Dosage and cycle effects of dacarbazine (DTIC) and fotemustine on O⁶-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells

Abstract

There is increasing experimental evidence to suggest that endogenous expression of O6-alkylguanine-DNA-alkyltransferase (ATase) is a major factor in cellular resistance to certain chemotherapeutic agents including dacarbazine (DTIC). We have recently shown wide interindividual variation in the depletion and subsequent regeneration of ATase in peripheral blood mononuclear cells (PMCs) following DTIC and this has now been extended to ascertain whether or not depletion is related to dosage of DTIC used and repeated treatment cycles of chemotherapy. ATase levels were measured in three groups of 25 patients (pts) up to 24 h after receiving DTIC at 400 mg m-2, 500 mg m-2 or 800 mg m-2. Each group also received fotemustine (100 mg m-2), 4 h after DTIC. The lowest extent of ATase depletion (highest nadir ATase) was seen in patients receiving 400 mg m-2. The mean nadir ATase, expressed as a percentage of pre-treatment ATase, was respectively 56.3%, 26.4% and 23.9% for 400 mg m-2, 500 mg m-2 and 800 mg m-2. The median nadir of ATase activity for pts receiving 800 mg m-2 pts was at 4-6 h and for pts given lower doses it was at 2-3 h. In addition, repeated measures analysis of variance of observations before chemotherapy, then at 2, 3, 4, 6 and 18 h after chemotherapy provides some evidence that ATase was depleted to a lesser extent after cycle 1 than after subsequent cycles (P = 0.025). It also provides evidence that the change in ATase activity over time varied with dose and cycle. The findings can be interpreted on the basis of a dosage-dependent metabolism of DTIC to an agent capable of methylation of DNA and subsequent depletion of PMC ATase: with higher DTIC doses, the extent of ATase depletion may be limited by the pharmacokinetics of DTIC metabolism. PMC ATase was measured in another group of 8 pts at various times after receiving only fotemustine (100 mg m-2) and in contrast to DTIC, no ATase depletion was seen suggesting that insufficient concentrations of fotemustine and/or its metabolites were available to react with DNA to produce a depletion of PMC ATase activity.