垂体腺瘤细胞培养及替莫唑胺治疗难治性垂体腺瘤的实验研究
|
摘要
垂体腺瘤(pituitary adenoma)是最多发的颅内肿瘤之一,其解剖检出率为25%。该肿瘤的生物学性状及临床表现存在较大个体差异。部分垂体腺瘤生长缓慢,无明显临床症状,只在体检时被发现,无需特殊治疗。而另有部分垂体腺瘤,常规手术、放疗及垂体药物(例如,多巴胺受体激动剂及生长抑素类似物)均难以将其治愈,病变反复发作、持续进展,少部分出现肿瘤组织的远位转移,即垂体腺癌,其发病率为0.2%。在筛选难治性垂体腺瘤替代治疗措施的过程中,替莫唑胺(temozolomide, TMZ)已被部分临床试验报道疗效确切。但另有部分报道未发现TMZ对该类肿瘤发挥稳定疗效,其对垂体腺瘤抑制作用的分子机制仍不明确。本实验研究以垂体腺瘤原代细胞及细胞系为平台,探讨TMZ对垂体腺瘤的效用及相关分子生物学机制,并报道一例不典型垂体腺瘤的替莫唑胺临床治疗情况。
第一部分垂体腺瘤细胞的体外培养
目的：分析影响垂体腺瘤细胞体外生存的因素,探讨适于垂体腺瘤细胞维持生物学性状的体外培养方案,改良人垂体腺瘤细胞体外生存条件,为临床及基础实验研究提供可靠的体外实验平台。
方法：取无功能垂体腺瘤手术标本33例,行体外分离、接种及培养。并就细胞的体外生存时间行生存相关因素分析。肿瘤细胞接种于Laminin、Matrigel、PPL Collagen及普通培养板界面,观察各细胞培养界面对垂体肿瘤细胞活力的影响。
结果：Kaplan Meier生存分析发现细胞体外存活时间与患者年龄、性别、肿瘤类型、肿瘤是否复发、肿瘤侵袭与否、术前是否接受过放疗及Ki-67 LI水平等均没有明显相关(P>0.05)。二维及三维培养界面无功能垂体腺瘤原代细胞活力对比分析显示,Matrigel、Laminin、Collagen组细胞活力明显大于细胞培养板裸面培养的细胞(Matrige、Laminin组vs. NC, P<0.01; Collagen组vs. NC, P<0.001)。而Lysine组与对照组相比没有明显差异(P>0.05)。Matrigel及Laminin组细胞活力大于其它各培养界面的细胞(P<0.001, vs. Lysine; P<0.01 vs.Collagen)。collagen组细胞活力则高于Lysine组(P<0.05)。Matrigel与Laminin组细胞活力没有统计学差异(P>0.05)。因此,各细胞培养界面的无功能垂体腺瘤细胞活力大小排序为：Matrigel、Laminin组>Collagen组>Lysine及普通培养板裸面组。
结论：体外培养的无功能垂体腺瘤细胞生长缓慢。其体外生存时间与患者年龄、性别、肿瘤类型、肿瘤是否复发、肿瘤侵袭与否、术前是否接受过放疗及Ki-67 LI水平等均没有明显相关。Laminin及Matrigel培养界面可以较PPL及Collagen三维培养界面更好地提升垂体腺瘤细胞的活力,可为垂体腺瘤体外实验研究提供活力更接近在体环境的细胞平台。
第二部分替莫唑胺对促性腺激素垂体腺瘤细胞的效用及机制
目的：常规手术、化疗及放疗多难以治愈侵袭性垂体腺瘤,新的替代疗法亟待研发。临床已尝试将替莫唑胺扩大适应症用于治疗侵袭性垂体腺瘤,但临床疗效报道存在分歧。本实验首次研究替莫唑胺对促性腺激素腺瘤细胞活力及激素分泌的抑制效果及可能机制。
方法：梯度浓度的替莫唑胺(31.25-1000μM)或溶剂对照孵育aT3-1细胞0-72 h后,CCK-8法检测细胞活力,并依据细胞生长抑制曲线获得IC5o值。收集IC5o浓度替莫唑胺处理的细胞样本行流式细胞技术、TUNEL染色及投射电子显微镜检测,对细胞周期改变及凋亡程度进行统计学分析。使用Caspase-Glo(?)试剂盒检测肿瘤细胞caspase-3/7,-8及-9的活性改变。Western blotting法检测凋亡相关蛋白Bcl-2及PARP的表达情况。Centaur(?) XP免疫测定系统检测细胞培养基上清促性腺激素水平变化。
结果：替莫唑胺剂量及时间依赖性抑制aT3-1细胞活力(P<0.01 vs. control,250μM,24 h)并导致肿瘤细胞周期S期延长及G2/M期阻滞(P<0.05 vs. control,250μM,24 h)。替莫唑胺孵育24 h可明显诱发早期细胞凋亡(P<0.001 vs. control,250μM),透射电镜及TUNEL染色发现肿瘤细胞核团缩、染色质浓聚等细胞凋亡形态学改变。替莫唑胺(250,μM)孵育24 h将aT3-1细胞caspase-3/7的活性提升了6倍,caspase-9活性提升了7倍,caspase-8活性提升了3倍,且显著负调抗凋亡蛋白Bcl-2的表达(P< 0.001 vs. control)并促进PARP的蛋白裂解。细胞培养基上清的FSH及LH水平在替莫唑胺孵育后明显下降(P<0.01 vs. control,250μM,24h)。
结论：替莫唑胺稳定抑制促性腺激素腺瘤细胞活力并下调促性腺激素水平,诱导垂体肿瘤细胞周期阻滞,且通过调控死亡受体及线粒体凋亡信号通路促进肿瘤细胞凋亡。替莫唑胺可能成为侵袭性垂体腺瘤的可靠替代疗法。
第三部分替莫唑胺对人原代垂体腺瘤细胞的药效及其与肿瘤MGMT表达水平的相关性分析
目的：观察替莫唑胺对人原代垂体腺瘤细胞的药效,并检验MGMT表达水平对肿瘤TMZ敏感性指示作用的准确度。
方法：取垂体腺瘤手术标本26例,行体外分离、接种及培养。原代细胞平台上行TMZ药物敏感试验,计算每株细胞的TMZ IC50数值。免疫组化法检测细胞来源肿瘤的MGMT表达水平,并将其与细胞的TMZ IC50数值进行Spearman相关分析。
结果：TMZ处理的26例原代垂体腺瘤细胞中,24例(92.31%,2例无功能垂体腺瘤除外)表现TMZ剂量依赖性活力抑制；9例(34.620%,3例GH腺瘤,6例无功能垂体腺瘤)出现小于最大给药浓度的IC50值。细胞来源患者的垂体腺瘤组织MGMT免疫组织化学染色结果显示,9例(34.62%,4例GH腺瘤,1例泌乳素腺瘤,4例无功能垂体腺瘤)为低表达,MGMT表达比率小于10%；14例(53.85%,12例无功能垂体腺瘤,2例生长激素腺瘤)为中度表达,MGMT表达比率大于10%但小于50%；3例(11.54%,均为无功能垂体腺瘤)为高表达,MGMT表达比率大于50%。对26例垂体腺瘤TMZ IC50数据集及MGMT表达比率值的Spearman相关性分析结果显示,二者的相关系数为-0.094,P>0.05,即TMZ IC50及MGMT表达比率之间没有明显相关关系。
结论：TMZ能够对约30%-40%的垂体腺瘤发挥稳定抑瘤作用。TMZ对垂体腺瘤细胞的IC50及肿瘤MGMT表达比率之间不存在明显相关关系,提示MGMT不能精确地指示垂体腺瘤对TMZ的敏感性。TMZ的在体疗效仍有待临床研究进一步阐明。
第四部分替莫唑胺治疗难治性垂体腺瘤一例
目的：探讨难治性垂体腺瘤的有效替代治疗方法。
方法：采用手术、伽马刀及再次手术治疗一例难治性垂体腺瘤患者。根据其原代肿瘤细胞的TMZ药敏试验结果,选用TMZ治疗两个疗程,总结分析其疗效。
结果：由于肿瘤生长迅速,常规手术、放疗及药物治疗均难以控制难治性垂体腺瘤的生长及病情进展。肿瘤组织病理检测结果提示,Ki-67 LI约40%-50%,MGMT表达属低水平。TMZ对该患者原代肿瘤细胞的IC50小于最大给药浓度,提示肿瘤细胞对TMZ敏感。患者服用替莫唑胺两个疗程,肿瘤停止快速生长,MRI示肿瘤出现液化坏死。
结论：对于常规手术、放疗及药物治疗无效的难治性垂体腺瘤,替莫唑胺化疗可能是一种有效替代治疗方法。
Pituitary adenomas are one of the most common types of intracranial tumors, with autopsy studies demonstrating an incidence of 25%. The biology of pituitary adenomas can vary substantially. Some pituitary adenomas are slow growing, incidentally found, and require no treatment whatsoever. On the other extreme, some pituitary adenomas prove refractory to surgery, radiation, and pituitary-suppressive medications (for example, dopamine receptor agonists and somatostatin analogs) and continue to progress. Pituitary carcinomas occur in 0.2% of patients and may metastasize within the CNS. Temozolomide has proven effective in the treatment of patients with high-grade gliomas. Anecdotal case reports have suggested that temozolomide may have efficacy for some patients with aggressive pituitary adenomas, includ-ing pituitary carcinomas. Low MGMT expression has been linked to a favorable clinical response in patients with aggressive pituitary adenomas undergoing treatment with temozolomide. This study evaluates the potential factors that associate with the invitro survival of pituitary adenoma cells and the response of primary pituitary adenoma cell cultures, gonadotroph adenoma cell lines and a patient suffered from refractory pituitary adenoma to temozolomide.
Section One Primary Pituitary Adenoma Cell Culture Invitro
Objective:To analyze the impact factors for the in vitro survival of pituitary adenoma cells and select the cell culture regimen that maintain the biological properties of pituitary adenoma cells in vitro so as to improve the survival of human pituitary adenoma cells in vitro and guarantee the quality of the cell line that used in the clinical and experimental research.
Methods:33 cases of surgical specimens of non-functional pituitary adenoma were isolated inoculated and cultured in vitro. The survial analysis based on the lifetime of these primary cell lines and different separate criteria was performed to evaluate the relevance between them. Cells seeded on Laminin, Matrigel, PPL, Collagen and general culture plate interface were used to observe the disparity of the effect on cell viability.
Results:Kaplan Meier survival analysis showed that there was no significant correlation (P> 0.05) between the survival time of pituitary adenoma cells and the age, sex, tumor type, tumor recurrence, tumor invasion, preoperative radiation therapy or the level of Ki-67 LI. Cell viability analysis, based on non-functional pituitary adenoma cell culture on two-dimensional and three-dimensional interface, showed that the effect of Matrigel, Laminin, Collagen group on cell viability was significantly greater than the bare surface of cell culture plates (Matrigel, Laminin group vs. NC, P<0.01; Collagen group vs. NC, P<0.001). There was no significant difference (P>0.05) when Lysine compared with the control group. Cell viability of the cells cultured on Laminin and Matrigel was significantly higher than other cells cultured on other interfaces (P<0.001, vs. Lysine; P <0.01 vs.Collagen). Cell viability collagen group were higher than those Lysine group (P <0.05) while there was no significant difference between Matrigel and Laminin group (P>0.05). Therefore, the sequence of the effect of different cell culture interfaces on pituitary adenoma cell viability was Matrigel, Laminin group> Collagen group> Lysine and general culture plate bare surface group.
Conclusion:The in vitro cultured non-functional pituitary adenoma cells growed slowly. There was no significant correlation (P> 0.05) between the survival time of pituitary adenoma cells and the age, sex, tumor type, tumor recurrence, tumor invasion, preoperative radiation therapy or the level of Ki-67 LI. Laminin and Matrigel culture interface can be more powerful than Collagen and PPL to enhance the vitality of the pituitary adenoma cells, and may guarantee a qualified platform for in vitro research.
Second Two Effect of Temozolomide on Cell Viability in Gonadotroph Adenoma Cell Lines
Background:Invasive pituitary adenomas are usually refractory to routine neurosurgery, radiosurgery or medications, and alternative therapies are expected. The effects of temozolomide (TMZ) on the inhibiton of gonadotroph adenoma cell viability and hormone secretion were evaluated.
Methods:Cell viability and IC50 values were evaluated afterαT3-1 cells were treated with TMZ (31.25-1000μM) or vehicle for 0-72 h. Cell cycle changes and extent of apoptosis were detected using flow cytometry, TUNEL and TEM. Molecular mechanism of TMZ was investigated by Caspase-Glo(?) assay and immunoblotting. Gonadotropin secretion were assessed by immunoassay system.
Results:TMZ dose-and time-dependently suppressed cell proliferation (P<0.01 vs. control,250μM,24 h) and induced S-phase accumulation and G2/M-phase arrest (P< 0.05 vs. control,250μM,24 h). Early apoptotic cells increased following a 24-h TMZ incubation (P<0.001 vs. control,250μM), consistent with TEM and TUNEL detection that exhibited morphological features of apoptosis. TMZ (250μM) increased the level of caspase-3/-7 6-fold, caspase-9 7-fold, and caspase-8 3-fold after a 24-h incubation, while attenuated Bcl-2 expression (P<0.001 vs. control) and raised the proteolysis of PARP. Both FSH and LH level were significantly decreased by TMZ (P<0.01 vs. control,250μM,24 h).
Conclusions:TMZ inhibited cell proliferation and hormone secretion, and induced cell cycle arrest and apoptotic cell death in gonadotroph adenoma cells via both death receptor and mitochondrial pathway, suggesting that it might represent a useful medical management of invasive gonadotroph adenomas.
Section Three Effect of Temozolomide on Human Pituitary Adenoma Cells and Its Relationship with the Expression of MGMT
Objective:To observe the effect of temozolomide on human pituitary adenoma cells and test the indicative efficacy of MGMT expression on the sensitivity of TMZ for pituitary tumors.
Methods:Surgical specimens of 26 patients with pituitary adenoma underwent isolation, inoculation and cell culture. Drug sensitivity test for TMZ on primary pituitary adenoma cells was performed, and the IC50 values was calculated for each cell line. Immunohistochemical detection for MGMT expression of these tumors was performed to correlate with those TMZ IC50 values by Spearman correlation analysis.
