Zagorski William A, Knudsen Erik S, Reed Michael F
Division of Thoracic Surgery, Department of Surgery, The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine and Department of Surgery, Cincinnati VA Medical Center, Cincinnati, OH 45267-0558, USA.
Cancer Res. 2007 Sep 1;67(17):8264-73. doi: 10.1158/0008-5472.CAN-06-4753.
The retinoblastoma (RB) tumor suppressor is mutated or functionally inactivated in the majority of human malignancies, and p16(INK4a)-cyclin D1-cyclin-dependent kinase 4-RB pathway aberrations are present in nearly all cases of non-small cell lung cancer (NSCLC). Here, the distinct role of RB loss in tumorigenic proliferation and sensitivity to chemotherapeutics was determined in NSCLC cells. Attenuation of RB led to a proliferative advantage in vitro and aggressive tumorigenic growth in xenograft models. Clinically, such aggressive disease is treated with genotoxic and cytotoxic chemotherapeutic agents. In vitro analysis showed that RB deficiency resulted in bypass of the checkpoint response to multiple chemotherapeutic challenges concomitant with an elevated apoptotic response. Correspondingly, RB deficiency in xenograft models led to increased chemosensitivity. However, this response was transient, and a durable response was dependent on prolonged chemotherapeutic administration. Together, these findings show that although RB deficiency enhances sensitivity to chemotherapeutic challenge, efficient and sustainable response is highly dependent on the specific therapeutic regimen, in addition to the molecular environment.
视网膜母细胞瘤（RB）肿瘤抑制因子在大多数人类恶性肿瘤中发生突变或功能失活，并且在几乎所有非小细胞肺癌（NSCLC）病例中都存在p16（INK4a）-细胞周期蛋白D1-细胞周期蛋白依赖性激酶4-RB途径异常。在此，研究了RB缺失在NSCLC细胞的致瘤增殖和对化疗药物敏感性中的独特作用。RB的减弱导致体外增殖优势和异种移植模型中侵袭性致瘤生长。临床上，这种侵袭性疾病用基因毒性和细胞毒性化疗药物治疗。体外分析表明，RB缺乏导致对多种化疗挑战的检查点反应旁路，同时凋亡反应升高。相应地，异种移植模型中的RB缺乏导致化疗敏感性增加。然而，这种反应是短暂的，持久反应依赖于延长的化疗给药。总之，这些发现表明，尽管RB缺乏增强了对化疗挑战的敏感性，但除分子环境外，有效和可持续的反应高度依赖于特定的治疗方案。
