Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer
Preclinical evaluation of synergistic effect of telomerase-specific oncolytic virotherapy and gemcitabine for human lung cancer
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DOI：
10.1158/1535-7163.mct-08-0901
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发表时间：
2009-04-01
影响因子：
5.7
通讯作者：
Fujiwara, Toshiyoshi
中科院分区：
文献类型：
--
作者：
Liu, Dong;Kojima, Toru;Fujiwara, Toshiyoshi
端粒酶特异性溶瘤腺病毒OBP-301（端粒溶素）的I期剂量递增研究目前正在美国进行，以评估其在晚期实体瘤患者中的可行性并表征其药代动力学。本临床前研究调查OBP-301和常用于肺癌治疗的化疗剂吉西他滨是否能够增强体外和体内的抗肿瘤作用。采用2，3-二[2-甲氧基-4-硝基-5-磺基苯基]-2H-四氮唑-5-甲酰苯胺内盐法评价OBP-301感染和吉西他滨的抗肿瘤作用。在nu/nu小鼠s.c.异种移植的人肺肿瘤OBP-301感染联合吉西他滨在人肺癌细胞中产生非常有效的协同细胞毒性。OBP-301作用24 h后，三种人肺癌细胞株均出现S期聚集。S期细胞比例在H460细胞中从43.85%增加到56.41%，在H322细胞中从46.72%增加到67.09%，在H358细胞中从38.22%增加到57.67%。肿瘤内注射OBP-301联合全身给药吉西他滨在人肺肿瘤异种移植物中显示出治疗协同作用。我们的数据表明，OBP-301和吉西他滨的组合增强了对人肺癌的抗肿瘤作用。我们还发现，协同作用的机制可能是由于OBP-301介导的细胞周期积累在S期。这些结果对人类肺癌的治疗具有重要意义。[Mol癌症治疗2009;8（4）：980-7]
A phase I dose-escalation study of telomerase-specific oncolytic adenovirus, OBP-301 (Telomelysin), is now under way in the United States to assess feasibility and to characterize its pharmacokinetics in patients with advanced solid tumors. The present preclinical study investigates whether OBP-301 and a chemotherapeutic agent that is commonly used for lung cancer treatment, gemcitabine, are able to enhance antitumor effects in vitro and in vivo. The antitumor effects of OBP-301 infection and gemcitabine were evaluated by 2,3-bis[2-methoxy-4-nitro-5-sulfophenyl]-2H-tetrazolium-5-carboxanilide inner salt assay. In vivo antitumor effects of intratumoral injection of OBP-301 in combination with systemic administration of gemcitabine were assessed on nu/nu mice s.c. xenografted with human lung tumors. OBP-301 infection combined with gemcitabine resulted in very potent synergistic cytotoxicity in human lung cancer cells. The three human lung cancer cell lines treated with OBP-301 for 24 hours tended to accumulate in S phase compared with controls. The proportion of cells in S phase increased from 43.85% to 56.41% in H460 cells, from 46.72% to 67.09% in H322 cells, and from 38.22% to 57.67% in H358 cells. Intratumoral injection of OBP-301 combined with systemic administration of gemcitabine showed therapeutic synergism in human lung tumor xenografts. Our data suggest that the combination of OBP-301 and gemcitabine enhances the antitumor effects against human lung cancer. We also found that the synergistic mechanism may be due to OBP-301-mediated cell cycle accumulation in S phase. These results have important implications for the treatment of human lung cancer. [Mol Cancer Ther 2009;8(4):980-7]