DNA base adducts in urine andwhite blood cells of cancer patients receiving combination chemotherapies which include N-methyl-N-nitrosourea

Abstract

Urinary 3-methyladenine (3-MeAde) excretion andlymphocyte DNA adduct formation was studied in 15 patients receiving methylnitrosourea (MNU) at several dose levels (250 mg, 300 mg and600 mg total dose, 143–385 mg m⁻²) as part of various combination chemotherapies for advanced tumours (malignant melanoma, lymphoblastic lymphosarcorna andHodgkin's disease). Urinary 3-MeAde levels were significantly increased over background in patients at all dose levels (p < 0.001) andthe increases were dose-dependent (r = 0.77, p < 0.01). There were large interindividual variations in the excretion of 3-MeAde at each dose of MNU. In a subset of patients, N7-methyl-2-deoxyguanosine (7-MedG) andO⁶-methyl-2′-deoxyguanosine (O⁶-WedG) levels in DNA from blood leucocytes showed dose-dependent increases, however there were no simple relationships between urinary methylated DNA bases andleucocyte DNA adducts. Levels of adducts in leucocyte DNA (7-MedG, < 17–217 μmol mol⁻¹ dG; O⁶-WedG, < 1.6–35 μmol mol⁻¹ dG) were comparable with those reported for other methylating chemotherapeutic drugs. Leucocyte DNA andurinary methyl adducts may be useful markers of individual responses to treatment with methylating drugs.

Key Words :

• 3-methyladenine in urine
• 7-methylguanine andO⁶-methylguanine in blood DNA
• chemotherapy
• N-methyHN-nitrosurea
• cancer patients