Results:Among 26 TMZ-treated primary pituitary adenoma cells,24 cases (92.31%, except for 2 cases of nonfunctioning pituitary adenomas cells) demonstrated dose-dependent inhibitory activity,9 cases (34.62%,3 cases of GH adenomas,6 cases of nonfunctioning pituitary adenomas) demonstrated minor IC50 values that less than the maximum dose of TMZ. MGMT immunohistochemistry results showed that 9 cases (34.62%,4 cases of GH adenomas,1 case of prolactinomas,4 cases of nonfunctioning pituitary adenomas) showed low MGMT expression, less than 10%; 14 cases (53.85%, 12 cases of nonfunctioning pituitary adenomas,2 cases of GH adenomas) showed moderate MGMT expression, greater than 10% but less than 50%; 3 cases (11.54%, non-functional pituitary adenomas) showed high level MGMT expression, MGMT expression ratio greater than 50%. Spearman correlation analysis for TMZ IC50 data and the value of MGMT expression ratio showed that the correlation coefficient was-0.094, P>0.05, namely the TMZ IC50 value and the rate of MGMT expression were not significantly correlated.
Conclusion:TMZ was able to steadily inhibit about 30%-40% of the primary pituitary adenoma cell lines. There was no significant correlation between TMZ IC50 value of pituitary adenoma cells and tumor MGMT expression ratio, suggesting that MGMT expression can not accurately indicate the sensitivity of pituitary adenoma to TMZ. Further research was needed to analyze the mechanism of TMZ tolerance.
Section Four Effect of Temozolomide on a Refractory Pituitary Adenoma
Objective:To explore the effective treatment for refractory pituitary adenomas.
Method:Based on MGMT expression and sensitive test of the primary pituitary adenoma cells to Temozolomide, we treated a refractory pituitary adenoma patient.
Result:MGMT expression in this case was at low level, and primary pituitary adenoma cells were sensitive to temozolomide in vitro. The tumor volume decreased after the first cycle Temozolomide therapy.
Conclusion:Temozolomide may be a salvage therapy for those refractory pituitary adenomas with low MGMT expression.
第一部分垂体腺瘤细胞的体外培养
目的：分析影响垂体腺瘤细胞体外生存的因素,探讨适于垂体腺瘤细胞维持生物学性状的体外培养方案,改良人垂体腺瘤细胞体外生存条件,为临床及基础实验研究提供可靠的体外实验平台。
方法：取无功能垂体腺瘤手术标本33例,行体外分离、接种及培养。并就细胞的体外生存时间行生存相关因素分析。肿瘤细胞接种于Laminin、Matrigel、PPL Collagen及普通培养板界面,观察各细胞培养界面对垂体肿瘤细胞活力的影响。
结果：Kaplan Meier生存分析发现细胞体外存活时间与患者年龄、性别、肿瘤类型、肿瘤是否复发、肿瘤侵袭与否、术前是否接受过放疗及Ki-67 LI水平等均没有明显相关(P>0.05)。二维及三维培养界面无功能垂体腺瘤原代细胞活力对比分析显示,Matrigel、Laminin、Collagen组细胞活力明显大于细胞培养板裸面培养的细胞(Matrige、Laminin组vs. NC, P<0.01; Collagen组vs. NC, P<0.001)。而Lysine组与对照组相比没有明显差异(P>0.05)。Matrigel及Laminin组细胞活力大于其它各培养界面的细胞(P<0.001, vs. Lysine; P<0.01 vs.Collagen)。collagen组细胞活力则高于Lysine组(P<0.05)。Matrigel与Laminin组细胞活力没有统计学差异(P>0.05)。因此,各细胞培养界面的无功能垂体腺瘤细胞活力大小排序为：Matrigel、Laminin组>Collagen组>Lysine及普通培养板裸面组。
结论：体外培养的无功能垂体腺瘤细胞生长缓慢。其体外生存时间与患者年龄、性别、肿瘤类型、肿瘤是否复发、肿瘤侵袭与否、术前是否接受过放疗及Ki-67 LI水平等均没有明显相关。Laminin及Matrigel培养界面可以较PPL及Collagen三维培养界面更好地提升垂体腺瘤细胞的活力,可为垂体腺瘤体外实验研究提供活力更接近在体环境的细胞平台。
第二部分替莫唑胺对促性腺激素垂体腺瘤细胞的效用及机制
目的：常规手术、化疗及放疗多难以治愈侵袭性垂体腺瘤,新的替代疗法亟待研发。临床已尝试将替莫唑胺扩大适应症用于治疗侵袭性垂体腺瘤,但临床疗效报道存在分歧。本实验首次研究替莫唑胺对促性腺激素腺瘤细胞活力及激素分泌的抑制效果及可能机制。
方法：梯度浓度的替莫唑胺(31.25-1000μM)或溶剂对照孵育aT3-1细胞0-72 h后,CCK-8法检测细胞活力,并依据细胞生长抑制曲线获得IC5o值。收集IC5o浓度替莫唑胺处理的细胞样本行流式细胞技术、TUNEL染色及投射电子显微镜检测,对细胞周期改变及凋亡程度进行统计学分析。使用Caspase-Glo(?)试剂盒检测肿瘤细胞caspase-3/7,-8及-9的活性改变。Western blotting法检测凋亡相关蛋白Bcl-2及PARP的表达情况。Centaur(?) XP免疫测定系统检测细胞培养基上清促性腺激素水平变化。
结果：替莫唑胺剂量及时间依赖性抑制aT3-1细胞活力(P<0.01 vs. control,250μM,24 h)并导致肿瘤细胞周期S期延长及G2/M期阻滞(P<0.05 vs. control,250μM,24 h)。替莫唑胺孵育24 h可明显诱发早期细胞凋亡(P<0.001 vs. control,250μM),透射电镜及TUNEL染色发现肿瘤细胞核团缩、染色质浓聚等细胞凋亡形态学改变。替莫唑胺(250,μM)孵育24 h将aT3-1细胞caspase-3/7的活性提升了6倍,caspase-9活性提升了7倍,caspase-8活性提升了3倍,且显著负调抗凋亡蛋白Bcl-2的表达(P< 0.001 vs. control)并促进PARP的蛋白裂解。细胞培养基上清的FSH及LH水平在替莫唑胺孵育后明显下降(P<0.01 vs. control,250μM,24h)。
结论：替莫唑胺稳定抑制促性腺激素腺瘤细胞活力并下调促性腺激素水平,诱导垂体肿瘤细胞周期阻滞,且通过调控死亡受体及线粒体凋亡信号通路促进肿瘤细胞凋亡。替莫唑胺可能成为侵袭性垂体腺瘤的可靠替代疗法。
第三部分替莫唑胺对人原代垂体腺瘤细胞的药效及其与肿瘤MGMT表达水平的相关性分析
目的：观察替莫唑胺对人原代垂体腺瘤细胞的药效,并检验MGMT表达水平对肿瘤TMZ敏感性指示作用的准确度。
方法：取垂体腺瘤手术标本26例,行体外分离、接种及培养。原代细胞平台上行TMZ药物敏感试验,计算每株细胞的TMZ IC50数值。免疫组化法检测细胞来源肿瘤的MGMT表达水平,并将其与细胞的TMZ IC50数值进行Spearman相关分析。
结果：TMZ处理的26例原代垂体腺瘤细胞中,24例(92.31%,2例无功能垂体腺瘤除外)表现TMZ剂量依赖性活力抑制；9例(34.620%,3例GH腺瘤,6例无功能垂体腺瘤)出现小于最大给药浓度的IC50值。细胞来源患者的垂体腺瘤组织MGMT免疫组织化学染色结果显示,9例(34.62%,4例GH腺瘤,1例泌乳素腺瘤,4例无功能垂体腺瘤)为低表达,MGMT表达比率小于10%；14例(53.85%,12例无功能垂体腺瘤,2例生长激素腺瘤)为中度表达,MGMT表达比率大于10%但小于50%；3例(11.54%,均为无功能垂体腺瘤)为高表达,MGMT表达比率大于50%。对26例垂体腺瘤TMZ IC50数据集及MGMT表达比率值的Spearman相关性分析结果显示,二者的相关系数为-0.094,P>0.05,即TMZ IC50及MGMT表达比率之间没有明显相关关系。
结论：TMZ能够对约30%-40%的垂体腺瘤发挥稳定抑瘤作用。TMZ对垂体腺瘤细胞的IC50及肿瘤MGMT表达比率之间不存在明显相关关系,提示MGMT不能精确地指示垂体腺瘤对TMZ的敏感性。TMZ的在体疗效仍有待临床研究进一步阐明。
第四部分替莫唑胺治疗难治性垂体腺瘤一例
目的：探讨难治性垂体腺瘤的有效替代治疗方法。
方法：采用手术、伽马刀及再次手术治疗一例难治性垂体腺瘤患者。根据其原代肿瘤细胞的TMZ药敏试验结果,选用TMZ治疗两个疗程,总结分析其疗效。
结果：由于肿瘤生长迅速,常规手术、放疗及药物治疗均难以控制难治性垂体腺瘤的生长及病情进展。肿瘤组织病理检测结果提示,Ki-67 LI约40%-50%,MGMT表达属低水平。TMZ对该患者原代肿瘤细胞的IC50小于最大给药浓度,提示肿瘤细胞对TMZ敏感。患者服用替莫唑胺两个疗程,肿瘤停止快速生长,MRI示肿瘤出现液化坏死。
结论：对于常规手术、放疗及药物治疗无效的难治性垂体腺瘤,替莫唑胺化疗可能是一种有效替代治疗方法。
Pituitary adenomas are one of the most common types of intracranial tumors, with autopsy studies demonstrating an incidence of 25%. The biology of pituitary adenomas can vary substantially. Some pituitary adenomas are slow growing, incidentally found, and require no treatment whatsoever. On the other extreme, some pituitary adenomas prove refractory to surgery, radiation, and pituitary-suppressive medications (for example, dopamine receptor agonists and somatostatin analogs) and continue to progress. Pituitary carcinomas occur in 0.2% of patients and may metastasize within the CNS. Temozolomide has proven effective in the treatment of patients with high-grade gliomas. Anecdotal case reports have suggested that temozolomide may have efficacy for some patients with aggressive pituitary adenomas, includ-ing pituitary carcinomas. Low MGMT expression has been linked to a favorable clinical response in patients with aggressive pituitary adenomas undergoing treatment with temozolomide. This study evaluates the potential factors that associate with the invitro survival of pituitary adenoma cells and the response of primary pituitary adenoma cell cultures, gonadotroph adenoma cell lines and a patient suffered from refractory pituitary adenoma to temozolomide.
Section One Primary Pituitary Adenoma Cell Culture Invitro
Objective:To analyze the impact factors for the in vitro survival of pituitary adenoma cells and select the cell culture regimen that maintain the biological properties of pituitary adenoma cells in vitro so as to improve the survival of human pituitary adenoma cells in vitro and guarantee the quality of the cell line that used in the clinical and experimental research.
Methods:33 cases of surgical specimens of non-functional pituitary adenoma were isolated inoculated and cultured in vitro. The survial analysis based on the lifetime of these primary cell lines and different separate criteria was performed to evaluate the relevance between them. Cells seeded on Laminin, Matrigel, PPL, Collagen and general culture plate interface were used to observe the disparity of the effect on cell viability.
Results:Kaplan Meier survival analysis showed that there was no significant correlation (P> 0.05) between the survival time of pituitary adenoma cells and the age, sex, tumor type, tumor recurrence, tumor invasion, preoperative radiation therapy or the level of Ki-67 LI. Cell viability analysis, based on non-functional pituitary adenoma cell culture on two-dimensional and three-dimensional interface, showed that the effect of Matrigel, Laminin, Collagen group on cell viability was significantly greater than the bare surface of cell culture plates (Matrigel, Laminin group vs. NC, P<0.01; Collagen group vs. NC, P<0.001). There was no significant difference (P>0.05) when Lysine compared with the control group. Cell viability of the cells cultured on Laminin and Matrigel was significantly higher than other cells cultured on other interfaces (P<0.001, vs. Lysine; P <0.01 vs.Collagen). Cell viability collagen group were higher than those Lysine group (P <0.05) while there was no significant difference between Matrigel and Laminin group (P>0.05). Therefore, the sequence of the effect of different cell culture interfaces on pituitary adenoma cell viability was Matrigel, Laminin group> Collagen group> Lysine and general culture plate bare surface group.
Conclusion:The in vitro cultured non-functional pituitary adenoma cells growed slowly. There was no significant correlation (P> 0.05) between the survival time of pituitary adenoma cells and the age, sex, tumor type, tumor recurrence, tumor invasion, preoperative radiation therapy or the level of Ki-67 LI. Laminin and Matrigel culture interface can be more powerful than Collagen and PPL to enhance the vitality of the pituitary adenoma cells, and may guarantee a qualified platform for in vitro research.
Second Two Effect of Temozolomide on Cell Viability in Gonadotroph Adenoma Cell Lines
Background:Invasive pituitary adenomas are usually refractory to routine neurosurgery, radiosurgery or medications, and alternative therapies are expected. The effects of temozolomide (TMZ) on the inhibiton of gonadotroph adenoma cell viability and hormone secretion were evaluated.
Methods:Cell viability and IC50 values were evaluated afterαT3-1 cells were treated with TMZ (31.25-1000μM) or vehicle for 0-72 h. Cell cycle changes and extent of apoptosis were detected using flow cytometry, TUNEL and TEM. Molecular mechanism of TMZ was investigated by Caspase-Glo(?) assay and immunoblotting. Gonadotropin secretion were assessed by immunoassay system.
Results:TMZ dose-and time-dependently suppressed cell proliferation (P<0.01 vs. control,250μM,24 h) and induced S-phase accumulation and G2/M-phase arrest (P< 0.05 vs. control,250μM,24 h). Early apoptotic cells increased following a 24-h TMZ incubation (P<0.001 vs. control,250μM), consistent with TEM and TUNEL detection that exhibited morphological features of apoptosis. TMZ (250μM) increased the level of caspase-3/-7 6-fold, caspase-9 7-fold, and caspase-8 3-fold after a 24-h incubation, while attenuated Bcl-2 expression (P<0.001 vs. control) and raised the proteolysis of PARP. Both FSH and LH level were significantly decreased by TMZ (P<0.01 vs. control,250μM,24 h).
