HEPATIC METABOLISM OF ANTICANCER DRUGS

抗癌药物的肝脏代谢

• 批准号: 6633008
• 负责人: DAVID J WAXMAN
• 金额: $ 26.28万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 1991
• 资助国家: 美国
• 起止时间: 1991-07-16 至 2004-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6633008
• 关键词: Retroviridae; SCID mouse; aldehyde dehydrogenases; antineoplastics; antisense nucleic acid; apoptosis; chemosensitizing agent; combination cancer therapy; cyclophosphamide; cytochrome P450; disease /disorder model; drug interactions; drug metabolism; gene targeting; gene therapy; genetic enhancer element; human tissue; laboratory rat; liver metabolism; neoplasm /cancer chemotherapy; neoplastic cell; nonhuman therapy evaluation; p53 gene /protein; prodrugs; transfection /expression vector

Gene therapy techniques utilizing prodrug activation genes have shown substantial therapeutic promise for cancer treatment. Prodrug activation-based cancer gene therapy is an attractive strategy to sensitize tumor cells to cytotoxic drugs, since the observed chemosensitization can extend beyond the cells that express the prodrug-activation gene to include surrounding tumor cells, allowing for an effective chemotherapeutic response even if only a minor fraction of tumor cells is transduced with the therapeutic gene. This proposal focuses on a novel prodrug activation cancer gene therapy strategy developed during the past project period. This strategy is based on the combination of a cytochrome P450 gene with a cancer chemotherapeutic prodrug, such as cyclophosphamide, which is activated via a P450-catalyzed monooxygenase reaction. The cancer therapeutic potential of P450 gene transfer derives, in part, from the striking cytotoxic enhancement that is associated with intratumoral, as compared to hepatic, prodrug activation. This approach is unique among current prodrug activation strategies, insofar as it utilizes mammalian genes in combination with proven and tested chemotherapeutic prodrugs currently employed in cancer treatment, rather than novel prodrugs whose ultimate therapeutic efficacy is uncertain. The proposed studies will test a series of hypotheses developed to further improve the high activity and the selectivity of antitumor responses associated with P450 gene therapy. The specific objectives of this project are: 1) to enhance the selectivity and the potency of intratumoral P450-catalyzed prodrug activation; 2) to increase the chemosensitivity' of the target tumor cell; 3) to improve the tumor targeting specificity for P450 gene delivery; and 4) to integrate the most promising of these advances into preclinical models of in vivo gene delivery and cancer prodrug chemotherapy. Together, these studies will establish a rational basis for enhancing intratumoral activation of established cancer chemotherapeutic drugs in a manner that decreases systemic toxic responses and improves therapeutic effects, and will thereby advance the development and implementation of P450-based gene therapy for cancer treatment.

利用前药激活基因的基因治疗技术已显示出癌症治疗的实质性治疗前景。基于前药激活的癌症基因疗法是使肿瘤细胞对细胞毒性药物敏感的有吸引力的策略，因为观察到的化学敏化可以超越表达前药激活基因的细胞延伸以包括周围的肿瘤细胞，即使只有在肿瘤细胞的较小分数中也可以带来有效的化学治疗反应，即使肿瘤细胞的较小分数也可以转化为更具症状的基因。该提案的重点是在过去的项目期间制定的一种新型的前药激活癌症基因治疗策略。该策略基于细胞色素P450基因与癌症化学治疗前药的组合，例如环磷酰胺，该前药是通过P450催化的单加氧酶反应激活的。 p450基因转移的癌症治疗潜力部分源于与肝内药物相比，与肿瘤内相关的惊人细胞毒性增强。这种方法在当前的前药激活策略中是独一无二的，只要它利用哺乳动物基因与目前用于癌症治疗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，而不是新颖的前药，其最终的治疗功效不确定。拟议的研究将检验一系列假设，以进一步提高与P450基因治疗相关的抗肿瘤反应的高活动性和选择性。该项目的具体目标是：1）增强肿瘤内P450催化前药激活的选择性和效力； 2）提高靶肿瘤细胞的化学敏感性； 3）改善P450基因递送的肿瘤靶向特异性； 4）将这些进步最有希望的结果整合到体内基因递送和癌症药物治疗化疗的临床前模型中。总之，这些研究将建立一个合理的基础，以增强已建立的癌症化学治疗药物的肿瘤内激活，从而减少全身有毒反应并改善治疗作用，从而提高基于P450的基因疗法的癌症治疗的发展和实施。