新型免疫增强剂T肽对术后残瘤生长的抑制作用及相关分子机制研究
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摘要
肿瘤是威胁人类生命的主要疾病之一,发生率呈现逐年上升的趋势。手术、放疗、化疗等是目前治疗肿瘤患者的主要手段,近年来通过提高自身免疫系统的天然防御机制达到抗肿瘤的免疫治疗手段同样受到了人们的重视。我国对肿瘤的早期筛查还不普及,相当多的肿瘤患者一旦确诊,就已经处于中晚期,大多数已经发生严重的局部浸润和远处转移。对于实体癌患者来说,手术切除瘤体是首选的治疗措施。目前手术能最大限度地减低肿瘤负荷,但除净肿瘤细胞的可能性较小,相当一部分病人只能进行姑息性手术。因此许多肿瘤患者手术后,仍然存在术后的残余瘤灶和远处转移的微小瘤灶的客观现实。一些临床观察和动物实验研究表明,手术后残余肿瘤组织的生长速度往往更快,盲目采取手术切除肿瘤,会使残余肿瘤细胞生长速度大大提高,加速肿瘤转移和复发。手术后给予患者放化疗措施,使病人经受手术和放化疗毒副作用的双重打击,不堪忍受。事实上有许多中晚期癌症病人进行手术后,生存期限可能会更短、生活质量更差。肿瘤患者手术后的治疗,消除残存的肿瘤灶和避免肿瘤复发,是医学工作者的重要关注点。
目前抗癌药物临床前药效评价模型主要包括小鼠移植瘤模型、缺少T细胞免疫的裸鼠移植瘤模型以及既缺少T细胞免疫也缺少B细胞免疫的SCID鼠模型。无论是免疫功能正常的小鼠模型,还是免疫功能有缺陷的裸鼠或SCID鼠模型,现存的动物评价模型对免疫抗癌药物的筛选和评价均存在一定的限制。因为肿瘤所处的微环境是一个深度免疫抑制区,是免疫细胞进入肿瘤内部、杀伤肿瘤细胞的屏障;且存在于肿瘤微环境内部的免疫细胞,其功能也会发生明显的改变,尤其是巨噬细胞。因此设计合理的免疫药物临床前药效评价动物模型对于免疫药物的筛选和评价十分重要。手术切除破坏了肿瘤微环境的平衡,可能为免疫增强剂发挥抗癌作用提供机会。临床上,免疫治疗逐渐用于术后免疫干预,那么,建立更贴近临床的动物模型是我们工作的第一步。
在本研究中,我们成功的建立了一种新型的肿瘤药效学研究模型---小鼠术后残瘤模型,即将小鼠皮下已经生长至一定体积的移植瘤手术切除部分瘤组织,无菌条件下缝合,再进行抗癌药物的体内药效学评价。在该模型建立的基础上,我们首先进一步证明了手术后肿瘤复发速度大大加快;继而我们观察了T肽抑制小鼠移植瘤术后残瘤生长的药效学实验,并得到了理想的实验结果。为了更近似的模拟临床上肿瘤患者的实际情况,我们在小鼠单瘤术后残瘤模型的基础上加以改进,在右侧皮下接种有移植瘤的小鼠左侧腋下也皮下接种肿瘤,但只将右侧肿瘤手术切除部分瘤组织,左侧肿瘤不进行手术,再进行药效学评价。术后单瘤残瘤模型和双瘤模型更符合临床实际情况,有利于免疫药物的体内抗肿瘤药效学评价。
脾脏是体内最重要的免疫器官之一。美国Tufts大学Najjar教授,于1970年发现一种来源于脾脏的四肽物质具有显著地抗肿瘤、抗病毒活性,并命名为Tuftsin,因其具有促进巨噬细胞的吞噬活性,又称为天然吞噬作用促进肽。其分子量为500,一级结构为苏-赖-脯-精。研究证实Tuftsin能激活粒细胞、单核细胞以及巨噬细胞,通过提高它们的趋化、游离、吞噬和CTL作用,增强体内淋巴系统的细胞免疫活性,产生抗肿瘤效应。Tuftsin是四肽结构,进入体内很快被体内的羧肽酶B等降解失去活性,成为抗癌新药的可能性较小。本实验室与其他公司合作通过对其结构进行改造得到了新的Tuftsin衍生物,命名为T肽,即通过赖氨酸将Tuftsin连接得到的化合物。T肽保持了原有四肽的功能、提高了其抗酶解能力、延长了体内半衰期。探讨T肽是否具有更强的抗癌效应,是本实验室进行研究的初衷。
在药效和机理研究实验中,我们首先观察了T肽对S180、H22、Lewis、B16-BL6等四种鼠源移植瘤以及HT-29结肠癌、HepG2肝癌、MCF-7乳腺癌、BGC-823胃癌等四种人源移植瘤手术后残瘤生长的抑制作用。实验结果显示,T肽可以明显抑制小鼠移植瘤术后残瘤的生长,最高抑制率达到80%; T肽对裸鼠移植瘤术后残瘤生长的抑制作用稍有降低,最高抑制率达到60%以上;而T肽对SCID鼠移植瘤术后残瘤生长的抑制作用最低,抑制率为45%。