Conclusions:TMZ inhibited cell proliferation and hormone secretion, and induced cell cycle arrest and apoptotic cell death in gonadotroph adenoma cells via both death receptor and mitochondrial pathway, suggesting that it might represent a useful medical management of invasive gonadotroph adenomas.
Section Three Effect of Temozolomide on Human Pituitary Adenoma Cells and Its Relationship with the Expression of MGMT
Objective:To observe the effect of temozolomide on human pituitary adenoma cells and test the indicative efficacy of MGMT expression on the sensitivity of TMZ for pituitary tumors.
Methods:Surgical specimens of 26 patients with pituitary adenoma underwent isolation, inoculation and cell culture. Drug sensitivity test for TMZ on primary pituitary adenoma cells was performed, and the IC50 values was calculated for each cell line. Immunohistochemical detection for MGMT expression of these tumors was performed to correlate with those TMZ IC50 values by Spearman correlation analysis.
Results:Among 26 TMZ-treated primary pituitary adenoma cells,24 cases (92.31%, except for 2 cases of nonfunctioning pituitary adenomas cells) demonstrated dose-dependent inhibitory activity,9 cases (34.62%,3 cases of GH adenomas,6 cases of nonfunctioning pituitary adenomas) demonstrated minor IC50 values that less than the maximum dose of TMZ. MGMT immunohistochemistry results showed that 9 cases (34.62%,4 cases of GH adenomas,1 case of prolactinomas,4 cases of nonfunctioning pituitary adenomas) showed low MGMT expression, less than 10%; 14 cases (53.85%, 12 cases of nonfunctioning pituitary adenomas,2 cases of GH adenomas) showed moderate MGMT expression, greater than 10% but less than 50%; 3 cases (11.54%, non-functional pituitary adenomas) showed high level MGMT expression, MGMT expression ratio greater than 50%. Spearman correlation analysis for TMZ IC50 data and the value of MGMT expression ratio showed that the correlation coefficient was-0.094, P>0.05, namely the TMZ IC50 value and the rate of MGMT expression were not significantly correlated.
Conclusion:TMZ was able to steadily inhibit about 30%-40% of the primary pituitary adenoma cell lines. There was no significant correlation between TMZ IC50 value of pituitary adenoma cells and tumor MGMT expression ratio, suggesting that MGMT expression can not accurately indicate the sensitivity of pituitary adenoma to TMZ. Further research was needed to analyze the mechanism of TMZ tolerance.
Section Four Effect of Temozolomide on a Refractory Pituitary Adenoma
Objective:To explore the effective treatment for refractory pituitary adenomas.
Method:Based on MGMT expression and sensitive test of the primary pituitary adenoma cells to Temozolomide, we treated a refractory pituitary adenoma patient.
Result:MGMT expression in this case was at low level, and primary pituitary adenoma cells were sensitive to temozolomide in vitro. The tumor volume decreased after the first cycle Temozolomide therapy.
Conclusion:Temozolomide may be a salvage therapy for those refractory pituitary adenomas with low MGMT expression.
引文
[1]Thompson,K.W.,V incent,M.M.,Jensen,E Ce tal.Production of hormones by human anterior pituitary cells in serial culture. Porc Soc Exp Biol Med.1959, 102:403-408
[2]Peillon F, Gourmelen M, Donnadieu M, Brandi A, Sevaux D. Organ culture of human somatotrophic pituitary adenomas:ultrastructure and growth hormone production. Acta Endocrinol (Copenh).1975 79(2):217-29.
[3]Fuller PJ, Lim AT,Barlow JW:White EL, Khalid BA, Copolov DL, Lolait S,Funder JW,Stockigt JR(1 984). A pituitary tumor producing high molecular weight adrenoconicotropin-related peptides:clinical and cell culture studies. J Clin Endocrinol Metab.58(1):1 34-42.
[4]Missale. C, Boroni. F,Losa. M, Giovalli. M, Zanellato. A, Dal. Tos. R, BalsariA, Spano. P(1993). Nerve growth factor suppresses the transforming phenotype of human prolactinomas. Proc Natl Acad Sci USA.90(17):7961-5.
[5]Long Jin, Elzbieta Kulig, Xiang Qian et al. A Human Pituitary Adenoma Cell Line Proliferates and Maintains Some Differentiated Functions Following Expression of SV40 Large T-Antigen. Endocrine Pathology,1998,9(2):169-184.
[6]Fujimoto N, Maruyama S, Ito A. Establishment of an estrogen responsive rat pituitary cell sub-line MtT/E-2. Endocr J,1999,46(3):389-396.
[7]Jones TH, Justice SK and Price A. Suppression of Tyrosine Kinase Activity Inhibits [3H]Thymidine Uptake in Cultured Human Pituitary Tumor Cells. The Journal of Clinical Endocrinology&Metabolism,1997,82(7):2143-2147.
[8]Florio T, Thellung S, Corsaro A, et al. Characterization of the intracellular mechanisms mediating somatostatin and lanreotide inhibition of DNA synthesis and growth hormone release from dispersed human GH—secreting pituitary adenoma cells in vitro. Clin Endocrinol(Oxf),2003,59(1):115-128.
[9]Kabuto M, Kubota T, Kobayashi H, Nakagawa T. Modified procedure of monolayer culture of human pituitary adenoma cells on microporous membrane coated with extracellular matrix. Neurol Res.1993 Oct;15(5):304-9.
[10]Asa SL, Gerrie BM, Singer W, Horvath E, Kovacs K, Smyth HS.Gonadotropin secretion in vitro by human pituitary null cell adenomas and oncocytomas.J Clin Endocrinol Metab.1986,62(5):1011-9.
[11]Dumesic DA, Goldsmith PC, Jaffe RB. Estradiol sensitization of cultured human fetal pituitary cells to gonadotropin-releasing hormone. J Clin Endocrinol Metab.1987, 65(6):1147-53.
[12]Jaquet P, Hassoun J, Delori P, Gunz G, Grisoli F, Weintraub BD.A human pituitary adenoma secreting thyrotropin and prolactin:immunohistochemical, biochemical, and cell culture studies. J Clin Endocrinol Metab.1984 Nov;59(5):817-24.
[13]Giannelli, G., Antonaci, S., Biological and clinical relevance of Laminin-5 in cancer. Clin. Exp. Metastasis 2000.18,439-443.
[14]Kitayama, J., Nagawa, H., Tsuno, N., Osada, T., Hatano, K., Sunami,E., Saito, H., Muto, T., Laminin mediates tethering and spreading of colon cancer cells in physiological shear flow. Br. J.Cancer 1999.80,1927-1934.
[15]De lorio, P., Midulla, C., Pisani, T., Valli, C., Grillo, L., Di Cocco, B.,Nofroni, I., Vecchione, A.. Implication of laminin and collagen type IV expression in the progression of breast carcinoma. Anticancer Res.2001,21,1395-1399.
[16]Mettouchi, A., Klein, S., Guo, W., Lopez-Lago, M., Lemichez, E.,Westwick, J.K., Giancotti, F.G.. Integrin-specific activation of rac controls progression through the G(1) phase of the cell cycle.Mol. Cell,2001,8,115-127.
[17]Yoshida, Y., Hosokawa, K., Dantes, A., Kotsuji, F., Kleinman, H.K.,Amsterdam, A. Role of laminin in ovarian cancer tumor growth and metastasis via regulation of Mdm2 and Bcl-2 expression. Int. J. Oncol.2001,18,913-921.
[18]Lekmine, F., Lausson, S., Pidoux, E., Segond, N., Roos, B., Treilhou-Lahille, F., Jeanne, A.. Influence of laminin substratum on cell proliferation and CALC I gene expression in medullary thyroid carcinoma C cell lines. Mol. Cell. Endocrinol.1999, 157,181-189.
[19]Tougard, C., Louvard, D., Picart, R., Tixier-Vidal, A..Immunocytochemical localization of laminin in rat anterior pituitary cells in vivo and in vitro. In Vitro Cell Dev. Biol.1985,21,57-61.
[20]Vila-Porcile, E., Picart, R., Tixier-Vidal, A., Tougard, C.. Cellular and subcellular distribution of laminin in adult rat anterior pituitary. J. Histochem. Cytochem.1987,35, 287-299.
[21]de Carvalho, D.F., Silva, K.L., de Oliveria, D.A., Villa-Verde, D.M.,Coelho, H.S., Silva, L.C., Nasciutti, L.E.. Characterization and distribution of extracellular matrix components and receptors in GH3B6 prolactin cells. Biol. Cell,2000,92,351-362.
[22]Horacek, M.J., Thompson, J.C., Dada, M.O., Terracio, L.. The extracellular matrix components laminin, fibronectin, and collagen IV are present among the epithelial cells forming Rathke's pouch. Acta Anat. (Basel),1993,147,69-74.
[23]Denduchis, B., Rettori, V., McCann, S.M.. Role of laminin on prolactin and gonadotrophin release from anterior pituitaries of male rats. Life Sci.1994,55, 1757-1765.
[1]Selman WR, Laws ER, Jr., Scheithauer BW, Carpenter SM. The occurrence of dural invasion in pituitary adenomas. J Neurosurg.1986; 64:402-407.
[2]Asa SL, Ezzat S. The pathogenesis of pituitary tumours. Nat Rev Cancer.2002; 2:836-849.
[3]Korbonits M, Carlsen E. Recent clinical and pathophysiological advances in non-functioning pituitary adenomas. Horm Res.2009; 71 Suppl 2:123-130.
[4]Ho DM, Hsu CY, Ting LT, Chiang H. The clinicopathological characteristics of gonadotroph cell adenoma:a study of 118 cases. Hum Pathol.1997;28:905-911.
[5]Snyder PJ. Gonadotroph cell adenomas of the pituitary. Endocr Rev. 1985;6:552-563.
[6]Delellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and genetics of tumours of endocrine organs. Lyons:World Health Organization, IARC Press.2004; 270-311.
[7]Chanson P:Gonadotroph pituitary adenomas. Ann Endocrinol (Paris). 2000;61:258-268.
[8]Bei R, Marzocchella L, Turriziani M. The use of temozolomide for the treatment of malignant tumors:clinical evidence and molecular mechanisms of action. Recent Pat Anticancer Drug Discov.2010;5:172-187.
[9]Kulke MH, Chan JA, Meyerhardt JA, et al. A prospective phase Ⅱ study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol.2010 [Epub ahead of print].
[10]Syro LV, Ortiz LD, Scheithauer BW, et al. Treatment of pituitary neoplasms with temozolomide:A review. Cancer.2010; 117:454-462.
[11]Bush ZM, Longtine JA, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab.2010; 95:E280-290.
[12]Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience. J Clin Endocrinol Metab.2010; 95:4592-4599.
[13]Mohammed S, Kovacs K, Mason W, Smyth H, Cusimano MD. Use of temozolomide in aggressive pituitary tumors:case report. Neurosurgery.2009; 64:E773-774; discussion E774.
[14]Lim S, Shahinian H, Maya MM, Yong W, Heaney AP. Temozolomide:a novel treatment for pituitary carcinoma. Lancet Oncol.2006; 7:518-520.
[15]Fadul CE, Kominsky AL, Meyer LP, et al. Long-term response of pituitary carcinoma to temozolomide. Report of two cases. J Neurosurg.2006; 105:621-626.
[16]Syro LV, Scheithauer BW, Ortiz LD, et al. Effect of temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma. Hormones (Athens). 2009;8:303-306.
[17]Sheehan J, Rainey J, Nguyen J, Grimsdale R, Han S. Temozolomide-induced inhibition of pituitary adenoma cells. J Neurosurg.2010 [Epub ahead of print].
[18]Morin E, Berthelet F, Weisnagel J, Bidlingmaier M, Serri O. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly. Pituitary.2010 [Epub ahead of print].
[19]Windle JJ, Weiner RI, Mellon PL. Cell lines of the pituitary gonadotrope lineage derived by targeted oncogenesis in transgenic mice. Mol Endocrinol.1990;4:597-603.
[20]Kaina B, Fritz G, Mitra S, Coquerelle T. Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells:the role of MGMT in protection against the genotoxic effects of alkylating agents. Carcinogenesis.1991; 12:1857-67.
[21]Villano JL, Seery TE, Bressler LR. Temozolomide in malignant gliomas:current use and future targets. Cancer Chemother Pharmacol.2009; 64:647-655.
[22]Pepponi R, Marra G, Fuggetta MP, et al. The effect of O6-alkylguanine-DNA alkyltransferase and mismatch repair activities on the sensitivity of human melanoma cells to temozolomide, 1,3-bis(2-chloroethyl)1-nitrosourea, and cisplatin. J Pharmacol Exp Ther.2003;304:661-668.
[23]D'Atri S, Tentori L, Lacal PM, et al. Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol Pharmacol.1998;54:334-341.
[24]Tisdale MJ. Antitumour imidazotetrazines-XI:Effect of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one [CCRG 81045; M and B 39831 NSC 362856] on poly(ADP-ribose) metabolism. Br J Cancer.1985; 52:789-792.
[25]Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G, Murcia JM. Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. J Biol Chem.1998;273:33533-33539.
[26]Ochs K, Kaina B. Apoptosis induced by DNA damage 06-methylguanine is Bcl-2 and caspase-9/3 regulated and Fas/caspase-8 independent. Cancer Res.2000; 60:5815-5824.
[27]Roos WP, Batista LF, Naumann SC, et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene. 2007;26:186-197.
[28]Djerassi A, Coutifaris C, West VA, et al. Gonadotroph adenoma in a premenopausal woman secreting follicle-stimulating hormone and causing ovarian hyperstimulation. J Clin Endocrinol Metab.1995;80:591-594.
[29]Catargi B, Felicie-Dellan E, Tabarin A. Comment on gonadotroph adenoma causing ovarian hyperstimulation. J Clin Endocrinol Me tab.1999; 84:3404.
[30]Murata Y, Ando H, Nagasaka T, et al. Successful pregnancy after bromocriptine therapy in an anovulatory woman complicated with ovarian hyperstimulation caused by follicle-stimulating hormone-producing plurihormonal pituitary microadenoma. J Clin Endocrinol Metab.2003; 88:1988-1993.
