CLINICAL SEQUENTIAL TOPOISOMERASE POISONING

描述(申请人的描述) 该提案旨在提供临床和药理学数据。 关于使用顺序拓扑异构酶I和II毒药的问题 癌症的治疗。这些药物是最有效的细胞毒性药物之一。 抗肿瘤药物。相当多的临床前证据表明 连续给药毒害这两种酶将导致 活动增强。所需要的是关于最优的 这些药物在治疗癌症患者中的联合应用。 目的I涉及一项序贯治疗的临床试验 9-硝基喜树碱和依托泊苷。拟议的研究是基于先前的 在最近一次使用9-氨基喜树碱的试验中观察到。患者血液 细胞表现出拓扑异构酶II蛋白表达增加 9-氨基喜树碱输液。拓扑异构酶II的类似增加 在对喜树碱耐药的细胞系中发现了表达，并已 与对拓扑异构酶II毒物的敏感性增加有关。这些 研究结果表明，适时添加拓扑异构酶II 中毒可能会增强喜树碱类似物的临床疗效。 这项研究中提出的时间表涉及依托泊苷的剂量递增。 在完成固定剂量后进行输液 9-硝基喜树碱。这项研究的结果将决定临床 以这种方式组合两种酶毒药的可行性和将 提供依托泊苷的最大耐受量。 为了优化这两种药物的给药时间表， 未来的试验，在AIM II中建议的研究包括重复测量 拓扑异构酶I和II的水平。针对这一目标设计了更多的研究 阐明喜树碱潜在的临床耐药机制。 来自9-氨基喜树碱试验的初步数据表明，血液 细胞拓扑异构酶I水平在给药过程中下降。数据 从拟议的试验中获得的信息应该可以确定这是否 这一现象代表了体内对拓扑异构酶I毒物的普遍反应。 此外，还建议进行研究，以评估在体内发生的 导致耐药性的拓扑异构酶I突变。

DESCRIPTION (APPLICANT'S DESCRIPTION) This proposal is designed to provide clinical and pharmacological data regarding the use of sequential topoisomerase I and II poisons in the treatment of cancer. These drugs are among the most effective cytotoxic antitumor agents. Considerable preclinical evidence suggests that sequential administration of drugs that poison both enzymes will lead to enhanced activity. What is needed is information regarding the optimal combination of these drugs in treating patients with cancer. Aim I involves a clinical trial of sequential therapy with 9-nitrocamptothecin and etoposide. The proposed study is based upon prior observations in a recent trial using 9-aminocamptothecin. Patient blood cells exhibited an increase in topoisomerase II protein expression during the 9-aminocamptothecin infusion. Similar increases in topoisomerase II expression have been seen in cell lines resistant to camptothecin, and have correlated with increased sensitivity to topoisomerase II poisons. These findings suggest that the properly timed addition of a topoisomerase II poison may enhance the clinical effectiveness of camptothecin analogues. The schedule proposed in this study involves dose escalation of an etoposide infusion administered after completion of a fixed dose of 9-nitrocamptothecin. Results from this study will determine the clinical feasibility of combining the two enzyme poisons in this manner and will provide a maximum-tolerated dose for etoposide. In order to optimize the schedule of administration of the two drugs in future trials, studies proposed in Aim II include repeated measurements of topoisomerase I and II levels. Additional studies in this Aim are designed to clarify potential clinical resistance mechanisms to camptothecins. Preliminary data from a trial with 9-aminocamptothecin suggest that blood cell topoisomerase I levels decline during drug administration. Data obtained from the proposed trial should allow determination of whether this phenomenon represents a general in vivo response to topoisomerase I poisons. In addition, studies are proposed to evaluate the occurrence in vivo of mutations in topoisomerase I that confer drug resistance.