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Mismatch Repair and p53 Independently Affect Sensitivity to N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea¹

Istituto Superiore di Sanitá, 00161 Rome, Italy [G. A., S. C., S. M., M. C., M. B.]; Molecular Oncogenesis Laboratory, Regina Elena Cancer Institute, 00158 Rome, Italy [S. S., M. C.]; and Imperial Cancer Research Fund, Clare Hall Laboratories, South Mimms EN6 3LD, United Kingdom [P. B., P. K.]

The contributions of defective mismatch repair (MMR) and the p53-response to cell killing by N-(2-chloroethyl)-N'-cyclohexyl-N-nitrosourea (CCNU) were evaluated. MMR defects were previously shown to be associated with CCNU sensitivity (G. Aquilina et al., Cancer Res., 58: 135–141, 1998). Unexpectedly, eight MMR-deficient variants of the A2780 human ovarian carcinoma cell line were 3-fold more resistant to CCNU than the MMR-proficient parental cells. The variants were members of a preexisting subpopulation of drug-resistant A2780 cells. In addition to deficient expression of the MMR protein hMLH1, an essential component of the hMutL repair complex, the variants exhibited alterations in the expression of other genes that influence drug sensitivity. Although A2780 cells possess a wild-type p53 gene, all of the clones contained a heterozygous G to T tranversion at codon 172. This change resulted in a Val to Phe substitution and was associated with a constitutive production of high levels of p53, which was inactive as a transcriptional activator of bax and p21. The hMLH1/p53 defective variants displayed a less prominent cell cycle arrest and reduced apoptosis after CCNU treatment. In contrast, MMR-defective A2780 variants, which had a similar hMutL defect but retained a wild-type p53, did exhibit the expected CCNU sensitivity. Expression of a dominant-negative p53val135 increased CCNU resistance of both MMR-proficient and MMR-deficient A2780 cells. Thus, defective MMR and p53 influence CCNU sensitivity in opposite directions. Their effects are independent, and sensitization by defective MMR does not require a functional p53 response.

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