D. E. Nanoparticles and the cardiovascular system:a critical review. Nanomedicine 2013,8,403-423.
77. Sarnat, J. A.; Schwartz, J.; Suh, H. H. Fine particulate air pollution and mortality in 20 US cities. New England Journal of Medicine 2001,344,1253-1254.
78. Pope, C. A.; Dockery, D. W. Health effects of fine particulate air pollution:Lines that connect. J. Air Waste Manage. Assoc.2006,56,709-742.
79. Pope, C. A. Epidemiology of fine particulate air pollution and human health: Biologic mechanisms and who's at risk? Environmental Health Perspectives 2000,108,713-723.
80. Chen, Z.; Meng, H.; Xing, G.; Yuan, H.; Zhao, F.; Liu, R.; Chang, X.; Gao, X.; Wang, T.; Jia, G.; Ye, C.; Chai, Z.; Zhao, Y. Age-Related Differences in Pulmonary and Cardiovascular Responses to SiO(2) Nanoparticle Inhalation: Nanotoxicity Has Susceptible Population. Environmental Science & Technology 2008,42,8985-8992.
81. Wang, Y.; Chen, Z.; Ba, T.; Pu, J.; Chen, T.; Song, Y.; Gu, Y.; Qian, Q.; Xu, Y.; Xiang, K.; Wang, H.; Jia, G. Susceptibility of Young and Adult Rats to the Oral Toxicity of Titanium Dioxide Nanoparticles. Small 2013,9,1742-1752.
82. Lanphear, B. P.; Vorhees, C. V.; Bellinger, D. C. Protecting Children from Environmental Toxins. PLoS Med.2005,2, e61.
83. Bobak, M. Outdoor air pollution, low birth weight, and prematurity. Environmental health perspectives 2000,108,173.
84. Woodruff, T. J.; Grillo, J.; Schoendorf, K. C. The relationship between selected causes of postneonatal infant mortality and particulate air pollution in the United States. Environmental health perspectives 1997,105,608.
85. Yang, H.; Sun, C.; Fan, Z.; Tian, X.; Yan, L.; Du, L.; Liu, Y.; Chen, C.; Liang, X.-j.; Anderson, G. J.; Keelan, J. A.; Zhao, Y.; Nie, G. Effects of gestational age and surface modification on materno-fetal transfer of nanoparticles in murine pregnancy. Scientific Reports 2012,2.
86. Tian, X.; Zhu, M.; Du, L.; Wang, J.; Fan, Z.; Liu, J.; Zhao, Y.; Nie, G. Intrauterine Inflammation Increases Materno-Fetal Transfer of Gold Nanoparticles in a Size-Dependent Manner in Murine Pregnancy. Small 2013,9, 2432-2439.
87. Yamashita, K.; Yoshioka, Y.; Higashisaka, K.; Mimura, K.; Morishita, Y.; Nozaki, M.; Yoshida, T.; Ogura, T.; Nabeshi, H.; Nagano, K. Silica and titanium dioxide nanoparticles cause pregnancy complications in mice. Nat. Nanotechnol.2011.
88. Myllynen, P. K.; Loughran, M. J.; Howard, C. V.; Sormunen, R.; Walsh, A. A.; Vahakangas, K. H. Kinetics of gold nanoparticles in the human placenta. Reproductive Toxicology 2008,26,130-137.
89. Sumner, S. C. J.; Fennell, T. R.; Snyder, R. W.; Taylor, G. F.; Lewin, A. H. Distribution of carbon-14 labeled C60 (C-14 C60) in the pregnant and in the lactating dam and the effect of C60 exposure on the biochemical profile of urine. J. Appl. Toxicol.2010,30,354-360.
90. Takeda, K.; Suzuki, K.-I.; Ishihara, A.; Kubo-Irie, M.; Fujimoto, R.; Tabata, M.; Oshio, S.; Nihei, Y.; Ihara, T.; Sugamata, M. Nanoparticles Transferred from Pregnant Mice to Their Offspring Can Damage the Genital and Cranial Nerve Systems. J. Health Sci.2009,55,95-102.
91. Tian, F.; Razansky, D.; Estrada, G. G.; Semmler-Behnke, M.; Beyerle, A.; Kreyling, W.; Ntziachristos, V.; Stoeger, T. Surface modification and size dependence in particle translocation during early embryonic development. Inhalation toxicology 2009,21 Suppl 1,92-6.
92. Chu, M.; Wu, Q.; Yang, H.; Yuan, R.; Hou, S.; Yang, Y.; Zou, Y.; Xu, S.; Xu, K.; Ji, A.; Sheng, L. Transfer of Quantum Dots from Pregnant Mice to Pups Across the Placental Barrier. Small 2010,6,670-678.
93. Pietroiusti, A.; Massimiani, M.; Fenoglio, I.; Colonna, M.; Valentini, F.; Palleschi, G.; Camaioni, A.; Magrini, A.; Siracusa, G.; Bergamaschi, A.; Sgambato, A.; Campagnolo, L. Low Doses of Pristine and Oxidized Single-Wall Carbon Nanotubes Affect Mammalian Embryonic Development. ACS Nano 2011,5, 4624-4633.
