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Research Articles: Therapeutics

DNA mismatch repair and p53 function are major determinants of the rate of development of cisplatin resistance

Department of Medicine and the Cancer Center, University of California, San Diego, La Jolla, California

Requests for reprints: Stephen B. Howell, Department of Medicine 0058, University of California, San Diego, La Jolla, CA 92093. Phone: 858-822-1110; Fax: 858-822-1111; E-mail: showell{at}ucsd.edu

As opposed to factors that control sensitivity to the acute cytotoxic effect of cisplatin, little is known about the factors that determine the rate at which resistance develops. This study examined how loss of p53 or DNA mismatch repair (MMR) function affected the rate of development of resistance to cisplatin in human colon carcinoma cells during sequential cycles of cisplatin exposure that mimic the way the drug is used in the clinic. We used a panel of sublines molecularly engineered to express either the MMR- and p53-proficient phenotype or singly or doubly deficient phenotypes. Loss of either MMR or p53 alone increased the rate of development of resistance to cisplatin by 1.8- and 2.4-fold, respectively; however, loss of both MMR and p53 increased the rate by 4.8-fold. Inhibition of DNA polymerase by suppression of the expression of its REV3 subunit eliminated the increased rate of development of resistance observed in the MMR-deficient cells. Loss of p53 or MMR increased the steady-state level of REV3 and of REV1 mRNA; loss of both functions increased these levels much further by a factor of 20.2-fold for REV3 and 10.3-fold for REV1. The basal level of homologous recombination measured using a reporter vector was 1.3- to 1.7-fold higher in cells that had lost either p53 or MMR function, and 2.6-fold higher in cells that had lost both. In the p53- and MMR-proficient cells, cisplatin induced a 17-fold increase in homologous recombination even when the recombining sequences that did not contain cisplatin adducts; the magnitude of induction was even greater in cells that had lost either one or both functions. We conclude that separate from effects on sensitivity to the acute cytotoxic effect of cisplatin, loss of MMR, especially when combined with loss of p53, results in rapid evolution of cisplatin resistance during sequential rounds of drug exposure that is likely mediated by enhanced mutagenic translesion synthesis. The DNA damage response activated by cisplatin is accompanied by a p53- and MMR-dependent increase in homologous recombination even between adduct-free sequences. [Mol Cancer Ther 2006;5(5):1239–47]

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: X. Lin and S.B. Howell are Foundation for Research investigators.

Received 11/28/05; revised 1/21/06; accepted 3/ 2/06.