小鼠模型机体免疫系统正常,既有T淋巴细胞,也有B淋巴细胞,T肽可以明显抑制小鼠移植瘤术后残瘤的生长;裸鼠模型缺少胸腺,缺少T淋巴细胞,B淋巴细胞功能稍有缺陷,而T肽对裸鼠移植瘤术后残瘤生长的抑制作用明显低于对小鼠残瘤生长的抑制作用,说明T肽对B淋巴细胞和T淋巴细胞的功能均产生影响;SCID鼠模型既缺少T淋巴细胞的免疫功能,也缺少B淋巴细胞的免疫功能,但仍有巨噬细胞、自然杀伤细胞等免疫细胞发挥功能,T肽对SCID鼠移植瘤术后残瘤生长的抑制作用比对裸鼠残瘤生长的抑制作用又进一步降低,说明T肽对巨噬细胞、自然杀伤细胞的功能也有明显影响。我们进一步建立了小鼠双瘤模型---即在小鼠右侧肩部和左侧腋下均接种肿瘤,当肿瘤生长至一定体积时,手术切除右侧肩部的部分瘤组织,术后24h给药;实验结果显示,T肽不仅可以抑制术后残留的生长,对双瘤模型未手术瘤生长的抑制率也达到70%。进而,我们又设计了假手术实验,结果显示,手术应激对T肽发挥抗肿瘤作用的影响并不显著。在体内药效学实验结果的基础上,我们又通过MTT、流式检测、ELISA、免疫组化、RT-PCR、Western Blot等研究了T肽的作用机理。在体外药效学实验中,T肽可以明显促进巨噬细胞的生长速度以及吞噬功能;ELISA、RT-PCR等实验证实了T肽对TNF-α、NO等因子的影响;免疫组化、Western等证实了T肽对MIP-1α以及VEGF等的影响。以上结果预示着T肽有潜力成为预防术后残瘤生长的新药。
综上所述,我们成功建立了一种新型体内抗肿瘤药效学评价模型-术后残瘤模型,研究了T肽对术后残瘤生长的抑制作用;并以该模型为基础,探索T肽的抗癌作用机理,发现T肽对巨噬细胞吞噬功能的影响;该模型的建立为免疫制剂抗肿瘤药物的体内药效学评价提供有力帮助。
As an important disease threat anthropohealth, the incidence of cancer rises every year. Surgery, radiotherapy and chemotherapy are major methods for clinical patients with malignancy. Currently, although immunotherapies for the treatment of cancer are now gaining wider acceptance as viable alternative therapies for treating certain tumor types, such was not always the case. Surgery is still the main curative therapeutic modality for many solid tumors, and reduces the primary tumor burden maximumly. But the process of surgery could increase the risk of recurrence and metastases of residual cancer cells to other sites. Furthermore, there is severe toxicity of radiotherapy and chemotherapy as postoperative therapies, that patients can’t suffer from. It is well known that major surgery are associated with severe alterations of the host defense mechanisms, making the patients hightly susceptible inflammatory responses, which intimately correlated with tumor recurrence. A few studies indicated that surgical removal of tumors is insufficient to conquer the profound immunosuppression in patients. Thus, immunotherapy as a promising approaches is used for postoperative cancer patiens.
