Abstract |
In an effort to improve the efficacy of cancer chemotherapy by intervening into the cellular responses to chemotherapeutic change, we have used adenoviral overexpression of N-methylpurine DNA glycosylase (MPG or ANPG/AAG) in breast cancer cells to study its ability to imbalance base excision repair (BER) and sensitize cancer cells to alkylating agents. Our results show that MPG-overexpressing cells are significantly more sensitive to the alkylating agents methyl methanesulfonate, N-methyl-N'-nitro-N-nitrosoguanidine, methylnitrosourea, dimethyl sulfate, and the clinical chemotherapeutic temozolomide. Sensitivity is further increased through coadministration of the BER inhibitor methoxyamine, which covalently binds abasic or apurinic/apyrimidinic (AP) sites and makes them refractory to subsequent repair. Methoxyamine reduction of cell survival is significantly greater in cells overexpressing MPG than in control cells, suggesting a heightened production of AP sites that, if made persistent, results in increased cellular toxicity. We further explored the mechanism of MPG-induced sensitivity and found that sensitivity was associated with a significant increase in the number of AP sites and/or single-strand breaks in overexpressing cells, confirming a MPG-driven accumulation of toxic BER intermediates. These data establish transient MPG overexpression as a potential therapeutic approach for increasing cellular sensitivity to alkylating agent chemotherapy.
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Authors | Mikael Rinne, David Caldwell, Mark R Kelley |
Journal | Molecular cancer therapeutics
(Mol Cancer Ther)
Vol. 3
Issue 8
Pg. 955-67
(Aug 2004)
ISSN: 1535-7163 [Print] United States |
PMID | 15299078
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)
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Chemical References |
- Alkylating Agents
- Antineoplastic Agents, Alkylating
- Hydroxylamines
- Oligonucleotides
- Sulfuric Acid Esters
- Methylnitronitrosoguanidine
- Methylnitrosourea
- Dacarbazine
- methoxyamine
- Methyl Methanesulfonate
- DNA Glycosylases
- dimethyl sulfate
- Temozolomide
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Topics |
- Adenoviridae
(genetics)
- Alkylating Agents
(pharmacology)
- Antineoplastic Agents, Alkylating
(pharmacology)
- Apoptosis
- Blotting, Western
- Breast Neoplasms
(genetics, metabolism, therapy)
- Cell Line, Tumor
- Cell Proliferation
- Cell Survival
- Comet Assay
- DNA Glycosylases
(chemistry, genetics)
- DNA Repair
- Dacarbazine
(analogs & derivatives, pharmacology)
- Dose-Response Relationship, Drug
- Genetic Therapy
(methods)
- Genetic Vectors
- Humans
- Hydroxylamines
(chemistry)
- Immunohistochemistry
- Methyl Methanesulfonate
(chemistry)
- Methylnitronitrosoguanidine
(chemistry)
- Methylnitrosourea
(pharmacology)
- Oligonucleotides
(chemistry)
- Sensitivity and Specificity
- Sulfuric Acid Esters
(pharmacology)
- Temozolomide
- Time Factors
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