Cooperation of the Agonistic DR5 Antibody Apomab with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival
Cooperation of the Agonistic DR5 Antibody Apomab with Chemotherapy to Inhibit Orthotopic Lung Tumor Growth and Improve Survival
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DOI：
10.1158/1078-0432.ccr-08-0670
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发表时间：
2008-12-01
影响因子：
11.5
通讯作者：
Ashkenazi, Avi
中科院分区：
文献类型：
--
作者：
Jin, Hongkui;Yang, Renhui;Ashkenazi, Avi
目的：Apomab是一种全人源单克隆抗体，通过促凋亡受体DR 5在多种癌细胞中诱导程序性细胞死亡，但在正常细胞中不诱导程序性细胞死亡。几种肺癌细胞系表达DR 5和apomab在vitro.Experimental Design中表现出细胞凋亡反应：我们研究了apomab在基于人NCI-H460非小细胞肺癌细胞的异种移植模型中的疗效及其与化疗的相互作用。在建立的s.c.肿瘤异种移植物、apomab或泰素加卡铂化疗延迟了肿瘤进展，而联合治疗导致肿瘤消退和显著更长的生长延迟。为了测试apomab活性的设置，可能更接近模拟肺癌患者的病理，我们开发了一个肺原位model.Results：在这个模型中，显微计算机断层扫描成像显示，apomab，化疗，或联合治疗显着抑制肿瘤生长相比，车辆，而组合造成更大的抑制肿瘤生长相对于化疗或apomab。同样，组织学分析显示，与溶媒相比，apomab、化疗或联合用药显著缩小了肿瘤大小，而联合用药比化疗或apomab诱导的肿瘤大小缩小幅度更大。此外，相对于溶媒，联合治疗改善了105天存活率（P = 0.0023）以及apomab（P = 0.0445）或化疗（P = 0.0415）。这些结果表明apomab与化疗之间存在积极的相互作用，表现为显著抑制肿瘤生长以及改善生存率，从而支持在肺癌患者中进一步研究这种治疗方法。
Purpose: Apomab is a fully human monoclonal antibody that induces programmed cell death through the proapoptotic receptor DR5 in various cancer cells but not in normal cells. Several lung cancer cell lines express DR5 and exhibit apoptosis in response to apomab in vitro.Experimental Design: We investigated the efficacy of apomab and its interaction with chemotherapy in xenograft models based on human NCI-H460 non-small-cell lung carcinoma cells. In an established model of s.c. tumor xenografts, apomab or Taxol plus carboplatin chemotherapy delayed tumor progression, whereas combined treatment caused tumor regression and a substantially longer growth delay. To test apomab activity in a setting that may more closely mimic lung cancer pathology in patients, we developed a lung orthotopic model.Results: In this model, microcomputed tomography imaging showed that apomab, chemotherapy, or combination treatment significantly inhibited tumor growth compared with vehicle, whereas the combination caused greater inhibition in tumor growth relative to chemotherapy or apomab. Similarly, histologic analysis revealed that apomab, chemotherapy, or the combination significantly reduced tumor size compared with vehicle, whereas the combination induced significantly greater reduction in tumor size than did chemotherapy or apomab. Furthermore, combined treatment improved 105-day survival relative to vehicle (P = 0.0023) as well as to apomab (P = 0.0445) or chemotherapy (P = 0.0415).Conclusion: These results show a positive interaction of apomab with chemotherapy, evidenced by significant inhibition of tumor growth as well as improved survival, thus supporting further investigation of this therapeutic approach in lung cancer patients.