The immunomodulator tuftsin is a nature tetrapeptide (Thr-Lys-Pro-Arg)derived from spleen,isolated at Tufts University by Najjara and co-workers in 1970s. It binds specifically to macrophages, monocytes, and polymorpho-nuclear leukocytes and stimulates them to evoke immunomodulatory activity and tumoricidal properties. The features of tuftsin, coupled with its low toxicity, make the peptide an attractive candidate for immunotherapy. A few studies have reported that tuftsin prevented spontaneous tumor development, after administered for 6 months at the dose of 10μg once a week. However, tuftsin, short half-life (CL = 0.34 L/h,t1/2 = 2.8 h) was degraded in vivo by carboxypeptidase B easily. So tuftsin is less likely to be a novel medicine. In our laboratory in cooperation with a company, the structure of tuftsin has been transformed to obtain a new tuftsin derivative, named T-peptide (TP), which maintained the original function of tetrapeptide, increased anti-enzyme capacity and stability, andextended in vivo half-life.
Currently, preclinical oncological evaluation models, including murine xenografts models, nude murine xenograft models that are short of T lymphocytes, and SCID murine xenograft models that are short of T and B lymphocytes, all confine the anticancer evaluation of many immunoagents. Because tumor microenvironment is a deep immunodepression area, in which functions of many immunocytes can be inhibited or changed, such as Type M1 and Type M2 macrophages. Currently, immunotherapy is used for postsurgerical intervention. It is important that a kind of murine model is established, which is close to clinical status and used for the pharmacodynamic evaluation of immunoagents.
B ased on the studies mentioned above, we successfully established a novel murine pharmacodynamics model---mice with a postsurgery residual tumor. Our present studies demonstrated surgery had a promoting effect on tumor growth, if postsurgery residual tumor still remained in body. As a immunotherapeutic drugs, the effect of TP on traditional murine xenograft model and directly killing tumor cells was not conspicuous. Because of some anticancer effects of TP administated before tumors grew out and no effects administrated after tumor volumes reached 150mm3,the experiments suggested that many factors possibly confined TP to play actions, such as immune escape, tumor microenvironment, cytokines and immunosuppression. Before the formation of tumor environment,TP could activate macrophages,T lymphocyte,NK, etc. to play anticancer effects. Perhaps, tumor environment as a screen or a black hole, limited drugs to penetrate tumor tissue and to reach all of the tumor cells, in which the anticancer functions of immunocytes were severely inhibited. Based on the studies of traditional murine models in vivo, we researched the anticancer effects of TP on murine mice with postsurgery residual tumors. The results displayed better effcts that the inhibition rate reached above 80% maximally, and almost no toxicity.
C ompared with clinical conditions,many tumor patients may have postsurgery residual tumors and metastasis that is not discovered. TP can apparently inhibit the growth of postsurgery residual tumors,and can it inhibit the growth of distant metastasis? We designed another murine model with a postsurgery residual tumor on right and a nonsurgery tumor on left. Suprisingly,TP is also able to inhibite the growth of nonsurgery tumor on left. The effects of surgery on nonsurgery tumors may be attributed to a number of factors, including immunodepression after surgical stress, action of cytokines or changes of tumor microenvironment.To deplete the inflence of surgery stress on the anticancer effects of TP, we designed a murine model with a pseudosurgery tumor mentioned above. The results certified surgery stress did not apperently affect the anticancer action of TP.
T he anticancer effects might be related to the postoperative interaction of TP and immunocytes that result in the changes of immune state and the production of cytokines, such as Tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Based on anticancer pharmacodynamic action of TP in vitro and in vivo, we furtherly studied the effects of TP on T lymphocytes and macrophages by flow cytometry, RT-PCR, immunohistochemistry, ELISA, and so on. As one of the most important and perplexing immunocytes residing in tumor microenvironment for long terms, macrophage gradually formed its distinct phenotypes and functions, being type M2 macrophage, i.e. tumor- associated macrophages. TAMs are also associated with increased angiogenesis in cancer tissues. Macrophage inflammatory protein 1α(MIP-1α) is from the CC (cysteinecystein) chemokine subfamily, known to be secreted from monocytes, activated macrophages, lymphocytes, and other cell types. Meanwhile, MIP-1αrelates with tumor metastases and angiogenesis.We are interested in the decrease in MIP-1αof tumor tissues and the increase expression of spleen tissues by RT-PCR and immunohistochemistry analysis.The results indicated TP might inhibite the functions of TAMs, but promote phagocytosis of macrophages.And then,we also measured the level of mouse vascular endothelial growth factor (VEGF)in tumor and Ana-1 cells by Western blotting.
