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Vol. 56, Issue 2, 390-395, August 1999
Department of Medicine and the Cancer Center, University of
California at San Diego, La Jolla, California
Loss of DNA mismatch repair (MMR) causes genomic instability by
markedly increasing the frequency of sporadic mutations in both coding
and noncoding sequences. Little is known about how loss of MMR affects
sensitivity to the mutagenic effect of chemotherapeutic agents. We
wanted to determine how loss of MMR affects the ability of cisplatin, a
known mutagen, to generate human tumor cell variants resistant to other
drugs with which cisplatin is commonly combined in treatment regimens.
We compared the ability of cisplatin to produce variants resistant to
topotecan, gemcitabine, and paclitaxel in two pairs of MMR-proficient
and -deficient cells that included sublines of the human colon
carcinoma cell line HCT-116 and sublines of the human endometrial
adenocarcinoma cell line HEC59. Cells were exposed to increasing
concentrations of cisplatin for 1 h, and the surviving population
was tested for the frequency of variants resistant to these single
molecular target drugs 10 days later. The frequency of variants
increased linearly with cisplatin concentration for all three drugs.
Cisplatin was 2.6 ± 0.3- (S.D.), 3.6 ± 0.9-, and 2.3 ± 0.1-fold more potent at producing topotecan-, gemcitabine-, and
paclitaxel-resistant variants in the MMR-deficient than in the
MMR-proficient HCT116 cells (P < .05 for all).
Cisplatin was 1.4 ± 0.3- and 1.4 ± 0.4-fold more potent at
generating topotecan- and gemcitabine-resistant variants in
MMR-deficient HEC59 cells than in MMR-proficient HEC59+ch2 cells.
Cisplatin was not more potent in generating paclitaxel-resistant
variants in the MMR-deficient HEC59 cells. Spontaneous rates of
generation of cells resistant to these three drugs were also measured
in the HCT116 sublines. MMR-deficient HCT116 cells exhibited rates of
generation of resistant variants that were 1.94- and 1.51-fold higher
(P < .05) than those in the MMR-proficient cells
for topotecan and gemcitabine, respectively; loss of MMR had no effect
on the rate of generation of variants resistant to paclitaxel. We
conclude that the loss of MMR increases the ability of cisplatin to
generate variants resistant to topotecan, gemcitabine, and possibly
paclitaxel and that MMR also plays a role in controlling the
spontaneous rate of generation of variants resistant to topotecan and gemcitabine.
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