Mm. Delasalas et al., LOSS OF DNA MISMATCH REPAIR - EFFECTS ON THE RATE OF MUTATION TO DRUG-RESISTANCE, Journal of the National Cancer Institute, 89(20), 1997, pp. 1537-1541
Background: The loss of the ability of cells to repair mismatches in d
ouble-stranded DNA is a common finding in human tumors, This defect re
sults in genomic instability and in increased resistance to several of
the drugs used in cancer chemotherapy, The human colon cancer cell li
ne HCT116 is deficient in DNA mismatch repair (MMR) because of a genet
ic 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 contr
ol]) have a higher rate of mutation to resistance to commonly used che
motherapeutic agents (i.e., cisplatin, doxorubicin, paclitaxel [Taxol]
, and etoposide) than MMR-proficient HCT116+chr3 cells (i.e., HCT116 c
ells into which chromosome 3 has been transferred to provide a wild-ty
pe copy of the hMLH1 gene), Methods: Spontaneous mutation rates were c
alculated from measurements of the mutant fractions of cells before an
d after their expansion through a known number of generations (also kn
own as the technique of maximum likelihood estimation), Aliquots of 50
0 000 cells were expanded in culture over a period of 2 weeks, and the
mutant fractions were determined both before and after expansion of s
econdary cultures (each also with an initial 500 000 cells) in drug co
ncentrations that produced survival fractions of 0.0002%, Results: Mut
ation rates in MMR-proficient and MMR-deficient cells did not differ o
n exposure to cisplatin, doxorubicin, or paclitaxel; however, the rela
tive 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 targe
ts for mutation when the loss of MMR destabilizes the genome, Tumors c
ontaining large fractions of MMR-deficient cells may demonstrate more
rapid emergence of clinical resistance to etoposide.