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

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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.

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