Hypersensitivity of human tumor xenografts lacking O6-alkylguanine-DNA alkyltransferase to the anti-tumor agent 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea

Abstract

Human tumor cell strains having different activities of O⁶-alkylguanine-DNA alkyltransferase (ATR) were transplanted into nude mice and chemotherapeutic responses of tumor xenografts were compared after intraperitoneal injection of the anti-tumor drug 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU). The tumor strains used were four Mer⁺ strains possessing high ATR activity and three Mer⁻ strains lacking this activity. Included in these Mer⁺ strains was a clone 5'dD which expresses the Escherichia coli ATR in Mer⁻ HeLa cells and thus shows the Mer⁺phenotype. All the Mer⁻ tumor xenografts were much more sensitive than tumors of Mer⁺ strains, including the clone 5’dD; after the highest ACNU dose (three injections of 50 mg/kg), some Mer⁻ tumors disappeared completely and the growth of other tumors was severely retarded, whereas all Mer⁺ tumors continued to grow. These results demonstrate that ATR activity in tumor cells is a major determinant of tumor response to ACNU, and further suggest that measurement of ATR activity in biopsy specimens may provide a useful guide to predict the response to chemotherapy.