CHEMOPROTECTION OF NORMAL-TISSUES BY TRANSFER OF DRUG-RESISTANCE GENES

The effectiveness of many types of antitumour agent is limited by (i) acute dose limiting cytotoxicity, principally myelosuppression but als o lung, liver and gastrointestinal tract toxicity, (ii) the risk of th erapy 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 haematol ogical malignancies, are anticipated to increase. Furthermore, attempt s to overcome tumour cell resistance to treatment can lead to increase d collateral damage in normal tissues. One approach to circumventing b oth the acute toxic and chronic carcinogenic effects of chemotherapy w ould be to use gene therapy to achieve high levels of expression of dr ug resistance proteins in otherwise drug-sensitive tissues. To date th e products of the multi-drug resistance (MDR-1) and the human O-6-alky lguanine-DNA-alkyltransferase (ATase) gene have been used in preclinic al experiments to demonstrate proof of principle, and the former of th ese is now being tested in a clinical situation. Here we discuss the p otential of drug-resistance gene therapy to provide chemoprotection to normal tissues and examine the prospects for a dual approach which co mbines this with pharmacological sensitisation of tumours to chemother apeutic agents.