94. Refuerzo, J. S.; Godin, B.; Bishop, K.; Srinivasan, S.; Shah, S. K.; Amra, S.; Ramin, S. M.; Ferrari, M. Size of the nano vectors determines the transplacental passage in pregnancy:study in rats. Am. J. Obstet. Gynecol.2011,204, 546.e5-546.e9.
95. http://www.who.int/mediacentre/news/notes/2010/breastfeeding_20100730/zh/.
96. Anderson, P. O. Drug use during breast-feeding. Clin. Pharm.1991,10,594-624.
97.苗丽；邓万俊.妊娠及哺乳期应用抗生素的研究现状.国外医药：抗生素分册2008,29,248-254.
98. Tankeyoon, M.; Dusitsin, N.; Chalapati, S.; Koetsawang, S.; Saibiang, S.; Sas, M.; Gellen, J.; Ayeni, O.; Gray, R.; Pinol, A. Effects of hormonal contraceptives on milk volume and infant growth:WHO Special Programme of Research and Development and Research Training in Human Reproduction. Contraception 1984,30,505-522.
99.朱斌.哺乳期用药的安全性.中国医院用药评价与分析 2001,1,251.
100. Neville, M. C.; McFadden, T. B.; Forsyth, I. Hormonal regulation of mammary differentiation and milk secretion. J. Mammary Gland Biol. Neoplasia 2002,7, 49-66.
101. Tsukita, S.; Furuse, M. The structure and function of claudins, cell adhesion molecules at tight junctions. In Epithelial Transport and Barrier Function: Pathomechanisms in Gastrointestinal Disorders, Schulzke, J. D.; Fromm, M.; Riecken, E. O.; Binder, H. J., Eds.2000; Vol.915, pp 129-135.
102. Baumgart, D. C.; Dignass, A. U. Intestinal barrier function. Current Opinion in Clinical Nutrition & Metabolic Care 2002,5,685-694.
103.McManaman, J. L.; Neville, M. C. Mammary physiology and milk secretion. Adv. Drug Deliv. Rev.2003,55,629-641.
104. Gao, X.; Yin, S.; Tang, M.; Chen, J.; Yang, Z.; Zhang, W.; Chen, L.; Yang, B.; Li, Z.; Zha, Y.; Ruan, D.; Wang, M. Effects of Developmental Exposure to TiO2 Nanoparticles on Synaptic Plasticity in Hippocampal Dentate Gyrus Area:an In Vivo Study in Anesthetized Rats. Biol. Trace Elem. Res.2011,143,1616-1628.
105. Yeo, M.-K.; Kang, M. The biological toxicities of two crystalline phases and differential sizes of TiO2 nanoparticles during zebrafish embryogenesis development. Mol. Cell. Toxicol.2012,8,317-326.
106.Wang, J. X.; Liu, Y.; Jiao, F.; Lao, F.; Li, W.; Gu, Y. Q.; Li, Y. F.; Ge, C. C.; Zhou, G. Q.; Li, B.; Zhao, Y. L.; Chai, Z. F.; Chen, C. Y. Time-dependent translocation and potential impairment on central nervous system by intranasally instilled TiO2 nanoparticles. Toxicology 2008,254,82-90.
107. Bai, Y. H.; Zhang, Y.; Zhang, J. P.; Mu, Q. X.; Zhang, W. D.; Butch, E. R.; Snyder, S. E.; Yan, B. Repeated administrations of carbon nanotubes in male mice cause reversible testis damage without affecting fertility. Nat. Nanotechnol. 2010,5,683-689.
108. White, S. S.; Calafat, A. M.; Kuklenyik, Z.; Villanueva, L.; Zehr, R. D.; Helfant, L.; Strynar, M. J.; Lindstrom, A. B.; Thibodeaux, J. R.; Wood, C. Gestational PFOA exposure of mice is associated with altered mammary gland development in dams and female offspring. Toxicological sciences 2007,96,133-144.
109. Sonavane, G.; Tomoda, K.; Makino, K. Biodistribution of colloidal gold nanoparticles after intravenous administration:Effect of particle size. Colloids and Surfaces B:Biointerfaces 2008,66,274-280.
110. De Jong, W. H.; Hagens, W. I.; Krystek, P.; Burger, M. C.; Sips, A. J. A. M.; Geertsma, R. E. Particle size-dependent organ distribution of gold nanoparticles after intravenous administration. Biomaterials 2008,29,1912-1919.
111. Williamson, D. H.; Lund, P.; Evans, R. D. Substrate selection and oxygen uptake by the lactating mammary gland. Proc. Nutr. Soc.1995,54,165-175.
112. Couto-Moraes, R.; Felicio, L. F.; Bernardi, M. M. Post-partum testosterone administration does not reverse the effects of perinatal exposure to cadmium on rat offspring development. J. Appl. Toxicol.2010,30,233-241.
113. Klaassen, C. D.; Watkins, J. B. Casarett and Doull's toxicology:the basic science of poisons. McGraw-Hill:1999.
114. Ma, L.; Liu, J.; Li, N.; Wang, J.; Duan, Y.; Yan, J.; Liu, H.; Wang, H.; Hong, F. Oxidative stress in the brain of mice caused by translocated nanoparticulate TiO2 delivered to the abdominal cavity. Biomaterials 2010,31,99-105.