In conclusion,we successfully established a novel murine model with a postsurgery residual tumors for anticancer pharmacodynamics evaluation. And we researched the anticancer effects of TP on this novel murine model in vivo and in vitro. On the basis of the new model, we studied the mechanisms of TP on macrophages, TAMs and T leukomonocytes. The results and the known low toxicity are clues that TP might be a promising candidate drug for the treatment of clinical patients with postsurgery residual tumors or micrometastasis.
目前抗癌药物临床前药效评价模型主要包括小鼠移植瘤模型、缺少T细胞免疫的裸鼠移植瘤模型以及既缺少T细胞免疫也缺少B细胞免疫的SCID鼠模型。无论是免疫功能正常的小鼠模型,还是免疫功能有缺陷的裸鼠或SCID鼠模型,现存的动物评价模型对免疫抗癌药物的筛选和评价均存在一定的限制。因为肿瘤所处的微环境是一个深度免疫抑制区,是免疫细胞进入肿瘤内部、杀伤肿瘤细胞的屏障;且存在于肿瘤微环境内部的免疫细胞,其功能也会发生明显的改变,尤其是巨噬细胞。因此设计合理的免疫药物临床前药效评价动物模型对于免疫药物的筛选和评价十分重要。手术切除破坏了肿瘤微环境的平衡,可能为免疫增强剂发挥抗癌作用提供机会。临床上,免疫治疗逐渐用于术后免疫干预,那么,建立更贴近临床的动物模型是我们工作的第一步。
在本研究中,我们成功的建立了一种新型的肿瘤药效学研究模型---小鼠术后残瘤模型,即将小鼠皮下已经生长至一定体积的移植瘤手术切除部分瘤组织,无菌条件下缝合,再进行抗癌药物的体内药效学评价。在该模型建立的基础上,我们首先进一步证明了手术后肿瘤复发速度大大加快;继而我们观察了T肽抑制小鼠移植瘤术后残瘤生长的药效学实验,并得到了理想的实验结果。为了更近似的模拟临床上肿瘤患者的实际情况,我们在小鼠单瘤术后残瘤模型的基础上加以改进,在右侧皮下接种有移植瘤的小鼠左侧腋下也皮下接种肿瘤,但只将右侧肿瘤手术切除部分瘤组织,左侧肿瘤不进行手术,再进行药效学评价。术后单瘤残瘤模型和双瘤模型更符合临床实际情况,有利于免疫药物的体内抗肿瘤药效学评价。
脾脏是体内最重要的免疫器官之一。美国Tufts大学Najjar教授,于1970年发现一种来源于脾脏的四肽物质具有显著地抗肿瘤、抗病毒活性,并命名为Tuftsin,因其具有促进巨噬细胞的吞噬活性,又称为天然吞噬作用促进肽。其分子量为500,一级结构为苏-赖-脯-精。研究证实Tuftsin能激活粒细胞、单核细胞以及巨噬细胞,通过提高它们的趋化、游离、吞噬和CTL作用,增强体内淋巴系统的细胞免疫活性,产生抗肿瘤效应。Tuftsin是四肽结构,进入体内很快被体内的羧肽酶B等降解失去活性,成为抗癌新药的可能性较小。本实验室与其他公司合作通过对其结构进行改造得到了新的Tuftsin衍生物,命名为T肽,即通过赖氨酸将Tuftsin连接得到的化合物。T肽保持了原有四肽的功能、提高了其抗酶解能力、延长了体内半衰期。探讨T肽是否具有更强的抗癌效应,是本实验室进行研究的初衷。
在药效和机理研究实验中,我们首先观察了T肽对S180、H22、Lewis、B16-BL6等四种鼠源移植瘤以及HT-29结肠癌、HepG2肝癌、MCF-7乳腺癌、BGC-823胃癌等四种人源移植瘤手术后残瘤生长的抑制作用。实验结果显示,T肽可以明显抑制小鼠移植瘤术后残瘤的生长,最高抑制率达到80%; T肽对裸鼠移植瘤术后残瘤生长的抑制作用稍有降低,最高抑制率达到60%以上;而T肽对SCID鼠移植瘤术后残瘤生长的抑制作用最低,抑制率为45%。小鼠模型机体免疫系统正常,既有T淋巴细胞,也有B淋巴细胞,T肽可以明显抑制小鼠移植瘤术后残瘤的生长;裸鼠模型缺少胸腺,缺少T淋巴细胞,B淋巴细胞功能稍有缺陷,而T肽对裸鼠移植瘤术后残瘤生长的抑制作用明显低于对小鼠残瘤生长的抑制作用,说明T肽对B淋巴细胞和T淋巴细胞的功能均产生影响;SCID鼠模型既缺少T淋巴细胞的免疫功能,也缺少B淋巴细胞的免疫功能,但仍有巨噬细胞、自然杀伤细胞等免疫细胞发挥功能,T肽对SCID鼠移植瘤术后残瘤生长的抑制作用比对裸鼠残瘤生长的抑制作用又进一步降低,说明T肽对巨噬细胞、自然杀伤细胞的功能也有明显影响。我们进一步建立了小鼠双瘤模型---即在小鼠右侧肩部和左侧腋下均接种肿瘤,当肿瘤生长至一定体积时,手术切除右侧肩部的部分瘤组织,术后24h给药;实验结果显示,T肽不仅可以抑制术后残留的生长,对双瘤模型未手术瘤生长的抑制率也达到70%。进而,我们又设计了假手术实验,结果显示,手术应激对T肽发挥抗肿瘤作用的影响并不显著。在体内药效学实验结果的基础上,我们又通过MTT、流式检测、ELISA、免疫组化、RT-PCR、Western Blot等研究了T肽的作用机理。在体外药效学实验中,T肽可以明显促进巨噬细胞的生长速度以及吞噬功能;ELISA、RT-PCR等实验证实了T肽对TNF-α、NO等因子的影响;免疫组化、Western等证实了T肽对MIP-1α以及VEGF等的影响。以上结果预示着T肽有潜力成为预防术后残瘤生长的新药。
