Document Detail


Carmustine-resistant cancer cells are sensitized to temozolomide as a result of enhanced mismatch repair during the development of carmustine resistance.
MedLine Citation:
PMID:  18430789     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
The cytotoxicity of the monofunctional alkylator temozolomide (TMZ) is mediated by mismatch repair (MMR) triggered by O(6)-alkylguanine, whereas MMR protects cells against bifunctional alkylators, including carmustine (BCNU). Therefore, TMZ may be cytotoxic to BCNU-resistant cancer cells because MMR affects sensitivity to TMZ and BCNU in a converse way. We evaluated TMZ cytotoxicity on BCNU-resistant variant (CEM-R) compared with the parental CCRF-CEM cell line (CEM-S). The mechanisms of its BCNU-resistance involved DNA repairs including nucleotide excision repair, base excision repair, alkylguanine alkyltransferase, MMR, and apoptotic and survival pathways. In particular, transcript levels of MMR-related hMLH1 and hMSH2 were enhanced in CEM-R cells. CEM-R cells were 8-fold more BCNU-resistant but surprisingly 9-fold more TMZ-sensitive than were CEM-S cells. Although TMZ-induced adducts include N-alkylated purines and O(6)-alkylguaine, DNA excision repair was enhanced in CEM-R cells, suggesting the efficient repair of N-alkylation adducts. Cotreatment with methoxyamine, a base excision repair inhibitor, did not sensitize CEM-R cells to TMZ, suggesting little or no contribution of N-alkylation to TMZ-induced cytotoxicity. Cotreatment with O(6)-benzylguanine, an alkylguanine alkyltransferase inhibitor, further sensitized CEM-R cells to TMZ, confirming the cytotoxic impact of O(6)-alkylguanine. Cotreatment with cadmium chloride, an MMR inhibitor, disrupted the sensitivity of CEM-R cells to TMZ. The sensitivity to TMZ was reversed in the CEM-R variant clone that had been established by transfecting CEM-R cells with short hairpin hRNA against hMLH1, suggesting the critical role of MMR on sensitization to TMZ. In conclusion, BCNU-resistant CEM-R cells were sensitized to TMZ as a result of enhanced MMR during the development of BCNU resistance.
Authors:
Takahiro Yamauchi; Masami Ogawa; Takanori Ueda
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Publication Detail:
Type:  Journal Article     Date:  2008-04-22
Journal Detail:
Title:  Molecular pharmacology     Volume:  74     ISSN:  1521-0111     ISO Abbreviation:  Mol. Pharmacol.     Publication Date:  2008 Jul 
Date Detail:
Created Date:  2008-06-20     Completed Date:  2008-07-25     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0035623     Medline TA:  Mol Pharmacol     Country:  United States    
Other Details:
Languages:  eng     Pagination:  82-91     Citation Subset:  IM    
Affiliation:
Department of Hematology and Oncology, University of Fukui, 23 Shimoaizuki, Matsuoka, Eiheiji, Fukui 910-1193, Japan. tyamauch@u-fukui.ac.jp
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MeSH Terms
Descriptor/Qualifier:
Antineoplastic Agents, Alkylating / administration & dosage,  pharmacology*
Antineoplastic Combined Chemotherapy Protocols / pharmacology*
Apoptosis / drug effects
Cadmium Chloride / administration & dosage
Carmustine / pharmacology
Cell Line, Tumor
Cell Proliferation / drug effects
Comet Assay
DNA Mismatch Repair / drug effects*
Dacarbazine / analogs & derivatives*,  pharmacology
Dose-Response Relationship, Drug
Drug Resistance, Neoplasm / physiology
Guanine / administration & dosage,  analogs & derivatives
Humans
Hydroxylamines / administration & dosage
Nimustine / administration & dosage
Precursor Cell Lymphoblastic Leukemia-Lymphoma / drug therapy*,  genetics,  metabolism,  pathology
Chemical
Reg. No./Substance:
0/Antineoplastic Agents, Alkylating; 0/Hydroxylamines; 10108-64-2/Cadmium Chloride; 154-93-8/Carmustine; 19916-73-5/O(6)-benzylguanine; 42471-28-3/Nimustine; 4342-03-4/Dacarbazine; 67-62-9/methoxyamine; 73-40-5/Guanine; 85622-93-1/temozolomide

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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