115. Yang, S.-T.; Wang, X.; Jia, G.; Gu, Y.; Wang, T.; Nie, H.; Ge, C.; Wang, H.; Liu, Y Long-term accumulation and low toxicity of single-walled carbon nanotubes in intravenously exposed mice. Toxicology Letters 2008,181,182-189.
116. Liu, H.; Ma, L.; Liu, J.; Zhao, J.; Yan, J.; Hong, F. Toxicity of nano-anatase TiO2 to mice:Liver injury, oxidative stress. Toxicol. Environ. Chem.2010,92, 175-186.
117.Droge, W. Free radicals in the physiological control of cell function. Physiol. Rev. 2002,82,47-95.
118. Thannickal, V. J.; Fanburg, B. L. Reactive oxygen species in cell signaling. American Journal of Physiology-Lung Cellular and Molecular Physiology 2000, 279, L1005-L1028.
119. Nguyen, D. A. D.; Neville, M. C. Tight junction regulation in the mammary gland. J. Mammary Gland Biol. Neoplasia 1998,3,233-246.
120. Wang, B.; Feng, W. Y.; Wang, T. C.; Guang, J.; Wang, M.; Shi, J. W.; Zhang, F.; Zhao, Y L.; Chai, Z. F. Acute toxicity of nano- and micro-scale zinc powder in healthy adult mice. Toxicology Letters 2006,161,115-123.
121. Bonazzi, M.; Cossart, P. Impenetrable barriers or entry portals? The role of cell-cell adhesion during infection. J. Cell Biol.2011,195,349-58.
122. Uskokovic, V.; Lee, P. P.; Walsh, L. A.; Fischer, K. E.; Desai, T. A. PEGylated silicon nanowire coated silica microparticles for drug delivery across intestinal epithelium. Biomaterials 2012,33,1663-1672.
123. Brun, E.; Carriere, M.; Mabondzo, A. In vitro evidence of dysregulation of blood-brain barrier function after acute and repeated/long-term exposure to TiO2 nanoparticles. Biomaterials 2012,33,886-896.
124. Kobayashi, K.; Oyama, S.; Numata, A.; Rahman, M. M.; Kumura, H. Lipopolysaccharide Disrupts the Milk-Blood Barrier by Modulating Claudins in Mammary Alveolar Tight Junctions. PLoS One 2013,8.
125. Musch, M. W.; Walsh-Reitz, M. M.; Chang, E. B. Roles of ZO-1, occludin, and actin in oxidant-induced barrier disruption. American Journal of Physiology-Gastrointestinal and Liver Physiology 2006,290, G222-G231.
126. Singh, A.; Ramnath, R. D.; Foster, R. R.; Wylie, E, C.; Friden, V.; Dasgupta, I.; Haraldsson, B.; Welsh, G. I.; Mathieson, P. W.; Satchell, S. C. Reactive Oxygen Species Modulate the Barrier Function of the Human Glomerular Endothelial Glycocalyx. PLoS One 2013,8, e55852.
127. Ullen, A.; Singewald, E.; Konya, V.; Fauler, G.; Reicher, H.; Nusshold, C.; Hammer, A.; Kratky, D.; Heinemann, A.; Holzer, P.; Malle, E.; Sattler, W. Myeloperoxidase-Derived Oxidants Induce Blood-Brain Barrier Dysfunction
128. Stull, M. A.; Pai, V.; Vomachka, A. J.; Marshall, A. M.; Jacob, G. A.; Horseman, N. D. Mammary gland homeostasis employs serotonergic regulation of epithelial tight junctions. Proc. Natl. Acad. Sci. U. S. A.2007,104,16708-16713.
129. Svennersten-Sjaunja, K.; Olsson, K. Endocrinology of milk production. Domest. Anim. Endocrinol.2005,29,241-258.
130. Li, C.; Taneda, S.; Taya, K.; Watanabe, G.; Li, X.; Fujitani, Y.; Ito, Y.; Nakajima, T.; Suzuki, A. K. Effects of inhaled nanoparticle-rich diesel exhaust on regulation of testicular function in adult male rats. Inhalation Toxicology 2009,21,803-811.
131.Ramdhan, D. H.; Ito, Y.; Yanagiba, Y.; Yamagishi, N.; Hayashi, Y.; Li, C.; Taneda, S.; Suzuki, A. K.; Watanabe, G.; Taya, K.; Kamijima, M.; Nakajima, T. Nanoparticle-rich diesel exhaust may disrupt testosterone biosynthesis and metabolism via growth hormone. Toxicology Letters 2009,191,103-108.
132. Burgoyne, R.; Duncan, J. Secretion of Milk Proteins. J. Mammary Gland Biol. Neoplasia 1998,3,275-286.
133. Lonnerdal, B. Nutritional and physiologic significance of human milk proteins. Am. J. Clin. Nutr.2003,77,1537S-1543S.
