N7-Methylguanine and O⁶-methylguanine levels in DNA of white blood cells from cancer patients treated with dacarbazine

Abstract

Methyl-DNA adducts are induced by a number of lifestyle, environmental and occupational carcinogens, however knowledge about their kinetics is scarce. Here, N7-methylguanine (N7-MeGua) and O⁶-methylguanine (O⁶-MeGua) levels were determined in the DNA of white blood cells from eight cancer patients treated hr with the antitumour drug dacarbazine (DTIC). Five of the patients were treated with the drug as a single agent (a single dose of 800 mg m⁻²) and three on three successive days with dacarbazine (225 mg m⁻² day⁻¹) in combination with other drugs. The data indicate that maximum adduct levels are reached at 4–8 h after treatment and that the amount of N7-MeGua is at least 20-fold higher than that of O⁶-MeGua. The half-life of N7-MeGua is 40–96 h and that of O⁶-MeGua 25–27 h. Following treatment on three consecutive days, an accumulation of N7-MeGua was observed but not of O⁶-MeGua. The data show substantial interindividual differences in adduct levels but not in the ratio of N7/O⁶-MeGua. This may reflect differences in the metabolism of dacarbazine or in repair capacities.

Key Words :

• dacarbazine
• N7-methylguanine
• O⁶-methylguanine
• N-nitrosarnine