Mason Kylie D, Vandenberg Cassandra J, Scott Clare L, Wei Andrew H, Cory Suzanne, Huang David C S, Roberts Andrew W
The Walter and Eliza Hall Institute of Medical Research, Melbourne, Victoria 3050, Australia.
Proc Natl Acad Sci U S A. 2008 Nov 18;105(46):17961-6. doi: 10.1073/pnas.0809957105. Epub 2008 Nov 11.
Deregulated Myc expression drives many human cancers, including Burkitt's lymphoma and a highly aggressive subset of diffuse large cell lymphomas. Myc-driven tumors often display resistance to chemotherapeutics because of acquisition of mutations that impair the apoptosis pathway regulated by the Bcl-2 protein family. Given the need to identify new therapies for such lymphomas, we have evaluated the efficacy of ABT-737, a small molecule that mimics the action of the BH3-only proteins, natural antagonists of the prosurvival Bcl-2 proteins. ABT-737 selectively targets certain prosurvival proteins (Bcl-2, Bcl-x(L), and Bcl-w) but not others (Mcl-1 and A1). We treated mice transplanted with lymphomas derived either from Emu-myc transgenic mice or Emu-myc mice that also expressed an Emu-bcl-2 transgene. As a single agent, ABT-737 significantly prolonged the survival of mice transplanted with the myc/bcl-2 lymphomas but was ineffective for the myc lymphomas, probably because of the relatively higher Mcl-1 levels found in the latter. Strikingly, when combined with low-dose cyclophosphamide, ABT-737 produced sustained disease-free survival of all animals transplanted with two of three myc/bcl-2 lymphomas tested. The combination therapy was also more effective against some myc lymphomas than treatment with either agent alone. Our data suggest that antagonism of Bcl-2 with small organic compounds is an attractive approach to enhance the efficacy of conventional therapy for the treatment of Myc-driven lymphomas that over-express this prosurvival molecule.
Myc 表达失调会引发多种人类癌症，包括伯基特淋巴瘤和弥漫性大细胞淋巴瘤中极具侵袭性的一个亚群。Myc 驱动的肿瘤通常对化疗药物产生耐药性，这是因为获得了损害由 Bcl-2 蛋白家族调节的凋亡途径的突变。鉴于需要为这类淋巴瘤寻找新的治疗方法，我们评估了 ABT-737 的疗效，ABT-737 是一种小分子，可模拟仅含 BH3 结构域蛋白的作用，后者是促生存 Bcl-2 蛋白的天然拮抗剂。ABT-737 选择性地靶向某些促生存蛋白（Bcl-2、Bcl-x(L) 和 Bcl-w），而不靶向其他蛋白（Mcl-1 和 A1）。我们用源自 Emu-myc 转基因小鼠或同时表达 Emu-bcl-2 转基因的 Emu-myc 小鼠的淋巴瘤移植到小鼠体内进行治疗。作为单一药物，ABT-737 显著延长了移植了 myc/bcl-2 淋巴瘤小鼠的生存期，但对 myc 淋巴瘤无效，这可能是因为后者中 Mcl-1 水平相对较高。令人惊讶的是，当与低剂量环磷酰胺联合使用时，ABT-737 使所有移植了三种测试的 myc/bcl-2 淋巴瘤中的两种的动物实现了持续的无病生存。联合疗法对某些 myc 淋巴瘤也比单独使用任何一种药物治疗更有效。我们的数据表明，用小分子有机化合物拮抗 Bcl-2 是一种有吸引力的方法，可提高传统疗法对过表达这种促生存分子的 Myc 驱动淋巴瘤的治疗效果。
