Rafferty J A, Hickson I, Chinnasamy N, Lashford L S, Margison G P, Dexter T M, Fairbairn L J
CRC Department of Carcinogenesis, Paterson Institute for Cancer Research, Christie Hospital (NHS)-Trust, Manchester, UK.
Cancer Metastasis Rev. 1996 Sep;15(3):365-83. doi: 10.1007/BF00046348.
The effectiveness of many types of antitumour agent is limited by (i) acute dose limiting cytotoxicity, principally myelosuppression but also lung, liver and gastrointestinal tract toxicity, (ii) the risk of therapy related secondary malignancy and (iii) the inherent or acquired drug-resistance of tumour cells. As the management of the acute toxic effects improve, the more insidious effects, and particularly haematological malignancies, are anticipated to increase. Furthermore, attempts to overcome tumour cell resistance to treatment can lead to increased collateral damage in normal tissues. One approach to circumventing both the acute toxic and chronic carcinogenic effects of chemotherapy would be to use gene therapy to achieve high levels of expression of drug resistance proteins in otherwise drug-sensitive tissues. To date the products of the multi-drug resistance (MDR-1) and the human O6-alkylguanine-DNA-alkyltransferase (ATase) gene have been used in preclinical experiments to demonstrate proof of principle, and the former of these is now being tested in a clinical situation. Here we discuss the potential of drug-resistance gene therapy to provide chemoprotection to normal tissues and examine the prospects for a dual approach which combines this with pharmacological sensitisation of tumours to chemotherapeutic agents.
（i）急性剂量限制性细胞毒性，主要是骨髓抑制，也包括肺、肝和胃肠道毒性；（ii）治疗相关继发性恶性肿瘤的风险；（iii）肿瘤细胞固有的或获得性的耐药性。随着急性毒性效应管理的改善，预计更隐匿的效应，特别是血液系统恶性肿瘤会增加。此外，克服肿瘤细胞对治疗耐药性的尝试可能会导致正常组织中附带损害增加。一种规避化疗急性毒性和慢性致癌作用的方法是使用基因疗法，在原本对药物敏感的组织中实现耐药蛋白的高水平表达。迄今为止，多药耐药（MDR-1）和人O6-烷基鸟嘌呤-DNA烷基转移酶（ATase）基因的产物已用于临床前实验以证明原理，其中前者目前正在临床环境中进行测试。在此，我们讨论耐药基因疗法为正常组织提供化学保护的潜力，并探讨将其与肿瘤对化疗药物的药理学增敏相结合的双重方法的前景。