[31]Murakami T, Higashitsuji H, Yoshinaga K, Terada Y, Ito K, Ikeda H. Management of ovarian hyperstimulation due to follicle-stimulating hormone-secreting gonadotroph adenoma. Bjog.2004;111:1297-1300.
1. Villano J L, Seery T E, Bressler L R. Temozolomide in malignant gliomas:current use and future targets [J]. Cancer Chemother Pharmacol,2009,64:647-55
2. Bei R, Marzocchella L, Turriziani M. The use of temozolomide for the treatment of malignant tumors:clinical evidence and molecular mechanisms of action[J]. Recent Pat Anticancer Drug Discov,2010,5(3):172-187.
3. Syro LV, Scheithauer BW, Ortiz LD, et al. Effect of Temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma[J]. Hormones (Athens),2009, 8(4):303-306
4. Hagen C, Schroeder HD, Hansen S, et al. Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy[J]. Eur J Endocrinol,2009,161 631-637
5. Losa M, Mazza E, Terreni MR, et al. Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas:experience in six cases[J]. Eur J Endocrinol,2010,163(6):843-51.
6. Mohammed S, Kovacs K, Mason W, et al. Use of temozolomide in aggressive pituitary tumors:case report[J]. Neurosurgery,2009,64:E773-E774.
7. Dillard T H, Gultekin S H, Delashaw J J, et al. Temozolomide for corticotroph pituitary adenomas refractory to standard therapy [J]. Pituitary,2011,14(1):80-91.
8. Morin E, Berthelet F, Weisnagel J, et al. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly[J].. Pituitary,2010, [Epub ahead of print]
9. Syro L V, Ortiz L D, Scheithauer B W, et al. Treatment of Pituitary Neoplasms With Temozolomide [J]. Cancer,2010;1-9.
10. Kovacs K, Scheithauer BW, Lombardero M, et al. MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy [J].. Acta Neuropathol,2008 Feb,115(2):261-2.
11. McCormack A I, McDonald K L, Gill A J, et al. Low O6- methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours[J]. Clin Endocrinol (Oxf),2009 Aug,71(2):226-33.
12. Bush Z M, Longtine J A, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression[J]. J Clin Endocrinol Metab.2010,95(11):E280-E290.
13. Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience[J]. J Clin Endocrinol Metab,2010,95(10):4592-4599.
14. Mrugala MM, Chamberlain MC. Mechanisms of disease:temozolomide and glioblastoma—look to the future [J].. Nat Clin Pract Oncol,2008,5:476-486.
15. Murakami M, Mizutani A, Asano S, et al. A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma[J]. Neurosurgery,2011.
16. Thearle M S, Freda P U, Bruce J N, et al. Temozolomide (Temodar R) and capecitabine (XelodaR)treatment of an aggressive corticotroph pituitary tumor[J].. Pituitary,2009, [Epub ahead of print]
17. Neff LM, Weil M, Cole A, et al. Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists[J]. Pituitary,2007,10:81-86
18. Bode H, Seiz M, Lammert A, et al. SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases[J]. Exp Clin Endocrinol Diabetes,2010,118(10):760-763.
19. Quinn JA, Jiang SX, Reardon DA, et al. Phase Ⅱ trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol[J].2009,27:1262-1267.
20. Prasad G, Sottero T, Yang X, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide[J]. Neuro Oncol,2011,13(4):384-392.
21. Plummer R, Jones C, Middleton M, et al. Phase Ⅰ study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors[J]. Clin Cancer Res,2008,14(23):7917-7923.
22. Chaponis D, Barnes J W, Dellagatta J L, et al. Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas[J]. J Neurooncol,2011.
23. Ulasov I V, Nandi S, Dey M, et al. Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy[J]. Mol Med,2011,17(1-2):103-112.
24. Iyer R, Evans A E, Qi X, et al. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma[J]. Clin Cancer Res,2010,16(5):1478-1485.
25. Torres S, Lorente M, Rodriguez-Fornes F, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma[J]. Mol Cancer Ther,2011,10(1):90-103.
26. Gorshtein A, Rubinfeld H, Kendler E, et al. Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro[J]. Endocr Relat Cancer,2009,16:1017-1027
27. Yao C, Evans C O, Stevens V L, et al. Folate receptor alpha regulates cell proliferation in mouse gonadotroph alphaT3-1 cells [J]. Exp Cell Res, 2009,315(18):3125-3132.
1 Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab.2008,4:560-8.
2 Syro L V, Ortiz L D, Scheithauer B W, et al. Treatment of Pituitary Neoplasms With Temozolomide. Cancer.2010,1-9
3 Fadul CE, Kominsky AL, Meyer LP, et al. Pituitary carcinomas respond to temozolomide [abstract]. Neuro-Oncol.2004,6:374. Abstract TA-18
4 McCormack A I, McDonald K L, Gill A J, et al. Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol (Oxf).2009; Aug; 71(2):226-33.
5 Kovacs K, Scheithauer BW, Lombardero M, et al. MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy. Acta Neuropathol.2008,115(2):261-2
6 Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience. J Clin Endocrinol Metab.2010 Oct;95(10):4592-9.
7 Bush ZM, Longtine JA, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression.J Clin Endocrinol Metab.2010,95(11):E280-90
8 Morin E, Berthelet F, Weisnagel J, et al. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly. Pituitary.2010, [Epub ahead of print]
1 Farrel WE, Clayton RN:Molecular pathogenesis of pituitary tumors. Front Neuroendocrinol.2000; 21:174-198.
2 Asa SL, Ezzat S:The pathogenesis of pituitarytumours. Nat Rev Cancer 2002; 2: 836-849.
3 Korbonits M, Morris DG, Nanzer A, et al. Role of regulatory factors in pituitary tumour formation. Front Horm Res 2004; 32:63-95.
4 Heaney AP, Melmed S.Molecular targets in pituitary tumours. Nat Rev Cancer 2004; 4:285-295.
5 Lania AG, Mantovani G, Spada A. Mechanisms of disease:mutations of G proteins and protein-coupled receptors in endocrine diseases. Nat Clin Pract Endocrinol Metab 2006; 2:681-693.
6 Alexander JM, Biller BMK, Bikkal H, et al.Clinically nonfunctioning pituitary adenomas are monoclonal in origin. J Clin Invest 1990; 86:336-340.
7 Burrow GN, Wortzman G, Rewcastle NB, et al. Microadenomas of the pituitary and abnormal sella tomograms in an unselected autopsy series. N Engl J Med 1981; 304: 156-158.
8 Elster AD:Modern imaging of the pituitary. Radiology 1993; 187:1-14.
9 Karga HJ, Alexander JM, Hedley-Whyte ET,et al. Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 1992; 74:914-919.
10 Pei L, Melmed S, Scheithauer B, et al. H-ras mutations in human pituitary carcinoma metastasis. J Clin Endocrinol Metab 1994; 78:842-846.
11 Simpson DJ, Magnay J, Bicknell JE, et al. Chromosome 13q deletion mapping in pituitary tumors:Infrequent loss of the retinoblastoma susceptibility gene (RBI) despite loss of RB1 product in somatotropinomas. Cancer Res 1999; 59:1562-1566.
12 Levy A, Hall L, Yeudall WA, et al. p53 gene mutations in pituitary adenomas:rare events. Clin Endocrinol 1994; 41:809-814.
13 Asa S, Kovacs K, Stefaneanu L, et al. Pituitary adenomas in mice transgenic for growth hormone-releasing hormone. Endocrinology 1992; 131:2083-2089.
14 Thapar K, Kovacs K, Stefaneau L, et al. Overexpression of the growth-hormone-releasing hormone gene in acromegaly associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior. Am J Pathol 1997; 151:769-784
15 Spada A, Reza Elahi F, Lania A, et al. Hypothalamic peptides modulate cytosolic free Ca 2+levels and adenylyl cyclase activity in human nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 1991; 71:913-918.
16 De Keyzer Y, Rene P, Beldjord C, et al. Overexpression of vasopressin(V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours. Clin Endocrinol (Oxf) 1998; 49:475-482.
17 Barlier A, Zamora AJ, Grino M, et al. Expression of functional growth hormone secretagogue receptors in humanpituitary adenomas. Polymerase chain reaction, triple in-situ hybridization and cell culture studies. J Neuroendocrinol 1999; 11:491-502.
18 Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 1987; 330:566-567.
19 Landis C, Masters SB, Spada A, et al. GTPase inhibiting mutationsactivate the_chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989; 340: 692-696.
20 Alvaro V, Levy L, Dubray C, et al. Invasive human pituitary tumors express a point-mutated_-protein kinase C. J Clin Endocrinol Metab 1993; 77:1125-1129.
21 Esapa CT, Harris PE. Mutation analysis of protein kinase A catalytic subunit in thyroid adenomas and pituitary tumours. Eur J Endocrinol 1999; 141:409-412.
22 Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-regulatory subunit in patients with the Carney complex. Nat Genet 2000; 26:89-92.
23 Lania AG, Mantovani G, Ferrero S, et al. Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein. Cancer Res 2004;64:9193-9198.
24 Otsuka E, Tamiya T, Yamauchi T, et al. Quantitative analysis of growth-related factors in human pituitary adenomas-lowered insulin-like growth factor-I and its receptor mRNA in growth hormone-producing adenomas. Regul Pept 1999; 63:31-38.
25 McAndrew J, Paterson AJ, Asa SL, et al. Targeting of transforming growth factor-expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas.Endocrinology 1995; 136:4479-4488.
26 LeRiche V, Asa S, Ezzat S. Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas:EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 1996; 81:656-662.
27 Ezzat S, Smyth HS, Ramyar L, et al.Heterogeneous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. J Clin Endocrinol Metab 1995; 80:878-884.
28 Gonsky R, Herman V, Melmed S, et al. Transforming DNA sequences present in human prolactin-secreting pituitary tumors. Mol Endocrinol 1991; 5:1687-1695.
29 Ezzat S, Zheng L, Zhu XF, et al.Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. J Clin Invest 2002; 109:69-74.
30 Cavallaro U, Niedermeyer J, Fuxa M, et al. N-CAM modulates tumourcell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 2001; 3:650-657.
31 Marinissen MJ, Gutkind JS. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 2001; 22:368-376.
32 Naor Z, Benard O, Seger R. Activation of MAPK cascades by G-protein-coupled receptors:the case of gonadotropin-releasing hormone receptor. Trends Endocrinol Metab 2000; 11:91-99.
33 Lania A, Filopanti M, Corbetta S, et al. Effects of hypothalamic neuropeptides on extracellular signal-regulated kinase (ERK1 and ERK2) cascade in human tumoral pituitarycells. J Clin Endocrinol Metab 2003; 88:1692-1696.
34 Mantovani G, Bondioni S, Ferrero S, et al. Effect of cyclic adenosine 3,5-monophosphate protein kinase a pathway on markers of cell proliferation in nonfunctioning pituitary adenomas. J Clin EndocrinolMetab 2005; 90:6721-6724.
35 Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 2002; 12:258-266.
36 Kolch W. Coordinating ERK/MAPK signaling through scaffolds and inhibitors Nat Rev Mol Cell Biol 2005; 6:827-838.
37 Dickie MM, Wolley GW. Spontaneous basophilic tumor of the pituitary gland in gonadectomized mice. Cancer Res 1949; 16:372-384.
38 Furth J, Dent NN, Burnett WT. The mechanism of induction and the characteristics of pituitary tumors induced by thyroidectomy. J Clin Endocrinol Metab 1955; 15:81-87.
39 Snyder PJ. Gonadotropin cell adenomas of the pituitary. Endocr Rev 1985; 6: 552-564.
40 Beck Peccoz P, Brucker-Davis F, Persani L, et al. Thyrotropinsecreting pituitary tumors. Endocr Rev 1996;17:610-638.
41 Karl M, Lamberts SW, Koper JW, et al. Cushing's disease preceded by generalized glucocorticoid resistance:clinical consequences of a novel, dominantnegative glucocorticoid receptor mutation. Proc Assoc Am Physicians 1996; 108:29
42 Huizenga NA, de Lange P, Koper JW, et al. Human adrenocorticotropin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol Metab 1998; 83:917-921.
1 Turner HE, Wass JA. Are markers of proliferation valuable in the histological assessment of pituitary tumours? Pituitary,1999,1:1147-151.
2 Ma W, Ikeda H, Yoshimoto T. Clinicopathologic study of 123 cases of prolactin-secreting pituitary adenomas with special reference to multihormone production and clonality of adenomas. Cancer,2002,95:166-258.
3 Thapar K, Kovacs K, Scheithauer BW, et al. Proliferative activity and invasiveness among pituitary adenomas and carcinomas:an analysis using the MIB-1 antibody. Neurosurgery,1996,38:99-106.
4 Hsu DW, Hakim F, Biller BMK, et al. Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence. J Neurosurg,1993,78 753-761.
5 Atkin SL, Green VL, Hipkin LJ, et al. A comparison of proliferation indices in human anterior pituitary adenomas using formalin fixed tissue and in vitro cell culture. J Neurosurg,1997,87:85-88.
6 Delgrange E, Trouillas J, Maiter D, et al. Sexrelated difference in the growth of prolactinomas:a clinical and proliferation marker study. J Clin Endocrinol Metab, 1997,82:2102-2107.
7 Honegger J, Prettin C, Feuerhake F, et al. Expression of Ki-67 antigen in nonfunctioning pituitary adenomas:correlation with growth velocity and invasiveness. J Neurosurg,2003,99:674-679.
8 Widhalm G, Wolfsberger S, Preusser M, et al. Residual nonfunctioning pituitary adenomas:prognostic value of MIB-1 labeling index for tumor progression. J Neurosurg,2008, Nov 7. [Epub ahead of print]
9 Gejman R, Swearingen B, Hedley-Whyte ET. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol,2008, 39:758-66.
10 Scheithauer BW, Gaffey TA, Lloyd RV, et al. Pathobiology of pituitary adenomas and carcinomas, Neurosurgery,2006,59:341-53.
11 Zhang X, Horwitz GA, Heaney AP, et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab,1999,84:761-767.
12 Wierinckx A, Auger C, Devauchelle PA, et al. A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr Relat Cancer, 2007,14:887-900.
13 George Vlotides, Tamar Eigler, Shlomo Melmed, et al. Pituitary Tumor-Transforming Gene:Physiology and Implications for Tumorigenesis. Endocr Rev,2007,28:165-186.