134. Wheeler, T. T.; Callaghan, M. R.; Davis, S. R.; Prosser, C. G.; Wilkins, R. J. Milk Protein Synthesis, Gene Expression, and Hormonal Responsiveness in Primary Cultures of Mammary Cells from Lactating Sheep. Exp. Cell Res.1995,217, 346-354.
135. Lonnerdal, B.; Lien, E. L. Nutritional and Physiologic Significance of a-Lactalbumin in Infants. Nutr. Rev.2003,61,295-305.
136. Ohrvik, H.; Yoshioka, M.; Oskarsson, A.; Tallkvist, J. Cadmium-induced disturbances in lactating mammary glands of mice. Toxicology Lettens 2006,164, 207-213.
1. Gottesman, M. M.; Fojo, T.; Bates, S. E. Multidrug resistance in cancer:role of ATP-dependent transporters. Nat. Rev. Cancer 2002,2,48-58.
2. 高冬冬;孙宏新.肿瘤多药耐药治疗的研究进展.第三届国际中医,中西医结合肿瘤学术交流大会暨第十二届全国中西医结合种瘤学术大会论文汇编2010.
3. http://www.who.int/mediacentre/factsheets/fs297/zh/.
4.NCLC. http://www.lung.org/lunng-disease/lung-cancer/resources/facts-figures /lung-cancer-fact-sheet.html.
5. NCCN guideline. http://www.nccn.org/professionals/physician_gls/f_guidelines.asp#site
6.丁国钰；刘晓.乳腺癌患者对曲妥珠单抗的耐药机制与治疗策略.国际肿瘤学杂志2012,39,274-277.
7.王敏;刘荣玉.非小细胞肺癌分子靶向治疗的现状及进展.国际呼吸杂志2011,31,637-640.
8. Biedler, J. L.; Riehm, H. Cellular resistance to actinomycin D in Chinese hamster cells in vitro:cross-resistance, radioautographic, and cytogenetic studies. Cancer research 1970,30,1174-84.
9. Robert, J. Resistance to cytotoxic agents. Curr. Opin. Pharmacol.2001,1, 353-357.
10.孙志勇；余宏字；刘会敏；李玉莉；何金；孙静.P-gP, MRP, LRP, P53及c-erbB一2在非小细胞肺癌中的表达.第二军医大学学报2006,27,474.
11.戴春岭；符立梧.肿瘤多药耐药逆转剂的研究进展.中国药理学通报2005,21,513-518.
12. Kartner, N.; Ling, V. Cell surface P-glycoprotein associated with multidrug resistance in mammalian cell lines. Science 1983,221,1285-1288.
13. Ambudkar, S. V.; Kimchi-Sarfaty, C.; Sauna, Z. E.; Gottesman, M. M. P-glycoprotein:from genomics to mechanism. Oncogene 2003,22,7468-7485.
14. Eckford, P. D.; Sharom, F. J. ABC efflux pump-based resistance to chemotherapy drugs. Chemical reviews 2009,109,2989-3011.
15. Fletcher, J. I.; Haber, M.; Henderson, M. J.; Norris, M. D. ABC transporters in cancer:more than just drug efflux pumps. Nat. Rev. Cancer 2010,10,147-156.
16. Fojo, A.; Ueda, K.; Slamon, D.; Poplack, D.; Gottesman, M.; Pastan, I. Expression of a multidrug-resistance gene in human tumors and tissues. Proceedings of the National Academy of Sciences 1987,84,265-269.
17. Juliano, R. L.; Ling, V. A surface glycoprotein modulating drug permeability in Chinese hamster ovary cell mutants. Biochim. Biophys. Acta 1976,455,152-62.
18. Leonard, G. D.; Fojo, T.; Bates, S. E. The role of ABC transporters in clinical practice. The oncologist 2003,8,411-424.
19. Jin, M. S.; Oldham, M. L.; Zhang, Q.; Chen, J. Crystal structure of the multidrug transporter P-glycoprotein from Caenorhabditis elegans. Nature 2012,490, 566-+.
20. Aller, S. G.; Yu, J.; Ward, A.; Weng, Y.; Chittaboina, S.; Zhuo, R.; Harrell, P. M.; Trinh, Y. T.; Zhang, Q.; Urbatsch, I. L.; Chang, G. Structure of P-Glycoprotein Reveals a Molecular Basis for Poly-Specific Drug Binding. Science 2009,323, 1718-1722.
21. Ambudkar, S. V.; Kim, I.-W.; Sauna, Z. E. The power of the pump:Mechanisms of action of P-glycoprotein (ABCB1). Eur. J. Pharm. Sci.2006,27,392-400.
22. Cordon-Cardo, C.; O'Brien, J. P.; Boccia, J.; Casals, D.; Bertino, J. R.; Melamed, M. R. Expression of the multidrug resistance gene product (P-glycoprotein) in human normal and tumor tissues. The journal of histochemistry and cytochemistry:official journal of the Histochemistry Society 1990,38,1277-87.
23. Thiebaut, F.; Tsuruo, T.; Hamada, H.; Gottesman, M. M.; Pastan, I.; Willingham, M. C. Immunohistochemical localization in normal tissues of different epitopes in the multidrug transport protein P170:evidence for localization in brain capillaries and crossreactivity of one antibody with a muscle protein. The journal of histochemistry and cytochemistry:official journal of the Histochemistry Society 1989,37,159-64.