综上所述,我们成功建立了一种新型体内抗肿瘤药效学评价模型-术后残瘤模型,研究了T肽对术后残瘤生长的抑制作用;并以该模型为基础,探索T肽的抗癌作用机理,发现T肽对巨噬细胞吞噬功能的影响;该模型的建立为免疫制剂抗肿瘤药物的体内药效学评价提供有力帮助。
As an important disease threat anthropohealth, the incidence of cancer rises every year. Surgery, radiotherapy and chemotherapy are major methods for clinical patients with malignancy. Currently, although immunotherapies for the treatment of cancer are now gaining wider acceptance as viable alternative therapies for treating certain tumor types, such was not always the case. Surgery is still the main curative therapeutic modality for many solid tumors, and reduces the primary tumor burden maximumly. But the process of surgery could increase the risk of recurrence and metastases of residual cancer cells to other sites. Furthermore, there is severe toxicity of radiotherapy and chemotherapy as postoperative therapies, that patients can’t suffer from. It is well known that major surgery are associated with severe alterations of the host defense mechanisms, making the patients hightly susceptible inflammatory responses, which intimately correlated with tumor recurrence. A few studies indicated that surgical removal of tumors is insufficient to conquer the profound immunosuppression in patients. Thus, immunotherapy as a promising approaches is used for postoperative cancer patiens.
The immunomodulator tuftsin is a nature tetrapeptide (Thr-Lys-Pro-Arg)derived from spleen,isolated at Tufts University by Najjara and co-workers in 1970s. It binds specifically to macrophages, monocytes, and polymorpho-nuclear leukocytes and stimulates them to evoke immunomodulatory activity and tumoricidal properties. The features of tuftsin, coupled with its low toxicity, make the peptide an attractive candidate for immunotherapy. A few studies have reported that tuftsin prevented spontaneous tumor development, after administered for 6 months at the dose of 10μg once a week. However, tuftsin, short half-life (CL = 0.34 L/h,t1/2 = 2.8 h) was degraded in vivo by carboxypeptidase B easily. So tuftsin is less likely to be a novel medicine. In our laboratory in cooperation with a company, the structure of tuftsin has been transformed to obtain a new tuftsin derivative, named T-peptide (TP), which maintained the original function of tetrapeptide, increased anti-enzyme capacity and stability, andextended in vivo half-life.