14 Tfelt-Hansen J, Kanuparthi D, Chattopadhyay N. The emerging role of pituitary tumor transforming gene in tumorigenesis. Clin Med Res,2006,4:130-137.
15 Filippella M, Galland F, Kujas M, et al. Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas:a clinical and immunohistochemical study. Clin Endocrinol (Oxf),2006, 65:536-543.
16 Raverot G, Wierinckx A, Dantony E, et al. Prognostic Factors in Prolactin Pituitary Tumors:Clinical, Histological, and Molecular Data from a Series of 94 Patients with a Long Postoperative Follow-Up. J Clin Endocrinol Metab.2010 Feb 17. [Epub ahead of print]
17 Jordan S, Lidhar K, Korbonits M, et al. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol,2000,143:R1-6.
18 Turner HE, Nagy ZS, Sullivan N, et al. Expression analysis of cyclins in pituitary adenomas and the normal pituitary gland. Clin Endocrinol (Oxf),2000,53:337-344.
19 Pines J. Cyclins and cyclin-dependent kinases:theme and variations. Adv Cancer Res,1995,66:181-212.
20 Fedele M, Battista S, Kenyon L, et al. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene,2002,21: 3190-3198.
21 Fedele M, Pentimalli F, Baldassarre G, et al. Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene,2005,24:3427-35.
22 Fedele M, Visone R, De Martino I, et al. HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell,2006,9:459-71.
23 Finelli P, Pierantoni GM, Giardino D, et al. The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas. Cancer Res,2002,62: 2398-2405.
24 Qian ZR, Asa SL, Siomi H, et al. Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas. Mod Pathol,2009,22:431-41.
25 Edelman GM. Cell adhesion molecules in the regulation of animal form and tissue pattern. Annu Rev Cell Biol,1986,2:81-116.
26 Williams A,Barclay AN. The immunoglobulin superfamily, domains for cell surface recognition. Annu Rev Immunol,1988,6:381-405.
27 Sadoul R, Him M, Deagostini-Bazin H, et al. Adult and embryonic mouse neural cell adhesion molecules have different binding properties. Nature,1983,304:347-349.
28 Jin L, Hemperly JJ, Lloyd RV. Expression of neural cell adhesion molecule in normal and neoplastic human neuroendocrine tissues. Am J Pathol,1991,138: 961-969.
29 Figarella-Branger DF, Durbec PL, Rougon GN. Differential spectrum of expression of neural cell adhesion molecule isoforms and L1 adhesion molecules on human neuroectodermal tumors. Cancer Res,1990,50:6364-6370.
30 Komminoth P, Roth J, Lackie PM, et al. Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids. Am J Pathol, 1991,139:297-304.
31 Daniel L, Trouillas J, Renaud W, et al. Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy. Cancer Res,2000,60:80-85.
32 Trouillas J, Daniel L, Guigard MP, et al. Polysialylated neural cell adhesion molecules expressed in human pituitary tumors and related to extrasellar invasion. J Neurosurg,2003,98:1084-1093.
33 Gumbiner BM, McCrea PD. Catenins as mediators of the cytoplasmic functions of cadherins. J Cell Sci,1993,17:155-158.
34 Shibamoto S, Hayakawa M, Takeuchi K, et al. Association of p120, a tyrosine kinase substrate, with E-cadherin/catenin complexes. J Cell Biol,1995,128 949-957.
35 Van Aken E, De Wever O, Correia da Rocha AS et al. Defective Ecadherin/catenin complexes in human cancer. Virchows Archiv,2001,439:725-751.
36 Xu B, Sano T, Yoshimoto K, Yamada S. Downregulation of E-cadherin and its undercoat proteins in pituitary growth hormone cell adenomas with prominent fibrous bodies. Endocr Pathol,2002,13:341-351.
37 Sano T, Rong QZ, Kagawa N, Yamada S. Down-regulation of E-cadherin and catenins in human pituitary growth hormoneproducing adenomas. Front Horm Res,2004,32:127-132.
38 Obari A, Sano T, Ohyama K, et al. Clinicopathological features of growth hormone-producing pituitary adenomas:difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr Pathol, 2008,19:82-91.
39 Qian ZR, Li CC, Yamasaki H, et al. Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion molecules) in prolactinoma behavior. Mod Pathol,2002,15:1357-1365.
40 Zhi Rong Qian, Toshiaki Sano, Katsuhiko Yoshimoto, et al. Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas. Mod Pathol,2007, 20:1269-1277.
41 Kawamoto H, Mizoue T, Arita K, et al. Expression of epithelial cadherin and cavernous sinus invasion in human pituitary adenomas. J Neurooncol,1997,34: 105-109.
42 Paez-Pereda M, Kuchenbauer F, Arzt E et al. Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix. Braz J Med Biol Res, 2005,38:1487-1494.
43 Kuchenbauer F, Theodoropoulou M, Hopfner U, et al. Laminin inhibits lactotroph proliferation and is reduced in early prolactinoma development. Mol Cell Endocrinol, 2003,207:13-20.
44 Murphy G, Docherty AJ. The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol,1992,7:120-125.
45 Knappe UJ, Hagel C, Lisboa BW, et al. Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue. Acta Neuropathologica,2003,106:471-478.
46 Turner HE, Nagy Z, Esiri MM, et al. Role of matrix metalloproteinase 9 in pituitary tumor behavior. J Clin Endocrinol Metab,2000,85:2931-2935.
47 Koutroulis I, Zarros A, Theocharis S. The role of matrix metalloproteinases in the pathophysiology and progression of human nervous system malignancies:a chance for the development of targeted therapeutic approaches? Expert Opin Ther Targets, 2008,12:1577-86.
48 Onofri C, Losa M, Uhl E, et al. Immunohistochemical analysis of VEGF-C/VEGFR-3 system and lymphatic vessel extent in normal and adenomatous human pituitary tissues. Exp Clin Endocrinol Diabetes,2008,116:152-7.
49 McCabe CJ, Khaira JS, Boelaert K, et al. Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas:relationships to clinical tumour behaviour. Clin Endocrinol (Oxf),2003,58:141-50.
50 Jackson TA, Koterwas DM, Bradford AP. Differential regulation of cell growth and gene expression by FGF-2 and FGF-4 in pituitary lactotroph GH4 cells. Mol Cell Endocrinol,2006,247:183-91.
51 Mukdsi JH, De Paul AL, Petiti JP, et al. Pattern of FGF-2 isoform expression correlated with its biological action in experimental prolactinomas. Acta Neuropathol,2006,112:491-501.
52 Fan X, Childs GV. Epidermal growth factor and transforming growth factor-alpha messenger ribonucleic acids and their receptors in the rat anterior pituitary: localization and regulation. Endocrinology,1995,136:2284-2293.
53 Chabot JG, Walker P, Pelletier G. Distribution of epidermal growth factor binding sites in the adult rat anterior pituitary gland. Peptides,1986,7:45-50.
54 Jaffrain-Rea ML, Petrangeli E, Lubrano C, et al. Epidermal growth factor binding sites in human pituitary macroadenomas. J Endocrinol,1998,158:425-433.
1. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas:a systematic review[J]. Cancer,2004,101:613-19
2. Marek J. Pituitary adenomas--where is the treatment heading at the beginning of the 21st century? [J]. Vnitr Lek,2010 Jul,56(7):690-4
3. Zada G, Woodmansee W W, Ramkissoon S, et al. Atypical pituitary adenomas: incidence, clinical characteristics, and implications [J]. J Neurosurg,2011,114(2):336-344.
4. Aghi M K. Management of recurrent and refractory Cushing disease[J]. Nat Clin Pract Endocrinol Metab,2008,4(10):560-568.
5. Feigl G C, Pistracher K, Berghold A, et al. Pituitary insufficiency as a side effect after radiosurgery for pituitary adenomas:the role of the hypothalamus[J]. J Neurosurg,2010,113 Suppl:153-159.
6. Theodoropoulou M, Labeur M, Paez Pereda M, et al. Novel medical therapies for pituitary tumors[J]. Front Horm Res,2010,38:158-64.
7. Syro L V, Ortiz L D, Scheithauer B W, et al. Treatment of Pituitary Neoplasms With Temozolomide[J]. Cancer,2010;1-9.
8. Villano J L, Seery T E, Bressler L R. Temozolomide in malignant gliomas:current use and future targets[J]. Cancer Chemother Pharmacol,2009,64:647-55
9. Bei R, Marzocchella L, Turriziani M. The use of temozolomide for the treatment of malignant tumors:clinical evidence and molecular mechanisms of action[J]. Recent Pat Anticancer Drug Discov,2010,5(3):172-187.
10. Syro LV, Scheithauer BW, Ortiz LD, et al. Effect of Temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma[J]. Hormones (Athens),2009, 8(4):303-306
11. Hagen C, Schroeder HD, Hansen S, et al. Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy [J]. Eur J Endocrinol,2009,161 631-637
12. Losa M, Mazza E, Terreni MR, et al. Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas:experience in six cases[J]. Eur J Endocrinol,2010,163(6):843-51.
13. Mohammed S, Kovacs K, Mason W, et al. Use of temozolomide in aggressive pituitary tumors:case report[J]. Neurosurgery,2009,64:E773-E774.
14. Dillard T H, Gultekin S H, Delashaw J J, et al. Temozolomide for corticotroph pituitary adenomas refractory to standard therapy[J]. Pituitary,2011,14(1):80-91.
15. Morin E, Berthelet F, Weisnagel J, et al. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly[J].. Pituitary,2010, [Epub ahead of print]
16. Thearle M S, Freda P U, Bruce J N, et al. Temozolomide (Temodar R) and capecitabine (XelodaR)treatment of an aggressive corticotroph pituitary tumor [J].. Pituitary,2009, [Epub ahead of print]
17. Neff LM, Weil M, Cole A, et al. Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists [J]. Pituitary,2007,10:81-86
18. Bode H, Seiz M, Lammert A, et al. SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases[J]. Exp Clin Endocrinol Diabetes,2010,118(10):760-763.
19. Kovacs K, Scheithauer BW, Lombardero M, et al. MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy [J].. Acta Neuropathol,2008 Feb,115(2):261-2.
20. McCormack A I, McDonald K L, Gill A J, et al. Low 06-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours[J]. Clin Endocrinol (Oxf),2009 Aug,71(2):226-33.
21. Bush Z M, Longtine J A, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression[J]. J Clin Endocrinol Metab,2010,95(11):E280-E290.
22. Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience [J]. J Clin Endocrinol Metab,2010,95(10):4592-4599.
23. Murakami M, Mizutani A, Asano S, et al. A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma[J]. Neurosurgery,2011.
24. Mrugala MM, Chamberlain MC. Mechanisms of disease:temozolomide and glioblastoma—look to the future[J].. Nat Clin Pract Oncol,2008,5:476-486.
25. Quinn JA, Jiang SX, Reardon DA, et al. Phase Ⅱ trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol[J].2009,27:1262-1267.
26. Prasad G, Sottero T, Yang X, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide[J]. Neuro Oncol,2011,13(4):384-392.
27. Plummer R, Jones C, Middleton M, et al. Phase Ⅰ study of the poly(ADP-ribose) polymerase inhibitor, AGO 14699, in combination with temozolomide in patients with advanced solid tumors[J]. Clin Cancer Res,2008,14(23):7917-7923.
28. Chaponis D, Barnes J W, Dellagatta J L, et al. Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas[J]. J Neurooncol,2011.
29. Ulasov I V, Nandi S, Dey M, et al. Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy [J]. Mol Med,2011,17(1-2):103-112.
30. Iyer R, Evans A E, Qi X, et al. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma[J]. Clin Cancer Res,2010,16(5):1478-1485.
31. Torres S, Lorente M, Rodriguez-Fornes F, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma[J]. Mol Cancer Ther,2011,10(1):90-103.
32. Gorshtein A, Rubinfeld H, Kendler E, et al. Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro[J]. Endocr Relat Cancer,2009,16: 1017-1027
33. Yao C, Evans C O, Stevens V L, et al. Folate receptor alpha regulates cell proliferation in mouse gonadotroph alphaT3-1 cells [J]. Exp Cell Res,2009,315(18):3125-3132.
34. Moyes V J, Alusi G, Sabin H I, et al. Treatment of Nelson's syndrome with temozolomide[J]. European Journal of Endocrinology,2009,160(1):115.
35. Syro L V, Uribe H, Penagos L C, et al. Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm [J]. Clin Endocrinol (Oxf),2006,65(4):552-553.
36. Kovacs K, Horvath E, Syro L V, et al. Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm:Morphological findings [J]. Hum Pathol,2007,38(1):185-189.
[2]Peillon F, Gourmelen M, Donnadieu M, Brandi A, Sevaux D. Organ culture of human somatotrophic pituitary adenomas:ultrastructure and growth hormone production. Acta Endocrinol (Copenh).1975 79(2):217-29.
[3]Fuller PJ, Lim AT,Barlow JW:White EL, Khalid BA, Copolov DL, Lolait S,Funder JW,Stockigt JR(1 984). A pituitary tumor producing high molecular weight adrenoconicotropin-related peptides:clinical and cell culture studies. J Clin Endocrinol Metab.58(1):1 34-42.
[4]Missale. C, Boroni. F,Losa. M, Giovalli. M, Zanellato. A, Dal. Tos. R, BalsariA, Spano. P(1993). Nerve growth factor suppresses the transforming phenotype of human prolactinomas. Proc Natl Acad Sci USA.90(17):7961-5.
[5]Long Jin, Elzbieta Kulig, Xiang Qian et al. A Human Pituitary Adenoma Cell Line Proliferates and Maintains Some Differentiated Functions Following Expression of SV40 Large T-Antigen. Endocrine Pathology,1998,9(2):169-184.
[6]Fujimoto N, Maruyama S, Ito A. Establishment of an estrogen responsive rat pituitary cell sub-line MtT/E-2. Endocr J,1999,46(3):389-396.
[7]Jones TH, Justice SK and Price A. Suppression of Tyrosine Kinase Activity Inhibits [3H]Thymidine Uptake in Cultured Human Pituitary Tumor Cells. The Journal of Clinical Endocrinology&Metabolism,1997,82(7):2143-2147.
