Journal Article

Mechanisms of tolerance to DNA damaging therapeutic drugs

Peter Karran

in Carcinogenesis

Volume 22, issue 12, pages 1931-1937
Published in print December 2001 | ISSN: 0143-3334
Published online December 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.12.1931
Mechanisms of tolerance to DNA damaging therapeutic drugs

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The cytotoxic effect of many anticancer drugs relies on their ability to damage DNA. Drug resistance can be associated with the ability to remove potentially lethal DNA lesions. DNA damage tolerance offers an alternative route to resistance. In a drug-tolerant cell, persistent DNA damage has become uncoupled from cell death. Tolerance to some DNA damaging drugs is accompanied by inactivation of the cell's DNA mismatch repair pathway. This is widely acknowledged as the mechanism underlying resistance to methylating agents and to 6-thioguanine which produce structurally similar types of DNA damage. Defects in mismatch repair are also associated with resistance to numerous drugs that produce a wide variety of structurally diverse DNA lesions. Here I consider possible mechanisms by which mismatch repair might influence drug resistance and the extent to which loss of mismatch repair might be considered to confer a multidrug resistance phenotype.

Keywords: 2-AP, 2-aminopurine; DSB, double-strand break; O6-meGua, O6-methylguanine; MMR, mismatch repair; MSI, microsatellite instability; 6-meTG, 6-thiomethylguanine; PhIP, 2-amino 1-methyl-6-phenylimidazo [4,5-b]pyridine; 6-TG, 6-thioguanine.

Journal Article.  6407 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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