24. Szakacs, G.; Paterson, J. K.; Ludwig, J. A.; Booth-Genthe, C.; Gottesman, M. M. Targeting multidrug resistance in cancer. Nat. Rev. Drug Discov.2006,5, 219-234.
25. Tsuruo, T.; Iida, H.; Tsukagoshi, S.; Sakurai, Y. Overcoming of vincristine resistance in P388 leukemia in vivo and in vitro through enhanced cytotoxicity of vincristine and vinblastine by verapamil. Cancer research 1981,41,1967-72.
26. Thomas, H.; Coley, H. M. Overcoming multidrug resistance in cancer:an update on the clinical strategy of inhibiting p-glycoprotein. Cancer control:journal of the Moffitt Cancer Center 2003,10,159-65.
27. Krishna, R.; Mayer, L. D. Multidrug resistance (MDR) in cancer-Mechanisms, reversal using modulators of MDR and the role of MDR modulators in influencing the pharmacokinetics of anticancer drugs. Eur. J. Pharm. Sci.2000, 11,265-283.
28. Abolhoda, A.; Wilson, A. E.; Ross, H.; Danenberg, P. V.; Burt, M.; Scotto, K. W. Rapid activation of MDR 1 gene expression in human metastatic sarcoma after in vivo exposure to doxorubicin. Clin. Cancer Res.1999,5,3352-3356.
29. te Boekhorst, P. A.; van Kapel, J.; Schoester, M.; Sonneveld, P. Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive analogue SDZ PSC 833 in Chinese hamster ovary cells expressing the mdrl phenotype. Cancer Chemother. Pharmacol.1992,30,238-42.
30. Wandel, C.; Kim, R. B.; Kajiji, S.; Guengerich, F. P.; Wilkinson, G. R.; Wood, A. J. J. P-glycoprotein and cytochrome P-450 3A inhibition:Dissociation of inhibitory potencies. Cancer Research 1999,59,3944-3948.
31. Shepard, R. L.; Cao, J.; Starling, J. J.; Dantzig, A. H. Modulation of P-glycoprotein but not MRPI-or BCRP-mediated drug resistance by LY335979. Int. J. Cancer 2003,103,121-125.
32. Dantzig, A. H.; Shepard, R. L.; Cao, J.; Law, K. L.; Ehlhardt, W. J.; Baughman, T. M.; Bumol, T. F.; Starling, J. J. Reversal of P-glycoprotein-mediated multidrug resistance by a potent cyclopropyldibenzosuberane modulator, LY335979. Cancer Research 1996,56,4171-4179.
33. Mistry, P.; Stewart, A. J.; Dangerfield, W.; Okiji, S.; Liddle, C.; Bootle, D.; Plumb, J. A.; Templeton, D.; Charlton, P. In vitro and in vivo reversal of P-glycoprotein-mediated multidrug resistance by a novel potent modulator, XR9576. Cancer Research 2001,61,749-758.
34. Balayssac, D.; Cayre, A.; Ling, B.; Maublant, J.; Penault-Llorca, F.; Eschalier, A.; Coudore, F.; Authier, N. Increase in morphine antinociceptive activity by a P-glycoprotein inhibitor in cisplatin-induced neuropathy. Neurosci. Lett.2009, 465,108-112.
35. Wouters, W.; Janssens, F.; Van Dun, J.; Krekels, M.; Smets, G. R101933 is an antagonist of PgP and modulates resistance to different chemotherapy agents. Proc. Am. Assoc. Cancer Res. Annu. Meet.1999,40,663-663.
36. Mistry, P.; Folkes, A. ONT-093 (Ontogen). Current opinion in investigational drugs (London, England:2000) 2002,3,1666-71.
37. Pusztai, L.; Wagner, P.; Ibrahim, N.; Rivera, E.; Theriault, R.; Booser, D.; Symmans, F. W.; Wong, F.; Blumenschein, G.; Fleming, D. R.; Rouzier, R.; Boniface, G.; Hortobagyi, G. N. Phase II study of tariquidar, a selective P-glycoprotein inhibitor, in patients with chemotherapy-resistant, advanced breast carcinoma. Cancer 2005,104,682-691.
38. Scagliotti, G. V.; Novello, S.; Selvaggi, G. Multidrug resistance in non-small-cell lung cancer. Ann. Oncol.1999,10, S83-S86.
39. Borisy, A. A.; Elliott, P. J.; Hurst, N. W.; Lee, M. S.; Lehar, J.; Price, E. R.; Serbedzija, G.; Zimmermann, G. R.; Foley, M. A.; Stockwell, B. R. Systematic discovery of multicomponent therapeutics. Proceedings of the National Academy of Sciences 2003,100,7977-7982.
40. Fitzgerald, J. B.; Schoeberl, B.; Nielsen, U. B.; Sorger, P. K. Systems biology and combination therapy in the quest for clinical efficacy. Nat. Chem. Biol.2006, 2,458-466.
41.刘彦斌.组合药物数据库构建及药物协同作用机理分析.浙江大学,2011.
