title: O6-alkylguanine-DNA alkyltransferase depletion and regeneration in human peripheral lymphocytes following dacarbazine and fotemustine.
abstract: 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.
authors.affiliation: Department of Medical Oncology, Paterson Institute for Cancer Research, Christie Hospital, Manchester, United Kingdom.
authors.forename: S M
authors.initials: SM
authors.lastname: Lee
authors.forename: N
authors.initials: N
authors.lastname: Thatcher
authors.forename: G P
authors.initials: GP
authors.lastname: Margison
mesh_terms: D000251:Adenosine Triphosphatases / Q000378:metabolism; D000328:Adult; D000368:Aged; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D003606:Dacarbazine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007700:Kinetics; D008214:Lymphocytes / Q000187:drug effects / Q000201:enzymology*; D008297:Male; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology; D008780:Methyltransferases / Q000378:metabolism*; D008875:Middle Aged; D009607:Nitrosourea Compounds / Q000627:therapeutic use*; D019853:O(6)-Methylguanine-DNA Methyltransferase; D009943:Organophosphorus Compounds / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; D009943:Organophosphorus Compounds; D003606:Dacarbazine; D008780:Methyltransferases; D019853:O(6)-Methylguanine-DNA Methyltransferase; D000251:Adenosine Triphosphatases; C054368:fotemustine