Topoisomerase I Inhibitors in Leukemia and Solid Tumors

白血病和实体瘤中的拓扑异构酶 I 抑制剂

• 批准号: 6728214
• 负责人: SCOTT H KAUFMANN
• 金额: $ 22.22万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-01 至 2006-08-01
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6728214
• 关键词: BCL2 gene /protein; DNA topoisomerases; N methyl N' nitro N nitrosoguanidine; acute leukemia; clinical research; combination chemotherapy; drug interactions; drug resistance; enzyme activity; gemcitabine; glioma; human subject; irinotecan; kinase inhibitor; neoplasm /cancer pharmacology; ovary neoplasms; posttranslational modifications; protein kinase; stomach neoplasms; tissue /cell culture; topotecan

DESCRIPTION: (Applicant's Abstract) Two topoisomerase I (topo I) poisons, topotecan (TPT) and irinotecan (CPT-l1), are currently licensed for use in the U.S. Clinical responses to these agents are highly variable. Although preclinical studies have identified numerous factors that can affect the action of topo I poisons in vitro, few of these parameters have been examined in tumor samples or correlated with clinical response. Studies supported by this grant have investigated 1) mechanisms of resistance to topo I poisons in clinical leukemia specimens and 2) effects of combining topo I poisons with other agents. In pursuing the first goal, we have demonstrated during the current funding period that topo I content in acute myelogenous leukemia specimens varies widely but correlates with other markers of proliferation (e.g., PCNA); that the TPT concentration required to stabilize topo I-DNA complexes in acute leukemia specimens ex vivo varies over a 30-fold range irrespective of topo I content; and that this variation in TPT concentration required to stabilize topo I-DNA cleavage complexes can been recapitulated in a tissue culture model. Additional tissue culture studies have demonstrated enhanced sensitivity to TPT or SN-38 (the active metabolite of CPT-11) when activity of the DNA damage checkpoint kinase ATR is inhibited. While addressing the second goal, we have demonstrated that cytotoxic effects are more than additive when SN-38 is combined with the quinazoline-based kinase inhibitor CI1033 or with gemcitabine. Further studies have demonstrated that the SN-38/CI1033 synergy reflects enhanced drug accumulation as a result of CI1033-mediated inhibition of the ABC cassette transporter BCRP. To build on these results, we now propose to 1) evaluate the relationship between response of three well-defined cohorts of solid tumor patients receiving single-agent CPT-11 or TPT and various tumor cell parameters that have been implicated in drug resistance in preclinical models (including topo I content, p53 status, proliferative index, levels of anti-apoptotic Bcl-2 family members, and expression of replication checkpoint proteins); 2) use the recently developed tissue culture model to determine the mechanistic basis for the observation that different TPT concentrations are required to stabilize topo I-DNA complexes in different leukemia specimens; and 3) examine the mechanistic basis for the unanticipated synergy of the gemcitabine + SN-38 combination and determine the effect of combining SN-38 with other agents currently undergoing early clinical testing. Collectively, these studies should provide insight into factors that affect response to topo I poisons in the clinical setting and aid in the rational integration of topo I poisons into multidrug regimens.

描述：（申请人的摘要）两个拓扑异构酶i（topo i）毒药， 目前已获得托泊特坎（TPT）和伊立替康（CPT-L1）的许可 美国对这些药物的临床反应是高度可变的。虽然 临床前研究已经确定了许多可能影响动作的因素 在体外托托斯毒物的毒药中，在肿瘤中很少有人检查其中的这些参数 样品或与临床反应相关。这项赠款支持的研究 已经研究了1）临床中对托托斯毒药的抗性机制 白血病标本和2）将Topo I Poison与其他毒物相结合的影响 代理商。在追求第一个目标时，我们在当前表明了 资金期我在急性脊髓性白血病标本中满足 差异很大，但与其他增殖标记（例如PCNA）相关； 在急性中稳定TOPO I-DNA复合物所需的TPT浓度 白血病标本EX VIVO在30倍的范围内差异，而不论TOPO I 内容;并且稳定所需的TPT浓度变化 可以在组织培养模型中概括TOPO I-DNA裂解复合物。 其他组织培养研究表明对TPT的敏感性提高了 当DNA损伤活性时，SN-38（CPT-11的活性代谢产物） 检查点激酶ATR被抑制。在解决第二个目标时，我们有 证明当SN-38为 与基于喹唑啉基酶抑制剂CI1033或与 吉西他滨。进一步的研究表明，SN-38/CI1033协同作用 CI1033介导的抑制作用反映了药物积累的增强 ABC盒式转运蛋白BCRP的为基于这些结果，我们现在建议 到1）评估三个定义明确的队列的响应之间的关系 接受单药CPT-11或TPT和各种肿瘤的实体瘤患者 与临床前耐药性有关的细胞参数 模型（包括TOPO I内容，p53状态，增殖索引，级别 抗凋亡BCL-2家庭成员和复制检查点的表达 蛋白质）; 2）使用最近开发的组织培养模型来确定 观察到不同TPT浓度的机理基础是 需要在不同白血病标本中稳定topo I-DNA复合物；和 3）检查意外协同的机械基础 吉西他滨 + SN-38组合并确定组合SN-38的效果 目前正在进行早期临床测试的其他代理商。共同 这些研究应洞悉影响对TOPO反应的因素 我在临床环境中进行毒物，并有助于托普的合理整合 毒药成多药方案。