42. Chou, T.-C. Drug Combination Studies and Their Synergy Quantification Using the Chou-Talalay Method. Cancer Research 2010,70,440-446.
43. Druker, B. J.; Talpaz, M.; Resta, D. J.; Peng, B.; Buchdunger, E.; Ford, J. M.; Lydon, N. B.; Kantarjian, H.; Capdeville, R.; Ohno-Jones, S.; Sawyers, C. L. Efficacy and Safety of a Specific Inhibitor of the BCR-ABL Tyrosine Kinase in Chronic Myeloid Leukemia. New England Journal of Medicine 2001,344, 1031-1037.
44. Pao, W.; Miller, V.; Zakowski, M.; Doherty, J.; Politi, K.; Sarkaria, I.; Singh, B.; Heelan, R.; Rusch, V.; Fulton, L. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc. Nat1. Acad. Sci. U. S. A.2004,101,13306-13311.
45. Sams-Dodd, F. Target-based drug discovery:is something wrong? Drug Discov. Today 2005,10,139-147.
46. Pao, W.; Miller, V. A.; Politi, K. A.; Riely, G. J.; Somwar, R.; Zakowski, M. F.; Kris, M. G.; Varmus, H. Acquired resistance of lung adenocarcinomas to gefitinib or erlotinib is associated with a second mutation in the EGFR kinase domain. PLoS Med.2005,2, e73.
47. Bean, J.; Brennan, C.; Shih, J.-Y.; Riely, G.; Viale, A.; Wang, L.; Chitale, D.; Motoi, N.; Szoke, J.; Broderick, S. MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib. Proceedings of the National Academy of Sciences 2007, 104,20932-20937.
48. Teodori, E.; Dei, S.; Martelli, C.; Scapecchi, S.; Gualtieri, F. The functions and structure of ABC transporters:implications for the design of new inhibitors of Pgp and MRP1 to control multidrug resistance (MDR). Curr. Drug Targets 2006, 7,893-909.
49. Georges, E.; Sharom, J. Multidrug Resistance and Chemosensitization: Therapeutic Implications for. Adv. Pharmacol.1990,21,185.
50. Ford, J. Experimental reversal of P-glycoprotein-mediated multidrug resistance by pharmacological chemosensitisers. Eur, J. Cancer 1996,32,991-1001.
51. van Zuylen, L.; Nooter, K.; Sparreboom, A.; Verweij, J. Development of multidrug-resistance convertors:sense or nonsense? Invest. New Drugs 2000,18, 205-220.
52. Zhou, H.; Wu, S.; Zhai, S.; Liu, A.; Sun, Y.; Li, R.; Zhang, Y.; Ekins, S.; Swaan, P. W.; Fang, B. Design, synthesis, cytoselective toxicity, structure-activity relationships, and pharmacophore of thiazolidinone derivatives targeting drug-resistant lung cancer cells. J. Med. Chem.2008,51,1242-1251.
53. Mayer, L. D.; Harasym, T. O.; Tardi, P. G.; Harasym, N. L.; Shew, C. R.; Johnstone, S. A.; Ramsay, E. C.; Bally, M. B.; Janoff, A. S. Ratiometric dosing of anticancer drug combinations:controlling drug ratios after systemic administration regulates therapeutic activity in tumor-bearing mice. Molecular cancer therapeutics 2006,5,1854-1863.
54. Hopkins, A. L. Network pharmacology:the next paradigm in drug discovery. Nat. Chem. Biol.2008,4,682-690.
55. Lehar, J.; Krueger, A. S.; Avery, W.; Heilbut, A. M.; Johansen, L. M.; Price, E. R.; Rickles, R. J.; Short Iii, G. F.; Staunton, J. E.; Jin, X. Synergistic drug combinations tend to improve therapeutically relevant selectivity. Nat. Biotechnol.2009,27,659-666.
56. Raben, D.; Helfrich, B.; Chan, D. C.; Ciardiello, F.; Zhao, L.; Franklin, W.; Baron, A. E.; Zeng, C.; Johnson, T. K.; Bunn, P. A. The effects of cetuximab alone and in combination with radiation and/or chemotherapy in lung cancer. Clin. Cancer Res.2005,11,795-805.
57. Chou, T.-C. Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol. Rev.2006, 58.621-681.
58. Regales, L.; Gong, Y.; Shen, R.; de Stanchina, E.; Vivanco, I.; Goel, A.; Koutcher, J. A.; Spassova, M.; Ouerfelli, O.; Mellinghoff, I. K. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer. The Journal of clinical investigation 2009,119,3000.
59. Soriano, A. F.; Helfrich, B.; Chan, D. C.; Heasley, L. E.; Bunn, P. A.; Chou, T.-C. Synergistic effects of new chemopreventive agents and conventional cytotoxic agents against human lung cancer cell lines. Cancer research 1999,59, 6178-6184.
60. Dent, P.; Curiel, D. T.; Fisher, P. B.; Grant, S. Synergistic combinations of signaling pathway inhibitors:mechanisms for improved cancer therapy. Drug Resist. Updat.2009,12,65-73.
61. DiDiodato, G.; Sharom, F. J. Interaction of combinations of drugs, chemosensitizers, and peptides with the P-glycoprotein multidrug transporter. Biochemical pharmacology 1997,53,1789-1797.