Currently, preclinical oncological evaluation models, including murine xenografts models, nude murine xenograft models that are short of T lymphocytes, and SCID murine xenograft models that are short of T and B lymphocytes, all confine the anticancer evaluation of many immunoagents. Because tumor microenvironment is a deep immunodepression area, in which functions of many immunocytes can be inhibited or changed, such as Type M1 and Type M2 macrophages. Currently, immunotherapy is used for postsurgerical intervention. It is important that a kind of murine model is established, which is close to clinical status and used for the pharmacodynamic evaluation of immunoagents.
B ased on the studies mentioned above, we successfully established a novel murine pharmacodynamics model---mice with a postsurgery residual tumor. Our present studies demonstrated surgery had a promoting effect on tumor growth, if postsurgery residual tumor still remained in body. As a immunotherapeutic drugs, the effect of TP on traditional murine xenograft model and directly killing tumor cells was not conspicuous. Because of some anticancer effects of TP administated before tumors grew out and no effects administrated after tumor volumes reached 150mm3,the experiments suggested that many factors possibly confined TP to play actions, such as immune escape, tumor microenvironment, cytokines and immunosuppression. Before the formation of tumor environment,TP could activate macrophages,T lymphocyte,NK, etc. to play anticancer effects. Perhaps, tumor environment as a screen or a black hole, limited drugs to penetrate tumor tissue and to reach all of the tumor cells, in which the anticancer functions of immunocytes were severely inhibited. Based on the studies of traditional murine models in vivo, we researched the anticancer effects of TP on murine mice with postsurgery residual tumors. The results displayed better effcts that the inhibition rate reached above 80% maximally, and almost no toxicity.
C ompared with clinical conditions,many tumor patients may have postsurgery residual tumors and metastasis that is not discovered. TP can apparently inhibit the growth of postsurgery residual tumors,and can it inhibit the growth of distant metastasis? We designed another murine model with a postsurgery residual tumor on right and a nonsurgery tumor on left. Suprisingly,TP is also able to inhibite the growth of nonsurgery tumor on left. The effects of surgery on nonsurgery tumors may be attributed to a number of factors, including immunodepression after surgical stress, action of cytokines or changes of tumor microenvironment.To deplete the inflence of surgery stress on the anticancer effects of TP, we designed a murine model with a pseudosurgery tumor mentioned above. The results certified surgery stress did not apperently affect the anticancer action of TP.
T he anticancer effects might be related to the postoperative interaction of TP and immunocytes that result in the changes of immune state and the production of cytokines, such as Tumour necrosis factor-alpha (TNF-α) and interleukin-6 (IL-6). Based on anticancer pharmacodynamic action of TP in vitro and in vivo, we furtherly studied the effects of TP on T lymphocytes and macrophages by flow cytometry, RT-PCR, immunohistochemistry, ELISA, and so on. As one of the most important and perplexing immunocytes residing in tumor microenvironment for long terms, macrophage gradually formed its distinct phenotypes and functions, being type M2 macrophage, i.e. tumor- associated macrophages. TAMs are also associated with increased angiogenesis in cancer tissues. Macrophage inflammatory protein 1α(MIP-1α) is from the CC (cysteinecystein) chemokine subfamily, known to be secreted from monocytes, activated macrophages, lymphocytes, and other cell types. Meanwhile, MIP-1αrelates with tumor metastases and angiogenesis.We are interested in the decrease in MIP-1αof tumor tissues and the increase expression of spleen tissues by RT-PCR and immunohistochemistry analysis.The results indicated TP might inhibite the functions of TAMs, but promote phagocytosis of macrophages.And then,we also measured the level of mouse vascular endothelial growth factor (VEGF)in tumor and Ana-1 cells by Western blotting.
In conclusion,we successfully established a novel murine model with a postsurgery residual tumors for anticancer pharmacodynamics evaluation. And we researched the anticancer effects of TP on this novel murine model in vivo and in vitro. On the basis of the new model, we studied the mechanisms of TP on macrophages, TAMs and T leukomonocytes. The results and the known low toxicity are clues that TP might be a promising candidate drug for the treatment of clinical patients with postsurgery residual tumors or micrometastasis.
引文
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