title: Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.
abstract: We assessed whether split dosing with the methylating agent DTIC is an effective strategy for inactivating the DNA repair protein O6-alkylguanine DNA-ATase in order to decrease tumour resistance to BCNU. ATase levels in PBMCs were used as a surrogate for tumour ATase depletion to determine whether this correlated with either the pharmacokinetics of DTIC and its major metabolite AIC or other clinical sequelae. Two 1 hr infusions of DTIC (400 mg/m(2)) 4 hr apart followed another 4 hr later by BCNU (75 mg/m(2)) were administered every 6 weeks in 7 patients with heavily pretreated advanced breast cancer. The extent and kinetics of ATase depletion and recovery in PBMCs varied not only between patients but also between cycles in the same patient. Serial FNAs showed heterogeneity in tumour ATase expression but no clear pattern of change in ATase activity. DTIC and AIC exhibited biphasic clearance from the blood, consistent with a 2-compartment pharmacokinetic model. The AUC of AIC was strongly correlated with the percentage decrease in PBMC ATase levels. There were no clinical responses, and toxicity in neutrophils and platelets was marked. Split-dose DTIC therefore does not appear to be a clinically effective approach to overcome O(6)-alkylating agent resistance in advanced breast cancer.
authors.affiliation: Department of Medical Oncology, Cancer Research UK, Christie Hospital, Manchester, United Kingdom.
authors.forename: Mark
authors.initials: M
authors.lastname: Clemons
authors.forename: Malcolm
authors.initials: M
authors.lastname: Ranson
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Margison
authors.forename: Hassan
authors.initials: H
authors.lastname: El Teraifi
authors.forename: Audrey
authors.initials: A
authors.lastname: Griffiths
authors.forename: Jane
authors.initials: J
authors.lastname: Kelly
authors.forename: Charles Q
authors.initials: CQ
authors.lastname: Morris
authors.forename: Anthony
authors.initials: A
authors.lastname: Howell
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Margison
mesh_terms: D000328:Adult; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000493:pharmacokinetics* / Q000627:therapeutic use; D019540:Area Under Curve; D001707:Biopsy, Needle; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D002330:Carmustine / Q000008:administration & dosage / Q000493:pharmacokinetics; D003606:Dacarbazine / Q000008:administration & dosage / Q000493:pharmacokinetics; D004305:Dose-Response Relationship, Drug; D004351:Drug Resistance; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D008875:Middle Aged; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D003606:Dacarbazine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D002330:Carmustine