Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.
Ranson, Malcolm R
Margison, Jennifer M
El Teraifi, Hassan
Margison, Geoffrey P
AffiliationDepartment of Medical Oncology, Cancer Research UK, Christie Hospital, Manchester, United Kingdom.
MetadataShow full item record
AbstractWe 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.
CitationPharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer. 2003, 103 (5):686-92 Int. J. Cancer
JournalInternational Journal of Cancer
- Dosage and cycle effects of dacarbazine (DTIC) and fotemustine on O6-alkylguanine-DNA alkyltransferase in human peripheral blood mononuclear cells.
- Authors: Lee SM, Thatcher N, Dougal M, Margison GP
- Issue date: 1993 Feb
- O6-alkylguanine-DNA alkyltransferase depletion and regeneration in human peripheral lymphocytes following dacarbazine and fotemustine.
- Authors: Lee SM, Thatcher N, Margison GP
- Issue date: 1991 Jan 15
- Lomeguatrib, a potent inhibitor of O6-alkylguanine-DNA-alkyltransferase: phase I safety, pharmacodynamic, and pharmacokinetic trial and evaluation in combination with temozolomide in patients with advanced solid tumors.
- Authors: Ranson M, Middleton MR, Bridgewater J, Lee SM, Dawson M, Jowle D, Halbert G, Waller S, McGrath H, Gumbrell L, McElhinney RS, Donnelly D, McMurry TB, Margison GP
- Issue date: 2006 Mar 1
- In vivo depletion of O6-alkylguanine-DNA-alkyltransferase in lymphocytes and melanoma of patients treated with CB 10-277, a new DTIC analogue.
- Authors: Lee SM, Thatcher N, Crowther D, Margison GP
- Issue date: 1992
- Sequential therapy with dacarbazine and carmustine: a phase I study.
- Authors: Mitchell RB, Dolan ME, Janisch L, Vogelzang NJ, Ratain MJ, Schilsky RL
- Issue date: 1994