Search

The aim of aggressive antitumor chemotherapy is to kill the tumor with the largest possible dose of a cytotoxic drug. The maximum dose tolerated by the patient is limited by the toxicity to normal tissue, hematopoiesis being frequently the most sensitive system. Transfer of drug resistance genes to hematopoietic cells could protect them against chemotherapy-related toxicity and thus could be a way of gene therapy in cancer. Methylating and chloroethylating derivatives of nitrosourea are effective anticancer drugs, however, acute hematopoietic toxicity and late risk of leukemia are serious side effects. The major lesion responsible for toxic and mutagenic effects of alkylnitrosoureas is O6-alkylation of guanine in DNA. This lesion is specifically repaired by O6-alkylguanine-DNA-alkyltransferase and hematopoietic cells can be protected against toxic and mutagenic effect of nitrosoureas by alkyltransferase gene transfer. Endogenous alkyltransferase in tumor tissue could be inactivated by administration of O6-benzylguanine, while hematopoietic cells could still be chemoprotected by inhibitor-resistant alkyltransferase gene transfer. This approach could increase the therapeutic efficacy of nitrosoureas in gene therapy augmented cancer treatment.