62. Teraishi, F.; Wu, S.; Sasaki, J.; Zhang, L.; Zhu, H.-B.; Davis, J. J.; Fang, B. P-glycoprotein-independent apoptosis induction by a novel synthetic compound, MMPT [5-[(4-methylphenyl) methylene]-2-(phenylamino)-4 (5H)-thiazolone]. J. Pharmacol. Exp. Ther.2005,314,355-362.
63. Teraishi, F.; Wu, S.; Sasaki, J.; Zhang, L.; Davis, J. J.; Guo, W.; Dong, F.; Fang, B. JNK1-dependent antimitotic activity of thiazolidin compounds in human non-small-cell lung and colon cancer cells. Cellular and Molecular Life Sciences CMLS 2005,62,2382-2389.
64. Li, L.; Zhang, Q.; Liu, A.; Li, X.; Zhou, H.; Liu, Y.; Yan, B. Proteome Interrogation Using Nanoprobes To Identify Targets of a Cancer-Killing Molecule. Journal of the American Chemical Society 2011,133,6886-6889.
65. Zhang, Q.; Zhai, S.; Li, L.; Li, X.; Zhou, H.; Liu, A.; Su, G.; Mu, Q.; Du, Y.; Yan, B. Anti-tumor selectivity of a novel Tubulin and HSP90 dual-targeting inhibitor in non-small cell lung cancer models. Biochemical Pharmacology 2013,86, 351-360.
66. Hubbert, C.; Guardiola, A.; Shao, R.; Kawaguchi, Y.; Ito, A.; Nixon, A.; Yoshida, M.; Wang, X. F.; Yao, T. P. HDAC6 is a microtubule-associated deacetylase. Nature 2002,417,455-458.
67. Li, F. Z.; Ambrosini, G.; Chu, E. Y.; Plescia, J.; Tognin, S.; Marchisio, P. C.; Altieri, D. C. Control of apoptosis and mitotic spindle checkpoint by survivin. Nature 1998,396,580-584.
68. Harper, J. W.; Adami, G. R.; Wei, N.; Keyomarsi, K.; Elledge, S. J. The p21 Cdk-interacting protein Cipl is a potent inhibitor of G1 cyclin-dependent kinases. Cell 1993,75,805-16.
69. Singh, S. V.; Herman-Antosiewicz, A.; Singh, A. V.; Lew, K. L.; Srivastava, S. K.; Kamath, R.; Brown, K. D.; Zhang, L.; Baskaran, R. Sulforaphane-induced G(2)/M phase cell cycle arrest involves checkpoint kinase 2-mediated phosphorylation of cell division cycle 25C. J. Biol. Chem.2004,279, 25813-25822.
70. Elmore, S. Apoptosis:A review of programmed cell death. Toxicol. Pathol.2007, 35,495-516.
71. Breckenridge, D. G.; Germain, M.; Mathai, J. F.; Nguyen, M.; Shore, G. C. Regulation of apoptosis by endoplasmic reticulum pathways. Oncogene 2003,22, 8608-8618.
72. Rao, R. V.; Ellerby, H. M.; Bredesen, D. E. Coupling endoplasmic reticulum stress to the cell death program. Cell Death Differ.2004,11,372-380.
73. Janicke, R. U.; Sprengart, M. L.; Wati, M. R.; Porter, A. G. Caspase-3 is required for DNA fragmentation and morphological changes associated with apoptosis. J. Biol. Chem.1998,273,9357-9360.
74. Chen, C.-S.; Weng, S.-C.; Tseng, P.-H.; Lin, H.-P.; Chen, C.-S. Histone Acetylation-independent Effect of Histone Deacetylase Inhibitors on Akt through the Reshuffling of Protein Phosphatase 1 Complexes. J. Biol. Chem.2005,280, 38879-38887.
75. Chang, L.; Karin, M. Mammalian MAP kinase signalling cascades. Nature 2001, 410,37-40.
76. Martindale, J. L.; Holbrook, N. J. Cellular response to oxidative stress:Signaling for suicide and survival*. J. Cell. Physiol.2002,192,1-15.
77. Vijayaraghavalu, S.; Dermawan, J. K.; Cheriyath, V.; Labhasetwar, V. Highly synergistic effect of sequential treatment with epigenetic and anticancer drugs to overcome drug resistance in breast cancer cells is mediated via activation of p21 gene expression leading to G2/M cycle arrest. Molecular pharmaceutics 2012, 10,337-352.
78. Kawase, T.; Ichikawa, H.; Ohta, T.; Nozaki, N.; Tashiro, F.; Ohki, R.; Taya, Y. p53 target gene AEN is a nuclear exonuclease required for p53-dependent apoptosis. Oncogene 2008,27,3797-3810.
79. Yakovlev, A. G.; Di Giovanni, S.; Wang, G.; Liu, W.; Stoica, B.; Faden, A. I. BOK and NOXA are essential mediators of p53-dependent apoptosis. J. Biol. Chem.2004,279,28367-28374.
