© 1997 by Oxford University Press
Journal Of The National Cancer Institute, Vol 89, 1537-1541, Copyright © 1997 by Oxford University Press
MM de las Alas, S Aebi, D Fink, SB Howell and G Los
BACKGROUND: The loss of the ability of cells to repair mismatches in
double-stranded DNA is a common finding in human tumors. This defect
results in genomic instability and in increased resistance to several of
the drugs used in cancer chemotherapy. The human colon cancer cell line
HCT116 is deficient in DNA mismatch repair (MMR) because of a genetic
defect in the hMLH1 gene, which is located on chromosome 3. In this study,
we investigated whether MMR-deficient HCT116+chr2 cells (i.e., HCT116 cells
into which chromosome 2 has been transferred [as a control]) have a higher
rate of mutation to resistance to commonly used chemotherapeutic agents
(i.e., cisplatin, doxorubicin, paclitaxel [Taxol], and etoposide) than
MMR-proficient HCT116+chr3 cells (i.e., HCT116 cells into which chromosome
3 has been transferred to provide a wild-type copy of the hMLH1 gene).
METHODS: Spontaneous mutation rates were calculated from measurements of
the mutant fractions of cells before and after their expansion through a
known number of generations (also known as the technique of maximum
likelihood estimation). Aliquots of 500000 cells were expanded in culture
over a period of 2 weeks, and the mutant fractions were determined both
before and after expansion of secondary cultures (each also with an initial
500000 cells) in drug concentrations that produced survival fractions of
0.0002%. RESULTS: Mutation rates in MMR-proficient and MMR-deficient cells
did not differ on exposure to cisplatin, doxorubicin, or paclitaxel;
however, the relative mutation rate was 2.4-fold higher in MMR-deficient
cells exposed to etoposide (P=.002). CONCLUSION: These results suggest that
genes involved in the control of cellular sensitivity to etoposide are
targets for mutation when the loss of MMR destabilizes the genome. Tumors
containing large fractions of MMR- deficient cells may demonstrate more
rapid emergence of clinical resistance to etoposide.
ARTICLES
Loss of DNA mismatch repair: effects on the rate of mutation to drug resistance
Cancer Center and the Department of Medicine, University of Califonia-- San Diego, La Jolla 92093-0058, USA. mdelasal@sdcc.14.ucsd.edu
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