Characterization of MLH1 and MSH2 DNA mismatch repair proteins in cell lines of the NCI anticancer drug screen |
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| Authors: | Pietro Taverna Lili Liu Amy J Hanson Anne Monks Stanton L Gerson |
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| Institution: | (1) Division of Hematology-Oncology, Department of Medicine and Ireland Cancer Center, Case Western Reserve University School of Medicine and University Hospitals of Cleveland, BRB-3, 10900 Euclid Avenue, Cleveland, OH 44106-4937, USA e-mail: slg5@po.cwru.edu Tel.: +1-216-3681176; Fax: +1-216-3681166,;(2) SAIC-Frederick, DTP Screening Technologies Branch, Frederick, MD, USA, US |
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| Abstract: | Purpose and methods: The lack of a functional DNA mismatch repair (MMR) pathway has been recognized as a common characteristic of several different
types of human cancers due to mutation affecting one of the MMR genes or due to promoter methylation gene silencing. These
MMR-deficient cancers are frequently resistant to alkylating agent chemotherapy such as DNA-methylating or platinum-containing
compounds. To correlate drug resistance with MMR status in a large panel of human tumor cell lines, we evaluated by Western
blot the cellular levels of the two MMR proteins most commonly mutated in human cancers, MLH1 and MSH2, in the NCI human tumor
cell line panel. This panel consists of 60 cell lines distributed among nine different neoplastic diseases. Results: We found that in most of these cell lines both MLH1 and MSH2 were expressed, although at variable levels. Five cell lines
(leukemia CCRF-CEM, colon HCT 116 and KM12 and ovarian cancers SK-OV-3 and IGROV-1) showed complete deficiency in MLH1 protein.
MSH2 protein was detected in all 57 cell lines studied. Absence of MLH1 protein was always linked to resistance to the methylating
chemotherapeutic agent temozolomide. This resistance was independent of cellular levels of O6-alkylguanine DNA alkyltransferase. Based on data available for review in the NCI COMPARE database, cellular levels of MLH1
and MSH2 did not correlate significantly with sensitivity to any standard anticancer drug or with any characterized molecular
target already tested against the same panel of cell lines. Conclusion: Based on evaluation of 60 tumor cell lines in the NCI anticancer drug screen, MLH1 deficiency was more common than MSH2
deficiency and was always associated with a high degree of temozolomide resistance. These data will enable correlations with
other drug sensitivities and molecular targets in the COMPARE database to evaluate linked processes in tumor drug resistance.
Received: 13 December 1999 / Accepted: 27 July 2000 |
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| Keywords: | DNA mismatch repair NCI anticancer drug screen DNA repair Drug resistance Temozolomide |
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