80. Carvajal, L. A.; Hamard, P.-J.; Tonnessen, C.; Manfredi, J. J. E2F7, a novel target, is up-regulated by p53 and mediates DNA damage-dependent transcriptional repression. Genes Dev.2012,26,1533-1545.
81. Kawase, T.; Ohki, R.; Shibata, T.; Tsutsumi, S.; Kamimura, N.; Inazawa, J.; Ohta, T.; Ichikawa, H.; Aburatani, H.; Tashiro, F. PH domain-only protein PHLDA3 is a p53-regulated repressor of Akt. Cell 2009,136,535-550.
82. Zuco, V.; De Cesare, M.; Cincinelli, R.; Nannei, R.; Pisano, C.; Zaffaroni, N.; Zunino, F. Synergistic antitumor effects of novel HDAC inhibitors and paclitaxel in vitro and in vivo. PLoS One 2011,6, e29085.
83. Dokmanovic, M.; Clarke, C.; Marks, P. A. Histone deacetylase inhibitors: overview and perspectives. Mol. Cancer Res.2007,5,981-989.
84. Rosato, R. R.; Almenara, J. A.; Dai, Y.; Grant, S. Simultaneous activation of the intrinsic and extrinsic pathways by histone deacetylase (HDAC) inhibitors and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) synergistically induces mitochondrial damage and apoptosis in human leukemia cells. Molecular Cancer Therapeutics 2003,2,1273-1284.
85. Carew, J. S.; Giles, F. J.; Nawrocki, S. T. Histone deacetylase inhibitors: mechanisms of cell death and promise in combination cancer therapy. Cancer Lett.2008,269,7-17.
86. Lee, J.-H.; Choy, M.; Ngo, L.; Foster, S.; Marks, P. A. Histone deacetylase inhibitor induces DNA damage, which normal but not transformed cells can repair. Proceedings of the National Academy of Sciences 2010,107, 14639-14644.
87. Xu, W.; Parmigiani, R.; Marks, P. Histone deacetylase inhibitors:molecular mechanisms of action. Oncogene 2007,26,5541-5552.
88. Hubbert, C.; Guardiola, A.; Shao, R.; Kawaguchi, Y.; Ito, A.; Nixon, A.; Yoshida, M.; Wang, X.-F.; Yao, T.-P. HDAC6 is a microtubule-associated deacetylase. Nature 2002,417,455-458.
89. Bali, P.; Pranpat, M.; Bradner, J.; Balasis, M.; Fiskus, W.; Guo, F.; Rocha, K.; Kumaraswamy, S.; Boyapalle, S.; Atadja, P. Inhibition of histone deacetylase 6 acetylates and disrupts the chaperone function of heat shock protein 90 A novel basis for antileukemia activity of histone deacetylase inhibitors. J. Biol. Chem. 2005,280,26729-26734.
90. Kim, M. S.; Blake, M.; Baek, J. H.; Kohlhagen, G.; Pommier, Y.; Carrier, F. Inhibition of histone deacetylase increases cytotoxicity to anticancer drugs targeting DNA. Cancer research 2003,63,7291-7300.
91. Dowdy, S. C.; Jiang, S.; Zhou, X. C.; Hou, X.; Jin, F.; Podratz, K. C.; Jiang, S.-W. Histone deacetylase inhibitors and paclitaxel cause synergistic effects on apoptosis and microtubule stabilization in papillary serous endometrial cancer cells. Molecular cancer therapeutics 2006,5,2767-2776.
92. Arnold, N. B.; Arkus, N.; Gunn, J.; Korc, M. The histone deacetylase'inhibitor suberoylanilide hydroxamic acid induces growth inhibition and enhances gemcitabine-induced cell death in pancreatic cancer. Clin. Cancer Res.2007,13, 18-26.
93. Jane, E. P.; Premkumar, D. R.; Addo-Yobo, S. O.; Pollack, I. F. Abrogation of mitogen-activated protein kinase and Akt signaling by vandetanib synergistically potentiates histone deacetylase inhibitor-induced apoptosis in human glioma cells. J. Pharmacol. Exp. Ther.2009,331,327-337.
94. Yu, C.; Friday, B. B.; Lai, J.-P.; McCollum, A.; Atadja, P.; Roberts, L. R.; Adjei, A. A. Abrogation of MAPK and Akt signaling by AEE788 synergistically potentiates histone deacetylase inhibitor-induced apoptosis through reactive oxygen species generation. Clin. Cancer Res.2007,13,1140-1148.
95. Rahmani, M.; Reese, E.; Dai, Y.; Bauer, C.; Payne, S. G.; Dent, P.; Spiegel, S.; Grant, S. Coadministration of histone deacetylase inhibitors and perifosine synergistically induces apoptosis in human leukemia cells through Akt and ERK1/2 inactivation and the generation of ceramide and reactive oxygen species. Cancer Research 2005,65,2422-2432.
96. Giommarelli, C.; Zuco, V.; Favini, E.; Pisano, C.; Dal Piaz, F.; De Tommasi, N.; Zunino, F. The enhancement of antiproliferative and proapoptotic activity of HDAC inhibitors by curcumin is mediated by Hsp90 inhibition. Cell. Mol. Life Sci.2010,67,995-1004.