[8]Florio T, Thellung S, Corsaro A, et al. Characterization of the intracellular mechanisms mediating somatostatin and lanreotide inhibition of DNA synthesis and growth hormone release from dispersed human GH—secreting pituitary adenoma cells in vitro. Clin Endocrinol(Oxf),2003,59(1):115-128.
[9]Kabuto M, Kubota T, Kobayashi H, Nakagawa T. Modified procedure of monolayer culture of human pituitary adenoma cells on microporous membrane coated with extracellular matrix. Neurol Res.1993 Oct;15(5):304-9.
[10]Asa SL, Gerrie BM, Singer W, Horvath E, Kovacs K, Smyth HS.Gonadotropin secretion in vitro by human pituitary null cell adenomas and oncocytomas.J Clin Endocrinol Metab.1986,62(5):1011-9.
[11]Dumesic DA, Goldsmith PC, Jaffe RB. Estradiol sensitization of cultured human fetal pituitary cells to gonadotropin-releasing hormone. J Clin Endocrinol Metab.1987, 65(6):1147-53.
[12]Jaquet P, Hassoun J, Delori P, Gunz G, Grisoli F, Weintraub BD.A human pituitary adenoma secreting thyrotropin and prolactin:immunohistochemical, biochemical, and cell culture studies. J Clin Endocrinol Metab.1984 Nov;59(5):817-24.
[13]Giannelli, G., Antonaci, S., Biological and clinical relevance of Laminin-5 in cancer. Clin. Exp. Metastasis 2000.18,439-443.
[14]Kitayama, J., Nagawa, H., Tsuno, N., Osada, T., Hatano, K., Sunami,E., Saito, H., Muto, T., Laminin mediates tethering and spreading of colon cancer cells in physiological shear flow. Br. J.Cancer 1999.80,1927-1934.
[15]De lorio, P., Midulla, C., Pisani, T., Valli, C., Grillo, L., Di Cocco, B.,Nofroni, I., Vecchione, A.. Implication of laminin and collagen type IV expression in the progression of breast carcinoma. Anticancer Res.2001,21,1395-1399.
[16]Mettouchi, A., Klein, S., Guo, W., Lopez-Lago, M., Lemichez, E.,Westwick, J.K., Giancotti, F.G.. Integrin-specific activation of rac controls progression through the G(1) phase of the cell cycle.Mol. Cell,2001,8,115-127.
[17]Yoshida, Y., Hosokawa, K., Dantes, A., Kotsuji, F., Kleinman, H.K.,Amsterdam, A. Role of laminin in ovarian cancer tumor growth and metastasis via regulation of Mdm2 and Bcl-2 expression. Int. J. Oncol.2001,18,913-921.
[18]Lekmine, F., Lausson, S., Pidoux, E., Segond, N., Roos, B., Treilhou-Lahille, F., Jeanne, A.. Influence of laminin substratum on cell proliferation and CALC I gene expression in medullary thyroid carcinoma C cell lines. Mol. Cell. Endocrinol.1999, 157,181-189.
[19]Tougard, C., Louvard, D., Picart, R., Tixier-Vidal, A..Immunocytochemical localization of laminin in rat anterior pituitary cells in vivo and in vitro. In Vitro Cell Dev. Biol.1985,21,57-61.
[20]Vila-Porcile, E., Picart, R., Tixier-Vidal, A., Tougard, C.. Cellular and subcellular distribution of laminin in adult rat anterior pituitary. J. Histochem. Cytochem.1987,35, 287-299.
[21]de Carvalho, D.F., Silva, K.L., de Oliveria, D.A., Villa-Verde, D.M.,Coelho, H.S., Silva, L.C., Nasciutti, L.E.. Characterization and distribution of extracellular matrix components and receptors in GH3B6 prolactin cells. Biol. Cell,2000,92,351-362.
[22]Horacek, M.J., Thompson, J.C., Dada, M.O., Terracio, L.. The extracellular matrix components laminin, fibronectin, and collagen IV are present among the epithelial cells forming Rathke's pouch. Acta Anat. (Basel),1993,147,69-74.
[23]Denduchis, B., Rettori, V., McCann, S.M.. Role of laminin on prolactin and gonadotrophin release from anterior pituitaries of male rats. Life Sci.1994,55, 1757-1765.
[1]Selman WR, Laws ER, Jr., Scheithauer BW, Carpenter SM. The occurrence of dural invasion in pituitary adenomas. J Neurosurg.1986; 64:402-407.
[2]Asa SL, Ezzat S. The pathogenesis of pituitary tumours. Nat Rev Cancer.2002; 2:836-849.
[3]Korbonits M, Carlsen E. Recent clinical and pathophysiological advances in non-functioning pituitary adenomas. Horm Res.2009; 71 Suppl 2:123-130.
[4]Ho DM, Hsu CY, Ting LT, Chiang H. The clinicopathological characteristics of gonadotroph cell adenoma:a study of 118 cases. Hum Pathol.1997;28:905-911.
[5]Snyder PJ. Gonadotroph cell adenomas of the pituitary. Endocr Rev. 1985;6:552-563.
[6]Delellis RA, Lloyd RV, Heitz PU, Eng C. Pathology and genetics of tumours of endocrine organs. Lyons:World Health Organization, IARC Press.2004; 270-311.
[7]Chanson P:Gonadotroph pituitary adenomas. Ann Endocrinol (Paris). 2000;61:258-268.
[8]Bei R, Marzocchella L, Turriziani M. The use of temozolomide for the treatment of malignant tumors:clinical evidence and molecular mechanisms of action. Recent Pat Anticancer Drug Discov.2010;5:172-187.
[9]Kulke MH, Chan JA, Meyerhardt JA, et al. A prospective phase Ⅱ study of 2-methoxyestradiol administered in combination with bevacizumab in patients with metastatic carcinoid tumors. Cancer Chemother Pharmacol.2010 [Epub ahead of print].
[10]Syro LV, Ortiz LD, Scheithauer BW, et al. Treatment of pituitary neoplasms with temozolomide:A review. Cancer.2010; 117:454-462.
[11]Bush ZM, Longtine JA, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression. J Clin Endocrinol Metab.2010; 95:E280-290.
[12]Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience. J Clin Endocrinol Metab.2010; 95:4592-4599.
[13]Mohammed S, Kovacs K, Mason W, Smyth H, Cusimano MD. Use of temozolomide in aggressive pituitary tumors:case report. Neurosurgery.2009; 64:E773-774; discussion E774.
[14]Lim S, Shahinian H, Maya MM, Yong W, Heaney AP. Temozolomide:a novel treatment for pituitary carcinoma. Lancet Oncol.2006; 7:518-520.
[15]Fadul CE, Kominsky AL, Meyer LP, et al. Long-term response of pituitary carcinoma to temozolomide. Report of two cases. J Neurosurg.2006; 105:621-626.
[16]Syro LV, Scheithauer BW, Ortiz LD, et al. Effect of temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma. Hormones (Athens). 2009;8:303-306.
[17]Sheehan J, Rainey J, Nguyen J, Grimsdale R, Han S. Temozolomide-induced inhibition of pituitary adenoma cells. J Neurosurg.2010 [Epub ahead of print].
[18]Morin E, Berthelet F, Weisnagel J, Bidlingmaier M, Serri O. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly. Pituitary.2010 [Epub ahead of print].
[19]Windle JJ, Weiner RI, Mellon PL. Cell lines of the pituitary gonadotrope lineage derived by targeted oncogenesis in transgenic mice. Mol Endocrinol.1990;4:597-603.
[20]Kaina B, Fritz G, Mitra S, Coquerelle T. Transfection and expression of human O6-methylguanine-DNA methyltransferase (MGMT) cDNA in Chinese hamster cells:the role of MGMT in protection against the genotoxic effects of alkylating agents. Carcinogenesis.1991; 12:1857-67.
[21]Villano JL, Seery TE, Bressler LR. Temozolomide in malignant gliomas:current use and future targets. Cancer Chemother Pharmacol.2009; 64:647-655.
[22]Pepponi R, Marra G, Fuggetta MP, et al. The effect of O6-alkylguanine-DNA alkyltransferase and mismatch repair activities on the sensitivity of human melanoma cells to temozolomide, 1,3-bis(2-chloroethyl)1-nitrosourea, and cisplatin. J Pharmacol Exp Ther.2003;304:661-668.
[23]D'Atri S, Tentori L, Lacal PM, et al. Involvement of the mismatch repair system in temozolomide-induced apoptosis. Mol Pharmacol.1998;54:334-341.
[24]Tisdale MJ. Antitumour imidazotetrazines-XI:Effect of 8-carbamoyl-3-methylimidazo[5,1-d]-1,2,3,5-tetrazin-4(3H)-one [CCRG 81045; M and B 39831 NSC 362856] on poly(ADP-ribose) metabolism. Br J Cancer.1985; 52:789-792.
[25]Oliver FJ, de la Rubia G, Rolli V, Ruiz-Ruiz MC, de Murcia G, Murcia JM. Importance of poly(ADP-ribose) polymerase and its cleavage in apoptosis. Lesson from an uncleavable mutant. J Biol Chem.1998;273:33533-33539.
[26]Ochs K, Kaina B. Apoptosis induced by DNA damage 06-methylguanine is Bcl-2 and caspase-9/3 regulated and Fas/caspase-8 independent. Cancer Res.2000; 60:5815-5824.
[27]Roos WP, Batista LF, Naumann SC, et al. Apoptosis in malignant glioma cells triggered by the temozolomide-induced DNA lesion O6-methylguanine. Oncogene. 2007;26:186-197.
[28]Djerassi A, Coutifaris C, West VA, et al. Gonadotroph adenoma in a premenopausal woman secreting follicle-stimulating hormone and causing ovarian hyperstimulation. J Clin Endocrinol Metab.1995;80:591-594.
[29]Catargi B, Felicie-Dellan E, Tabarin A. Comment on gonadotroph adenoma causing ovarian hyperstimulation. J Clin Endocrinol Me tab.1999; 84:3404.
[30]Murata Y, Ando H, Nagasaka T, et al. Successful pregnancy after bromocriptine therapy in an anovulatory woman complicated with ovarian hyperstimulation caused by follicle-stimulating hormone-producing plurihormonal pituitary microadenoma. J Clin Endocrinol Metab.2003; 88:1988-1993.
[31]Murakami T, Higashitsuji H, Yoshinaga K, Terada Y, Ito K, Ikeda H. Management of ovarian hyperstimulation due to follicle-stimulating hormone-secreting gonadotroph adenoma. Bjog.2004;111:1297-1300.
1. Villano J L, Seery T E, Bressler L R. Temozolomide in malignant gliomas:current use and future targets [J]. Cancer Chemother Pharmacol,2009,64:647-55
2. Bei R, Marzocchella L, Turriziani M. The use of temozolomide for the treatment of malignant tumors:clinical evidence and molecular mechanisms of action[J]. Recent Pat Anticancer Drug Discov,2010,5(3):172-187.
3. Syro LV, Scheithauer BW, Ortiz LD, et al. Effect of Temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma[J]. Hormones (Athens),2009, 8(4):303-306
4. Hagen C, Schroeder HD, Hansen S, et al. Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy[J]. Eur J Endocrinol,2009,161 631-637
5. Losa M, Mazza E, Terreni MR, et al. Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas:experience in six cases[J]. Eur J Endocrinol,2010,163(6):843-51.
6. Mohammed S, Kovacs K, Mason W, et al. Use of temozolomide in aggressive pituitary tumors:case report[J]. Neurosurgery,2009,64:E773-E774.
7. Dillard T H, Gultekin S H, Delashaw J J, et al. Temozolomide for corticotroph pituitary adenomas refractory to standard therapy [J]. Pituitary,2011,14(1):80-91.
8. Morin E, Berthelet F, Weisnagel J, et al. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly[J].. Pituitary,2010, [Epub ahead of print]
9. Syro L V, Ortiz L D, Scheithauer B W, et al. Treatment of Pituitary Neoplasms With Temozolomide [J]. Cancer,2010;1-9.
10. Kovacs K, Scheithauer BW, Lombardero M, et al. MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy [J].. Acta Neuropathol,2008 Feb,115(2):261-2.
11. McCormack A I, McDonald K L, Gill A J, et al. Low O6- methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours[J]. Clin Endocrinol (Oxf),2009 Aug,71(2):226-33.
12. Bush Z M, Longtine J A, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression[J]. J Clin Endocrinol Metab.2010,95(11):E280-E290.
13. Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience[J]. J Clin Endocrinol Metab,2010,95(10):4592-4599.
14. Mrugala MM, Chamberlain MC. Mechanisms of disease:temozolomide and glioblastoma—look to the future [J].. Nat Clin Pract Oncol,2008,5:476-486.
15. Murakami M, Mizutani A, Asano S, et al. A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma[J]. Neurosurgery,2011.
16. Thearle M S, Freda P U, Bruce J N, et al. Temozolomide (Temodar R) and capecitabine (XelodaR)treatment of an aggressive corticotroph pituitary tumor[J].. Pituitary,2009, [Epub ahead of print]
17. Neff LM, Weil M, Cole A, et al. Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists[J]. Pituitary,2007,10:81-86
18. Bode H, Seiz M, Lammert A, et al. SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases[J]. Exp Clin Endocrinol Diabetes,2010,118(10):760-763.
19. Quinn JA, Jiang SX, Reardon DA, et al. Phase Ⅱ trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol[J].2009,27:1262-1267.
20. Prasad G, Sottero T, Yang X, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide[J]. Neuro Oncol,2011,13(4):384-392.
21. Plummer R, Jones C, Middleton M, et al. Phase Ⅰ study of the poly(ADP-ribose) polymerase inhibitor, AG014699, in combination with temozolomide in patients with advanced solid tumors[J]. Clin Cancer Res,2008,14(23):7917-7923.
22. Chaponis D, Barnes J W, Dellagatta J L, et al. Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas[J]. J Neurooncol,2011.
23. Ulasov I V, Nandi S, Dey M, et al. Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy[J]. Mol Med,2011,17(1-2):103-112.
24. Iyer R, Evans A E, Qi X, et al. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma[J]. Clin Cancer Res,2010,16(5):1478-1485.
25. Torres S, Lorente M, Rodriguez-Fornes F, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma[J]. Mol Cancer Ther,2011,10(1):90-103.
