Abstract
O6-alkylguanine-DNA-alkyltransferase (ATase) levels were measured in extracts of peripheral blood lymphocytes taken at various times during chemotherapy from 19 patients with various haematological malignancies. Seven patients with advanced Hodgkin's disease received preparative treatment consisting of cyclophosphamide (1.5 g m-2, daily) administered on days 1 to 4 and BCNU (600 mg m-2) on day 5 prior to autologous bone marrow rescue (ABMR) delivered on day 7. Treatment in the remaining 12 patients consisted of cyclophosphamide (1.8 g m-2, daily) given on days 1 and 2 followed at day 4 with total body irradiation (TBI) administered in six fractions over the subsequent 3 days to a total dose of 1200 cGy prior to bone marrow transplantation. In the Hodgkin's group, significant decreases in ATase activity were seen during the cyclophosphamide treatment, and the median ATase nadir was 32% (range 0% to 57%) of pretreatment levels following 4 days of cyclophosphamide. In one patient, no ATase activity was detectable following the 4th cyclophosphamide treatment. ATase activities decreased further after BCNU administration to a median of 19% (range 0% to 32%) of pretreatment levels. Extensive cyclophosphamide-induced reduction of lymphocyte ATase levels was also seen in the other group of 12 patients treated with cyclophosphamide/TBI: postcyclophosphamide median ATase nadir was 35% (range 12% to 78%) of the pretreatment levels. No ATase depletion was seen when cyclophosphamide (up to 10 mM) was incubated for 2 h with pure recombinant human ATase in vitro whereas ATase activity was reduced by 90% on preincubation with 100 microns acrolein or with greater than 1 mM phosphoramide mustard. This suggests that a cyclophosphamide-induced decrease in ATase levels in human peripheral lymphocytes in vivo may be due to depletion mediated by the production of intracellular acrolein. Since ATase appears to be a principal mechanism in cellular resistance to the cytotoxic effects of BCNU and related alkylating agents, these observations suggest that a cyclophosphamide-induced reduction in ATase activity may be an additional factor in the effectiveness of the combined sequential therapy.
Highlights
Erickson, 1984) or 06-methylguanine (Dolan et al, 1985; Gerson et al, 1988a; Yarosh et al, 1986) or 06-benzylguanine (Dolan et al, 1990) rendered the cells more sensitive to subsequent treatment with chloroethylating agents
Based on our recent observations of progressive depletion of ATase activity in human peripheral blood lymphocytes of patients with malignant melanoma treated with sequential dacarbazine and fotemustine (Lee et al, 1991a), we began to examine the kinetics of ATase depletion following BCNU prior to autologous bone marrow rescue (ABMR)
In three patients the first cyclophosphamide treatment caused reduction to 52%, 64% and 67% of their pretreatment levels while in two other patients the first treatment caused only a 10% loss in activity
Summary
1984) or 06-methylguanine (Dolan et al, 1985; Gerson et al, 1988a; Yarosh et al, 1986) or 06-benzylguanine (Dolan et al, 1990) rendered the cells more sensitive to subsequent treatment with chloroethylating agents. Transfer and expression of ATase genes in ATase deficient cells renders them more resistant to chloroethylating agents (Brennand & Margison, 1986; Margison & O'Connor, 1990). Results in the first patient to receive sequential cyclophosphamide and BCNU showed an unexpected decrease in ATase activity in the post-cyclophosphamide samples. This observation was pursued and we report here a marked decrease in ATase activity following cyclophosphamide treatment in seven patients with advanced Hodgkin's disease receiving cyclophosphamide and BCNU and in a further group of 12 patients with various haematological malignancies undergoing preparative treatment with cyclophosphamide and total body irradiation (TBI)
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