PMID: 8968088Dec 1, 1996Paper

Mismatch repair mutations override alkyltransferase in conferring resistance to temozolomide but not to 1,3-bis(2-chloroethyl)nitrosourea

Cancer Research
L LiuS L Gerson

Abstract

Cells with the mutator phenotype are tolerant to methylating damage from N-methylnitrosourea and N-methyl-N'-nitro-N-nitrosoguanine, exhibit replication repair errors, and have recently been found to be mutant in mismatch repair (MMR). However, resistance of cell lines with these defects to clinically used chemotherapeutic agents and the relationship of this resistance to expression of O6-alkylguanine-DNA alkyltransferase (AGT), which repairs DNA damage caused by methylating agents, has not been demonstrated. We compared resistance to the methylating agent temozolomide (TMZ) and to the chloroethylating agent 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with and without AGT inhibition by 06-bG in several colorectal carcinoma cell lines. Two cell lines had known microsatellite instability (replication repair error-positive) and high levels of AGT, as well as a mutation in one of two MMR genes, hMLH1 (HCT116) or GTBP (HCT15). Cell line SW480 had wild-type MMR genes and high AGT, and HCT116+Ch3 has previously been transduced with chromosome 3 (carrying wild-type hMLH1) and thus has a "corrected" MMR phenotype. SW480 exhibited the expected sensitivity to TMZ and BCNU and marked potentiation of cytotoxicity by O6-bG. In contrast, HCT...Continue Reading

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