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.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Breast Neoplasms/metabolism , Adult , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Area Under Curve , Biopsy, Needle , Breast Neoplasms/drug therapy , Breast Neoplasms/enzymology , Carmustine/administration & dosage , Carmustine/pharmacokinetics , Dacarbazine/administration & dosage , Dacarbazine/pharmacokinetics , Dose-Response Relationship, Drug , Drug Resistance , Female , Humans , Immunoenzyme Techniques , Middle Aged , O(6)-Methylguanine-DNA Methyltransferase/antagonists & inhibitors , O(6)-Methylguanine-DNA Methyltransferase/metabolismABSTRACT
Asmall sample of women (n=9) receiving high dose chemotherapy for advanced breast cancer were asked to complete a quality of life measure (QLQ-C30) at three time points: prior to, during and post treatment. Despite the onset of severe side effects, no significant deterioration in quality of life was recorded in terms of physical, role, emotional, cognitive or social functioning. The role of the clinical nurse specialist (CNS) in providing continuity of care as well as support and information for these women is discussed. Further work in this area with larger sample sizes is needed to confirm these findings and to further investigate the role of the CNS in this context.
