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O⁶-Alkylguanine-DNA Alkyltransferase Depletion and Regeneration in Human Peripheral Lymphocytes following Dacarbazine and Fotemustine¹

Departments of Medical Oncology [S. M. L., N. T.] and Carcinogenesis [G. P. M.], Paterson Institute for Cancer Research, Christie Hospital, Manchester M20 9BX, United Kingdom

O⁶-Alkylguanine-DNA alkyltransferase (ATase) levels were measured in peripheral blood lymphocytes of 13 patients with advanced malignant melanoma treated with sequential dacarbazine (DTIC) and fotemustine. Wide interindividual variation in the pretreatment levels and in depletion and regeneration of ATase activity was noted. Depletion of ATase was seen within the first h after DTIC administration with values ranging from 44 to 92% of pretreatment levels. In 10 patients, progressive depletion of ATase activity occurred with nadir activity occurring at about 4 to 6 h with values ranging from 0 to 67% of pretreatment activity; at 18 h after DTIC infusion, ATase activity varied from 6 to 81%. No significant difference was seen between the rates of ATase depletion or regeneration between the two groups of patients receiving either 500 or 800 mg/m² of DTIC with the same dose of fotemustine (100 mg/m²). In one patient, maximum depletion occurred within 1 h and no ATase activity was detectable over the next 18 h. In another patient, maximum depletion occurred at 2 h after DTIC followed by recovery of ATase activity to 71% at 18 h. In 2 patients who returned for subsequent cycles of chemotherapy, an increase in pretreatment ATase activity was seen. Overall, the extent of depletion of ATase following DTIC/fotemustine was directly proportional to the initial ATase level.

¹ This work was supported by funds from the Cancer Research Campaign, United Kingdom.

² To whom requests for reprints should be addressed.

Received 7/16/90. Accepted 11/ 1/90.

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