26. Gorshtein A, Rubinfeld H, Kendler E, et al. Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro[J]. Endocr Relat Cancer,2009,16:1017-1027
27. Yao C, Evans C O, Stevens V L, et al. Folate receptor alpha regulates cell proliferation in mouse gonadotroph alphaT3-1 cells [J]. Exp Cell Res, 2009,315(18):3125-3132.
1 Aghi MK. Management of recurrent and refractory Cushing disease. Nat Clin Pract Endocrinol Metab.2008,4:560-8.
2 Syro L V, Ortiz L D, Scheithauer B W, et al. Treatment of Pituitary Neoplasms With Temozolomide. Cancer.2010,1-9
3 Fadul CE, Kominsky AL, Meyer LP, et al. Pituitary carcinomas respond to temozolomide [abstract]. Neuro-Oncol.2004,6:374. Abstract TA-18
4 McCormack A I, McDonald K L, Gill A J, et al. Low O6-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours. Clin Endocrinol (Oxf).2009; Aug; 71(2):226-33.
5 Kovacs K, Scheithauer BW, Lombardero M, et al. MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy. Acta Neuropathol.2008,115(2):261-2
6 Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience. J Clin Endocrinol Metab.2010 Oct;95(10):4592-9.
7 Bush ZM, Longtine JA, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression.J Clin Endocrinol Metab.2010,95(11):E280-90
8 Morin E, Berthelet F, Weisnagel J, et al. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly. Pituitary.2010, [Epub ahead of print]
1 Farrel WE, Clayton RN:Molecular pathogenesis of pituitary tumors. Front Neuroendocrinol.2000; 21:174-198.
2 Asa SL, Ezzat S:The pathogenesis of pituitarytumours. Nat Rev Cancer 2002; 2: 836-849.
3 Korbonits M, Morris DG, Nanzer A, et al. Role of regulatory factors in pituitary tumour formation. Front Horm Res 2004; 32:63-95.
4 Heaney AP, Melmed S.Molecular targets in pituitary tumours. Nat Rev Cancer 2004; 4:285-295.
5 Lania AG, Mantovani G, Spada A. Mechanisms of disease:mutations of G proteins and protein-coupled receptors in endocrine diseases. Nat Clin Pract Endocrinol Metab 2006; 2:681-693.
6 Alexander JM, Biller BMK, Bikkal H, et al.Clinically nonfunctioning pituitary adenomas are monoclonal in origin. J Clin Invest 1990; 86:336-340.
7 Burrow GN, Wortzman G, Rewcastle NB, et al. Microadenomas of the pituitary and abnormal sella tomograms in an unselected autopsy series. N Engl J Med 1981; 304: 156-158.
8 Elster AD:Modern imaging of the pituitary. Radiology 1993; 187:1-14.
9 Karga HJ, Alexander JM, Hedley-Whyte ET,et al. Ras mutations in human pituitary tumors. J Clin Endocrinol Metab 1992; 74:914-919.
10 Pei L, Melmed S, Scheithauer B, et al. H-ras mutations in human pituitary carcinoma metastasis. J Clin Endocrinol Metab 1994; 78:842-846.
11 Simpson DJ, Magnay J, Bicknell JE, et al. Chromosome 13q deletion mapping in pituitary tumors:Infrequent loss of the retinoblastoma susceptibility gene (RBI) despite loss of RB1 product in somatotropinomas. Cancer Res 1999; 59:1562-1566.
12 Levy A, Hall L, Yeudall WA, et al. p53 gene mutations in pituitary adenomas:rare events. Clin Endocrinol 1994; 41:809-814.
13 Asa S, Kovacs K, Stefaneanu L, et al. Pituitary adenomas in mice transgenic for growth hormone-releasing hormone. Endocrinology 1992; 131:2083-2089.
14 Thapar K, Kovacs K, Stefaneau L, et al. Overexpression of the growth-hormone-releasing hormone gene in acromegaly associated pituitary tumors. An event associated with neoplastic progression and aggressive behavior. Am J Pathol 1997; 151:769-784
15 Spada A, Reza Elahi F, Lania A, et al. Hypothalamic peptides modulate cytosolic free Ca 2+levels and adenylyl cyclase activity in human nonfunctioning pituitary adenomas. J Clin Endocrinol Metab 1991; 71:913-918.
16 De Keyzer Y, Rene P, Beldjord C, et al. Overexpression of vasopressin(V3) and corticotrophin-releasing hormone receptor genes in corticotroph tumours. Clin Endocrinol (Oxf) 1998; 49:475-482.
17 Barlier A, Zamora AJ, Grino M, et al. Expression of functional growth hormone secretagogue receptors in humanpituitary adenomas. Polymerase chain reaction, triple in-situ hybridization and cell culture studies. J Neuroendocrinol 1999; 11:491-502.
18 Vallar L, Spada A, Giannattasio G. Altered Gs and adenylate cyclase activity in human GH-secreting pituitary adenomas. Nature 1987; 330:566-567.
19 Landis C, Masters SB, Spada A, et al. GTPase inhibiting mutationsactivate the_chain of Gs and stimulate adenylyl cyclase in human pituitary tumours. Nature 1989; 340: 692-696.
20 Alvaro V, Levy L, Dubray C, et al. Invasive human pituitary tumors express a point-mutated_-protein kinase C. J Clin Endocrinol Metab 1993; 77:1125-1129.
21 Esapa CT, Harris PE. Mutation analysis of protein kinase A catalytic subunit in thyroid adenomas and pituitary tumours. Eur J Endocrinol 1999; 141:409-412.
22 Kirschner LS, Carney JA, Pack SD, et al. Mutations of the gene encoding the protein kinase A type I-regulatory subunit in patients with the Carney complex. Nat Genet 2000; 26:89-92.
23 Lania AG, Mantovani G, Ferrero S, et al. Proliferation of transformed somatotroph cells related to low or absent expression of protein kinase a regulatory subunit 1A protein. Cancer Res 2004;64:9193-9198.
24 Otsuka E, Tamiya T, Yamauchi T, et al. Quantitative analysis of growth-related factors in human pituitary adenomas-lowered insulin-like growth factor-I and its receptor mRNA in growth hormone-producing adenomas. Regul Pept 1999; 63:31-38.
25 McAndrew J, Paterson AJ, Asa SL, et al. Targeting of transforming growth factor-expression to pituitary lactotrophs in transgenic mice results in selective lactotroph proliferation and adenomas.Endocrinology 1995; 136:4479-4488.
26 LeRiche V, Asa S, Ezzat S. Epidermal growth factor and its receptor (EGF-R) in human pituitary adenomas:EGF-R correlates with tumor aggressiveness. J Clin Endocrinol Metab 1996; 81:656-662.
27 Ezzat S, Smyth HS, Ramyar L, et al.Heterogeneous in vivo and in vitro expression of basic fibroblast growth factor by human pituitary adenomas. J Clin Endocrinol Metab 1995; 80:878-884.
28 Gonsky R, Herman V, Melmed S, et al. Transforming DNA sequences present in human prolactin-secreting pituitary tumors. Mol Endocrinol 1991; 5:1687-1695.
29 Ezzat S, Zheng L, Zhu XF, et al.Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis. J Clin Invest 2002; 109:69-74.
30 Cavallaro U, Niedermeyer J, Fuxa M, et al. N-CAM modulates tumourcell adhesion to matrix by inducing FGF-receptor signalling. Nat Cell Biol 2001; 3:650-657.
31 Marinissen MJ, Gutkind JS. G-protein-coupled receptors and signaling networks: emerging paradigms. Trends Pharmacol Sci 2001; 22:368-376.
32 Naor Z, Benard O, Seger R. Activation of MAPK cascades by G-protein-coupled receptors:the case of gonadotropin-releasing hormone receptor. Trends Endocrinol Metab 2000; 11:91-99.
33 Lania A, Filopanti M, Corbetta S, et al. Effects of hypothalamic neuropeptides on extracellular signal-regulated kinase (ERK1 and ERK2) cascade in human tumoral pituitarycells. J Clin Endocrinol Metab 2003; 88:1692-1696.
34 Mantovani G, Bondioni S, Ferrero S, et al. Effect of cyclic adenosine 3,5-monophosphate protein kinase a pathway on markers of cell proliferation in nonfunctioning pituitary adenomas. J Clin EndocrinolMetab 2005; 90:6721-6724.
35 Stork PJ, Schmitt JM. Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 2002; 12:258-266.
36 Kolch W. Coordinating ERK/MAPK signaling through scaffolds and inhibitors Nat Rev Mol Cell Biol 2005; 6:827-838.
37 Dickie MM, Wolley GW. Spontaneous basophilic tumor of the pituitary gland in gonadectomized mice. Cancer Res 1949; 16:372-384.
38 Furth J, Dent NN, Burnett WT. The mechanism of induction and the characteristics of pituitary tumors induced by thyroidectomy. J Clin Endocrinol Metab 1955; 15:81-87.
39 Snyder PJ. Gonadotropin cell adenomas of the pituitary. Endocr Rev 1985; 6: 552-564.
40 Beck Peccoz P, Brucker-Davis F, Persani L, et al. Thyrotropinsecreting pituitary tumors. Endocr Rev 1996;17:610-638.
41 Karl M, Lamberts SW, Koper JW, et al. Cushing's disease preceded by generalized glucocorticoid resistance:clinical consequences of a novel, dominantnegative glucocorticoid receptor mutation. Proc Assoc Am Physicians 1996; 108:29
42 Huizenga NA, de Lange P, Koper JW, et al. Human adrenocorticotropin-secreting pituitary adenomas show frequent loss of heterozygosity at the glucocorticoid receptor gene locus. J Clin Endocrinol Metab 1998; 83:917-921.
1 Turner HE, Wass JA. Are markers of proliferation valuable in the histological assessment of pituitary tumours? Pituitary,1999,1:1147-151.
2 Ma W, Ikeda H, Yoshimoto T. Clinicopathologic study of 123 cases of prolactin-secreting pituitary adenomas with special reference to multihormone production and clonality of adenomas. Cancer,2002,95:166-258.
3 Thapar K, Kovacs K, Scheithauer BW, et al. Proliferative activity and invasiveness among pituitary adenomas and carcinomas:an analysis using the MIB-1 antibody. Neurosurgery,1996,38:99-106.
4 Hsu DW, Hakim F, Biller BMK, et al. Significance of proliferating cell nuclear antigen index in predicting pituitary adenoma recurrence. J Neurosurg,1993,78 753-761.
5 Atkin SL, Green VL, Hipkin LJ, et al. A comparison of proliferation indices in human anterior pituitary adenomas using formalin fixed tissue and in vitro cell culture. J Neurosurg,1997,87:85-88.
6 Delgrange E, Trouillas J, Maiter D, et al. Sexrelated difference in the growth of prolactinomas:a clinical and proliferation marker study. J Clin Endocrinol Metab, 1997,82:2102-2107.
7 Honegger J, Prettin C, Feuerhake F, et al. Expression of Ki-67 antigen in nonfunctioning pituitary adenomas:correlation with growth velocity and invasiveness. J Neurosurg,2003,99:674-679.
8 Widhalm G, Wolfsberger S, Preusser M, et al. Residual nonfunctioning pituitary adenomas:prognostic value of MIB-1 labeling index for tumor progression. J Neurosurg,2008, Nov 7. [Epub ahead of print]
9 Gejman R, Swearingen B, Hedley-Whyte ET. Role of Ki-67 proliferation index and p53 expression in predicting progression of pituitary adenomas. Hum Pathol,2008, 39:758-66.
10 Scheithauer BW, Gaffey TA, Lloyd RV, et al. Pathobiology of pituitary adenomas and carcinomas, Neurosurgery,2006,59:341-53.
11 Zhang X, Horwitz GA, Heaney AP, et al. Pituitary tumor transforming gene (PTTG) expression in pituitary adenomas. J Clin Endocrinol Metab,1999,84:761-767.
12 Wierinckx A, Auger C, Devauchelle PA, et al. A diagnostic marker set for invasion, proliferation, and aggressiveness of prolactin pituitary tumors. Endocr Relat Cancer, 2007,14:887-900.
13 George Vlotides, Tamar Eigler, Shlomo Melmed, et al. Pituitary Tumor-Transforming Gene:Physiology and Implications for Tumorigenesis. Endocr Rev,2007,28:165-186.
14 Tfelt-Hansen J, Kanuparthi D, Chattopadhyay N. The emerging role of pituitary tumor transforming gene in tumorigenesis. Clin Med Res,2006,4:130-137.
15 Filippella M, Galland F, Kujas M, et al. Pituitary tumour transforming gene (PTTG) expression correlates with the proliferative activity and recurrence status of pituitary adenomas:a clinical and immunohistochemical study. Clin Endocrinol (Oxf),2006, 65:536-543.
16 Raverot G, Wierinckx A, Dantony E, et al. Prognostic Factors in Prolactin Pituitary Tumors:Clinical, Histological, and Molecular Data from a Series of 94 Patients with a Long Postoperative Follow-Up. J Clin Endocrinol Metab.2010 Feb 17. [Epub ahead of print]
17 Jordan S, Lidhar K, Korbonits M, et al. Cyclin D and cyclin E expression in normal and adenomatous pituitary. Eur J Endocrinol,2000,143:R1-6.
18 Turner HE, Nagy ZS, Sullivan N, et al. Expression analysis of cyclins in pituitary adenomas and the normal pituitary gland. Clin Endocrinol (Oxf),2000,53:337-344.
19 Pines J. Cyclins and cyclin-dependent kinases:theme and variations. Adv Cancer Res,1995,66:181-212.
20 Fedele M, Battista S, Kenyon L, et al. Overexpression of the HMGA2 gene in transgenic mice leads to the onset of pituitary adenomas. Oncogene,2002,21: 3190-3198.
21 Fedele M, Pentimalli F, Baldassarre G, et al. Transgenic mice overexpressing the wild-type form of the HMGA1 gene develop mixed growth hormone/prolactin cell pituitary adenomas and natural killer cell lymphomas. Oncogene,2005,24:3427-35.
22 Fedele M, Visone R, De Martino I, et al. HMGA2 induces pituitary tumorigenesis by enhancing E2F1 activity. Cancer Cell,2006,9:459-71.
23 Finelli P, Pierantoni GM, Giardino D, et al. The High Mobility Group A2 gene is amplified and overexpressed in human prolactinomas. Cancer Res,2002,62: 2398-2405.
