Hepatic Metabolism of Anti-cancer Drugs

抗癌药物的肝脏代谢

基本信息

批准号：
7226056
负责人：
DAVID J WAXMAN
金额：
$ 4.83万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
财政年份：
1991
资助国家：
美国
起止时间：
1991-07-16 至 2009-04-30
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Chemotherapy using cytotoxic drugs is presently the most commonly used weapon in the treatment of advanced cancer. However, the therapeutic efficacy of cancer chemotherapeutic agents is limited by factors such as tumor heterogeneity, host toxicity, and drug resistance. Recent advances in molecular medicine have provided new opportunities to improve cancer chemotherapy through the development of novel, more selective anti-cancer strategies. The long-range goal of this project is to translate recent advances in our understanding of the role of cytochrome P450 enzymes in cancer pharmacology into improved methods for sensitizing tumor cells to cytochrome P450-activated anti-cancer drugs. This proposal builds on progress made during the last project period in developing a novel, cytochrome P450 prodrug activation-based gene therapy for cancer treatment. The therapeutic potential of this P450 gene therapy derives, in part, from the striking cytotoxic enhancement that is associated with intratumoral, as compared to hepatic P450-catalyzed prodrug activation. This approach is unique among prodrug activation strategies, insofar as it utilizes mammalian genes in combination with proven and tested chemotherapeutic prodrugs currently used in the clinic, rather than novel prodrugs whose therapeutic efficacy and ultimate clinical utility is uncertain. The present application aims to further improve the responsiveness of tumor cells to the widely used, liver P450-activated oxazaphosphorine anti-cancer prodrug cyclophosphamide. Primary emphasis is placed on the elucidation of novel ways to enhance cyclophosphamide therapeutic activity by augmenting bystander cytotoxic responses at the tumor cell level and at the level of tumor-associated endothelial cells. The major aims of this proposal are: 1) to test the hypothesis that tumor cell bystander cytotoxicity, and hence the overall efficacy of P450 gene therapy, can be enhanced by introduction of caspase inhibitors that delay the death of 'P450 factory' tumor cells; and 2) to elucidate the mechanism for the dramatic anti-tumor response that is induced when large, P450-expressing tumors are given cyclophosphamide on a metronomic schedule; these latter studies will investigate the role of a tumor endothelial cell-directed bystander effect in this response, and will determine whether this effect can be enhanced by combination of metronomic cyclophosphamide scheduling with anti-angiogenic therapy. Together, the studies proposed will help elucidate a rational basis for increasing the activity of established anti-cancer prodrugs in a way that moderates toxic host responses and improves therapeutic effects, and will thereby advance the development and implementation of effective prodrug-based therapies for cancer treatment.

描述（由申请人提供）：使用细胞毒性药物的化学疗法目前是治疗晚期癌症中最常用的武器。但是，癌症化学治疗剂的治疗功效受到肿瘤异质性，宿主毒性和耐药性等因素的限制。分子医学的最新进展通过开发新型，更具选择性的抗癌策略为改善癌症化疗提供了新的机会。该项目的远距离目标是转化我们对细胞色素P450酶在癌症药理学中的作用的最新进展，以改进的方法，以使肿瘤细胞对细胞色素P450激活的抗癌药物敏感。该提案建立在最后一个项目期间在开发一种基于基于癌症治疗的基于基于原药的基因疗法的新型细胞色素P450药物治疗方面取得的进展。与肝P450催化的前药激活相比，该P450基因疗法的治疗潜力部分源于与肿瘤内相关的引人注目的细胞毒性增强。在前药激活策略中，这种方法是独一无二的，只要它利用哺乳动物基因与目前在诊所中使用的经过验证和测试的化学治疗前药结合使用，而不是新颖的药物，其治疗功效和最终临床实用性的新药物尚不确定。本应用旨在进一步提高肿瘤细胞对广泛使用的，肝P450激活的阿沙唑啉抗癌前药环磷酰胺的反应性。主要的重点是通过在肿瘤细胞水平和与肿瘤相关的内皮细胞水平上增强旁观者的细胞毒性反应来阐明增强环磷酰胺治疗活性的新方法。该提议的主要目的是：1）检验以下假设：肿瘤细胞旁观者的细胞毒性及其p450基因治疗的总体功效可以通过引入caspase抑制剂来增强，从而延迟“ P450工厂”肿瘤细胞死亡的caspase抑制剂； 2）为了阐明当在分析时间表中给出巨大的，表达P450的肿瘤的巨大抗肿瘤反应机制；这些后者的研究将研究肿瘤内皮细胞导向旁观者效应在此反应中的作用，并将确定是否可以通过将基因经济性环磷酰胺调度与抗血管生成疗法结合结合来增强这种作用。共同提出的研究将有助于阐明合理的基础，以增加既定的抗癌药物的活性，以调节有毒宿主反应并改善治疗作用，从而提高和实施有效的基于Prodrug的癌症治疗疗法。