Shoemaker Alex R, Mitten Michael J, Adickes Jessica, Ackler Scott, Refici Marion, Ferguson Debra, Oleksijew Anatol, O'Connor Jacqueline M, Wang Baole, Frost David J, Bauch Joy, Marsh Kennan, Tahir Steven K, Yang Xiufen, Tse Christin, Fesik Stephen W, Rosenberg Saul H, Elmore Steven W
Global Pharmaceutical Research and Development, Abbott, Abbott Park, IL, USA.
Clin Cancer Res. 2008 Jun 1;14(11):3268-77. doi: 10.1158/1078-0432.CCR-07-4622.
The purpose of this study was to characterize the activity of the Bcl-2 protein family inhibitor ABT-263 in a panel of small cell lung cancer (SCLC) xenograft models.
A panel of 11 SCLC xenograft models was established to evaluate the efficacy of ABT-263. Single agent activity was examined on a continuous dosing schedule in each of these models. The H146 model was used to further evaluate dose and schedule, comparison to standard cytotoxic agents, and induction of apoptosis.
ABT-263 exhibited a range of antitumor activity, leading to complete tumor regression in several models. Significant regressions of tumors as large as 1 cc were also observed. The efficacy of ABT-263 was also quite durable; in several cases, minimal tumor regrowth was noted several weeks after the cessation of treatment. Antitumor effects were equal or superior to that of several clinically approved cytotoxic agents. Regression of large established tumors was observed through several cycles of therapy and efficacy was retained in a Pgp-1 overexpressing line. Significant efficacy was observed on several dose and therapeutic schedules and was associated with significant induction of apoptosis.
ABT-263 is a potent, orally bioavailable inhibitor of Bcl-2 family proteins that has recently entered clinical trials. The efficacy data reported here suggest that SCLC is a promising area of clinical investigation with this agent.
本研究旨在表征Bcl-2蛋白家族抑制剂ABT-263在一组小细胞肺癌（SCLC）异种移植模型中的活性。
建立了一组11个SCLC异种移植模型以评估ABT-263的疗效。在这些模型中的每一个中，按照连续给药方案检测单药活性。使用H146模型进一步评估剂量和给药方案、与标准细胞毒性药物的比较以及凋亡诱导情况。
ABT-263表现出一系列抗肿瘤活性，在多个模型中导致肿瘤完全消退。还观察到直径达1 cc的肿瘤有显著消退。ABT-263的疗效也相当持久；在几个病例中，治疗停止数周后肿瘤的再生长微乎其微。抗肿瘤作用等同于或优于几种临床批准的细胞毒性药物。通过几个治疗周期观察到已形成的大肿瘤消退，并且在过表达Pgp-1的细胞系中疗效得以保留。在几种剂量和治疗方案下均观察到显著疗效，并且与显著的凋亡诱导相关。
ABT-263是一种强效的、口服生物可利用的Bcl-2家族蛋白抑制剂，最近已进入临床试验。此处报告的疗效数据表明，SCLC是使用该药物进行临床研究的一个有前景的领域。