24 Qian ZR, Asa SL, Siomi H, et al. Overexpression of HMGA2 relates to reduction of the let-7 and its relationship to clinicopathological features in pituitary adenomas. Mod Pathol,2009,22:431-41.
25 Edelman GM. Cell adhesion molecules in the regulation of animal form and tissue pattern. Annu Rev Cell Biol,1986,2:81-116.
26 Williams A,Barclay AN. The immunoglobulin superfamily, domains for cell surface recognition. Annu Rev Immunol,1988,6:381-405.
27 Sadoul R, Him M, Deagostini-Bazin H, et al. Adult and embryonic mouse neural cell adhesion molecules have different binding properties. Nature,1983,304:347-349.
28 Jin L, Hemperly JJ, Lloyd RV. Expression of neural cell adhesion molecule in normal and neoplastic human neuroendocrine tissues. Am J Pathol,1991,138: 961-969.
29 Figarella-Branger DF, Durbec PL, Rougon GN. Differential spectrum of expression of neural cell adhesion molecule isoforms and L1 adhesion molecules on human neuroectodermal tumors. Cancer Res,1990,50:6364-6370.
30 Komminoth P, Roth J, Lackie PM, et al. Polysialic acid of the neural cell adhesion molecule distinguishes small cell lung carcinoma from carcinoids. Am J Pathol, 1991,139:297-304.
31 Daniel L, Trouillas J, Renaud W, et al. Polysialylated-neural cell adhesion molecule expression in rat pituitary transplantable tumors (spontaneous mammotropic transplantable tumor in Wistar-Furth rats) is related to growth rate and malignancy. Cancer Res,2000,60:80-85.
32 Trouillas J, Daniel L, Guigard MP, et al. Polysialylated neural cell adhesion molecules expressed in human pituitary tumors and related to extrasellar invasion. J Neurosurg,2003,98:1084-1093.
33 Gumbiner BM, McCrea PD. Catenins as mediators of the cytoplasmic functions of cadherins. J Cell Sci,1993,17:155-158.
34 Shibamoto S, Hayakawa M, Takeuchi K, et al. Association of p120, a tyrosine kinase substrate, with E-cadherin/catenin complexes. J Cell Biol,1995,128 949-957.
35 Van Aken E, De Wever O, Correia da Rocha AS et al. Defective Ecadherin/catenin complexes in human cancer. Virchows Archiv,2001,439:725-751.
36 Xu B, Sano T, Yoshimoto K, Yamada S. Downregulation of E-cadherin and its undercoat proteins in pituitary growth hormone cell adenomas with prominent fibrous bodies. Endocr Pathol,2002,13:341-351.
37 Sano T, Rong QZ, Kagawa N, Yamada S. Down-regulation of E-cadherin and catenins in human pituitary growth hormoneproducing adenomas. Front Horm Res,2004,32:127-132.
38 Obari A, Sano T, Ohyama K, et al. Clinicopathological features of growth hormone-producing pituitary adenomas:difference among various types defined by cytokeratin distribution pattern including a transitional form. Endocr Pathol, 2008,19:82-91.
39 Qian ZR, Li CC, Yamasaki H, et al. Role of E-cadherin, alpha-, beta-, and gamma-catenins, and p120 (cell adhesion molecules) in prolactinoma behavior. Mod Pathol,2002,15:1357-1365.
40 Zhi Rong Qian, Toshiaki Sano, Katsuhiko Yoshimoto, et al. Tumor-specific downregulation and methylation of the CDH13 (H-cadherin) and CDH1 (E-cadherin) genes correlate with aggressiveness of human pituitary adenomas. Mod Pathol,2007, 20:1269-1277.
41 Kawamoto H, Mizoue T, Arita K, et al. Expression of epithelial cadherin and cavernous sinus invasion in human pituitary adenomas. J Neurooncol,1997,34: 105-109.
42 Paez-Pereda M, Kuchenbauer F, Arzt E et al. Regulation of pituitary hormones and cell proliferation by components of the extracellular matrix. Braz J Med Biol Res, 2005,38:1487-1494.
43 Kuchenbauer F, Theodoropoulou M, Hopfner U, et al. Laminin inhibits lactotroph proliferation and is reduced in early prolactinoma development. Mol Cell Endocrinol, 2003,207:13-20.
44 Murphy G, Docherty AJ. The matrix metalloproteinases and their inhibitors. Am J Respir Cell Mol Biol,1992,7:120-125.
45 Knappe UJ, Hagel C, Lisboa BW, et al. Expression of serine proteases and metalloproteinases in human pituitary adenomas and anterior pituitary lobe tissue. Acta Neuropathologica,2003,106:471-478.
46 Turner HE, Nagy Z, Esiri MM, et al. Role of matrix metalloproteinase 9 in pituitary tumor behavior. J Clin Endocrinol Metab,2000,85:2931-2935.
47 Koutroulis I, Zarros A, Theocharis S. The role of matrix metalloproteinases in the pathophysiology and progression of human nervous system malignancies:a chance for the development of targeted therapeutic approaches? Expert Opin Ther Targets, 2008,12:1577-86.
48 Onofri C, Losa M, Uhl E, et al. Immunohistochemical analysis of VEGF-C/VEGFR-3 system and lymphatic vessel extent in normal and adenomatous human pituitary tissues. Exp Clin Endocrinol Diabetes,2008,116:152-7.
49 McCabe CJ, Khaira JS, Boelaert K, et al. Expression of pituitary tumour transforming gene (PTTG) and fibroblast growth factor-2 (FGF-2) in human pituitary adenomas:relationships to clinical tumour behaviour. Clin Endocrinol (Oxf),2003,58:141-50.
50 Jackson TA, Koterwas DM, Bradford AP. Differential regulation of cell growth and gene expression by FGF-2 and FGF-4 in pituitary lactotroph GH4 cells. Mol Cell Endocrinol,2006,247:183-91.
51 Mukdsi JH, De Paul AL, Petiti JP, et al. Pattern of FGF-2 isoform expression correlated with its biological action in experimental prolactinomas. Acta Neuropathol,2006,112:491-501.
52 Fan X, Childs GV. Epidermal growth factor and transforming growth factor-alpha messenger ribonucleic acids and their receptors in the rat anterior pituitary: localization and regulation. Endocrinology,1995,136:2284-2293.
53 Chabot JG, Walker P, Pelletier G. Distribution of epidermal growth factor binding sites in the adult rat anterior pituitary gland. Peptides,1986,7:45-50.
54 Jaffrain-Rea ML, Petrangeli E, Lubrano C, et al. Epidermal growth factor binding sites in human pituitary macroadenomas. J Endocrinol,1998,158:425-433.
1. Ezzat S, Asa SL, Couldwell WT, et al. The prevalence of pituitary adenomas:a systematic review[J]. Cancer,2004,101:613-19
2. Marek J. Pituitary adenomas--where is the treatment heading at the beginning of the 21st century? [J]. Vnitr Lek,2010 Jul,56(7):690-4
3. Zada G, Woodmansee W W, Ramkissoon S, et al. Atypical pituitary adenomas: incidence, clinical characteristics, and implications [J]. J Neurosurg,2011,114(2):336-344.
4. Aghi M K. Management of recurrent and refractory Cushing disease[J]. Nat Clin Pract Endocrinol Metab,2008,4(10):560-568.
5. Feigl G C, Pistracher K, Berghold A, et al. Pituitary insufficiency as a side effect after radiosurgery for pituitary adenomas:the role of the hypothalamus[J]. J Neurosurg,2010,113 Suppl:153-159.
6. Theodoropoulou M, Labeur M, Paez Pereda M, et al. Novel medical therapies for pituitary tumors[J]. Front Horm Res,2010,38:158-64.
7. Syro L V, Ortiz L D, Scheithauer B W, et al. Treatment of Pituitary Neoplasms With Temozolomide[J]. Cancer,2010;1-9.
8. Villano J L, Seery T E, Bressler L R. Temozolomide in malignant gliomas:current use and future targets[J]. Cancer Chemother Pharmacol,2009,64:647-55
9. Bei R, Marzocchella L, Turriziani M. The use of temozolomide for the treatment of malignant tumors:clinical evidence and molecular mechanisms of action[J]. Recent Pat Anticancer Drug Discov,2010,5(3):172-187.
10. Syro LV, Scheithauer BW, Ortiz LD, et al. Effect of Temozolomide in a patient with recurring oncocytic gonadotrophic pituitary adenoma[J]. Hormones (Athens),2009, 8(4):303-306
11. Hagen C, Schroeder HD, Hansen S, et al. Temozolomide treatment of a pituitary carcinoma and two pituitary macroadenomas resistant to conventional therapy [J]. Eur J Endocrinol,2009,161 631-637
12. Losa M, Mazza E, Terreni MR, et al. Salvage therapy with temozolomide in patients with aggressive or metastatic pituitary adenomas:experience in six cases[J]. Eur J Endocrinol,2010,163(6):843-51.
13. Mohammed S, Kovacs K, Mason W, et al. Use of temozolomide in aggressive pituitary tumors:case report[J]. Neurosurgery,2009,64:E773-E774.
14. Dillard T H, Gultekin S H, Delashaw J J, et al. Temozolomide for corticotroph pituitary adenomas refractory to standard therapy[J]. Pituitary,2011,14(1):80-91.
15. Morin E, Berthelet F, Weisnagel J, et al. Failure of temozolomide and conventional doses of pegvisomant to attain biochemical control in a severe case of acromegaly[J].. Pituitary,2010, [Epub ahead of print]
16. Thearle M S, Freda P U, Bruce J N, et al. Temozolomide (Temodar R) and capecitabine (XelodaR)treatment of an aggressive corticotroph pituitary tumor [J].. Pituitary,2009, [Epub ahead of print]
17. Neff LM, Weil M, Cole A, et al. Temozolomide in the treatment of an invasive prolactinoma resistant to dopamine agonists [J]. Pituitary,2007,10:81-86
18. Bode H, Seiz M, Lammert A, et al. SOM230 (pasireotide) and temozolomide achieve sustained control of tumour progression and ACTH secretion in pituitary carcinoma with widespread metastases[J]. Exp Clin Endocrinol Diabetes,2010,118(10):760-763.
19. Kovacs K, Scheithauer BW, Lombardero M, et al. MGMT immunoexpression predicts responsiveness of pituitary tumors to temozolomide therapy [J].. Acta Neuropathol,2008 Feb,115(2):261-2.
20. McCormack A I, McDonald K L, Gill A J, et al. Low 06-methylguanine-DNA methyltransferase (MGMT) expression and response to temozolomide in aggressive pituitary tumours[J]. Clin Endocrinol (Oxf),2009 Aug,71(2):226-33.
21. Bush Z M, Longtine J A, Cunningham T, et al. Temozolomide treatment for aggressive pituitary tumors:correlation of clinical outcome with O(6)-methylguanine methyltransferase (MGMT) promoter methylation and expression[J]. J Clin Endocrinol Metab,2010,95(11):E280-E290.
22. Raverot G, Sturm N, de Fraipont F, et al. Temozolomide treatment in aggressive pituitary tumors and pituitary carcinomas:a French multicenter experience [J]. J Clin Endocrinol Metab,2010,95(10):4592-4599.
23. Murakami M, Mizutani A, Asano S, et al. A mechanism of acquiring temozolomide resistance during transformation of atypical prolactinoma into prolactin-producing pituitary carcinoma[J]. Neurosurgery,2011.
24. Mrugala MM, Chamberlain MC. Mechanisms of disease:temozolomide and glioblastoma—look to the future[J].. Nat Clin Pract Oncol,2008,5:476-486.
25. Quinn JA, Jiang SX, Reardon DA, et al. Phase Ⅱ trial of temozolomide plus O6-benzylguanine in adults with recurrent, temozolomide-resistant malignant glioma. J Clin Oncol[J].2009,27:1262-1267.
26. Prasad G, Sottero T, Yang X, et al. Inhibition of PI3K/mTOR pathways in glioblastoma and implications for combination therapy with temozolomide[J]. Neuro Oncol,2011,13(4):384-392.
27. Plummer R, Jones C, Middleton M, et al. Phase Ⅰ study of the poly(ADP-ribose) polymerase inhibitor, AGO 14699, in combination with temozolomide in patients with advanced solid tumors[J]. Clin Cancer Res,2008,14(23):7917-7923.
28. Chaponis D, Barnes J W, Dellagatta J L, et al. Lonafarnib (SCH66336) improves the activity of temozolomide and radiation for orthotopic malignant gliomas[J]. J Neurooncol,2011.
29. Ulasov I V, Nandi S, Dey M, et al. Inhibition of Sonic hedgehog and Notch pathways enhances sensitivity of CD133(+) glioma stem cells to temozolomide therapy [J]. Mol Med,2011,17(1-2):103-112.
30. Iyer R, Evans A E, Qi X, et al. Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma[J]. Clin Cancer Res,2010,16(5):1478-1485.
31. Torres S, Lorente M, Rodriguez-Fornes F, et al. A combined preclinical therapy of cannabinoids and temozolomide against glioma[J]. Mol Cancer Ther,2011,10(1):90-103.
32. Gorshtein A, Rubinfeld H, Kendler E, et al. Mammalian target of rapamycin inhibitors rapamycin and RAD001 (everolimus) induce anti-proliferative effects in GH-secreting pituitary tumor cells in vitro[J]. Endocr Relat Cancer,2009,16: 1017-1027
33. Yao C, Evans C O, Stevens V L, et al. Folate receptor alpha regulates cell proliferation in mouse gonadotroph alphaT3-1 cells [J]. Exp Cell Res,2009,315(18):3125-3132.
34. Moyes V J, Alusi G, Sabin H I, et al. Treatment of Nelson's syndrome with temozolomide[J]. European Journal of Endocrinology,2009,160(1):115.
35. Syro L V, Uribe H, Penagos L C, et al. Antitumour effects of temozolomide in a man with a large, invasive prolactin-producing pituitary neoplasm [J]. Clin Endocrinol (Oxf),2006,65(4):552-553.
36. Kovacs K, Horvath E, Syro L V, et al. Temozolomide therapy in a man with an aggressive prolactin-secreting pituitary neoplasm:Morphological findings [J]. Hum Pathol,2007,38(1):185-189.