Improved Use of Camptothecins for Small Cell Lung Cancer

描述(申请人提供)：喜树碱是一类重要的新型抗癌化合物，是抗小细胞肺癌(SCLC)的活性物质。然而，疗效受到获得性和内在耐药机制的限制，也受到这些药物产生的实质性毒性的限制。为了更好地了解喜树碱的细胞毒性机制，我们建立并鉴定了几个喜树碱耐药和部分逆转的KB细胞来源的人表皮样细胞系。在这个细胞模型中，我们发现暴露于喜树碱会导致靶标酶拓扑异构酶(TOPO)I的下调，这种下调可能导致对喜树碱的耐药性，并且Topo I的下调和耐药性都可以通过与蛋白酶体抑制剂的共同处理而被抑制。此外，我们和其他人已经表明，Topo I的下调是与增强DNA修复有关的喜树碱耐药的几种机制之一。在先前的临床研究中，我们还发现，在活体外周单个核细胞中，Topo I的表达在Topotecan治疗后发生下调。因此，这项建议的第一个目标将是进行第一阶段和药代动力学研究，以确定拓扑替康与PS-341联合的最佳剂量。对于复发的小细胞肺癌患者，将进一步评估该方案的疗效。第二个目的是确定添加PS-341是否可以阻止体内Topo I的下调。这些药效学研究将在外周单个核细胞和分解的肿瘤细胞中进行。此外，我们还将确定XRCC 1蛋白在肿瘤活检组织中的表达，因为我们已经确定了这种DNA修复蛋白在喜树碱耐药中的作用。这些研究产生的数据将为小细胞肺癌对喜树碱耐药的临床相关机制提供更多的洞察力。

DESCRIPTION (provided by applicant): The camptothecins are an important new class of anticancer compounds that are active agents against small cell lung cancer (SCLC). Nevertheless, efficacy is limited by both acquired and intrinsic mechanisms of resistance, and by the substantial toxicities produced by these drugs. To understand better the mechanisms involved in camptothecin cytotoxicity, we established and characterized several camptothecin resistant and partially revertant human epidermoid cell lines derived from KB cells. With this cell model, we showed that exposure to camptothecin resulted in down-regulation of the target enzyme topoisomerase (topo) I, that this down-regulation may contribute to resistance to camptothecin, and that both the down-regulation of topo I and resistance can be inhibited by co-treatment with a proteasome inhibitor. Furthermore, we and others have shown, that down-regulation of topo I is one of several mechanisms of resistance to camptothecin related to enhanced DNA repair. In a previous clinical study, we also showed that down-regulation of topo I occurs in peripheral mononuclear cells in vivo following treatment with topotecan. As a result, the first aim of this proposal will be to perform a phase I and pharmacokinetic study to establish the optimal doses of topotecan combined with PS-341. The efficacy of this regimen will be further evaluated for patients with relapsed SCLC. The second aim is to determine whether addition of PS-341 prevents down-regulation of topo I in vivo. These pharmacodynamic studies will be performed in peripheral mononuclear cells and in disaggregated tumor cells. In addition, we will determine the expression of the XRCC 1 protein in tumor biopsies, since we have established a role for this DNA repair protein in camptothecin resistance. The data generated by these studies will provide additional insight into clinically relevant mechanisms of resistance to camptothecin that occur in SCLC.