Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.

2.50
Hdl Handle:
http://hdl.handle.net/10541/79117
Title:
Pharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.
Authors:
Clemons, Mark; Ranson, Malcolm R; Margison, Jennifer M; El Teraifi, Hassan; Griffiths, Audrey; Kelly, Jane; Morris, Charles; Howell, Anthony ( 0000-0002-3879-5991 ) ; Margison, Geoffrey P
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.
Affiliation:
Department of Medical Oncology, Cancer Research UK, Christie Hospital, Manchester, United Kingdom.
Citation:
Pharmacokinetic, 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
Journal:
International Journal of Cancer
Issue Date:
20-Feb-2003
URI:
http://hdl.handle.net/10541/79117
DOI:
10.1002/ijc.10849
PubMed ID:
12494480
Type:
Article
Language:
en
ISSN:
0020-7136
Appears in Collections:
All Christie Publications

Full metadata record

DC FieldValue Language
dc.contributor.authorClemons, Mark-
dc.contributor.authorRanson, Malcolm R-
dc.contributor.authorMargison, Jennifer M-
dc.contributor.authorEl Teraifi, Hassan-
dc.contributor.authorGriffiths, Audrey-
dc.contributor.authorKelly, Jane-
dc.contributor.authorMorris, Charles-
dc.contributor.authorHowell, Anthony-
dc.contributor.authorMargison, Geoffrey P-
dc.date.accessioned2009-08-28T11:53:09Z-
dc.date.available2009-08-28T11:53:09Z-
dc.date.issued2003-02-20-
dc.identifier.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. Canceren
dc.identifier.issn0020-7136-
dc.identifier.pmid12494480-
dc.identifier.doi10.1002/ijc.10849-
dc.identifier.urihttp://hdl.handle.net/10541/79117-
dc.description.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.en
dc.language.isoenen
dc.subjectBreast Canceren
dc.subject.meshAdult-
dc.subject.meshAntineoplastic Combined Chemotherapy Protocols-
dc.subject.meshArea Under Curve-
dc.subject.meshBiopsy, Needle-
dc.subject.meshBreast Neoplasms-
dc.subject.meshCarmustine-
dc.subject.meshDacarbazine-
dc.subject.meshDose-Response Relationship, Drug-
dc.subject.meshDrug Resistance-
dc.subject.meshFemale-
dc.subject.meshHumans-
dc.subject.meshImmunoenzyme Techniques-
dc.subject.meshMiddle Aged-
dc.subject.meshO(6)-Methylguanine-DNA Methyltransferase-
dc.titlePharmacokinetic, biochemical and clinical effects of dimethyltriazenoimidazole-4-carboxamide-bischloroethylnitrosourea combination therapy in patients with advanced breast cancer.en
dc.typeArticleen
dc.contributor.departmentDepartment of Medical Oncology, Cancer Research UK, Christie Hospital, Manchester, United Kingdom.en
dc.identifier.journalInternational Journal of Canceren

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