Carcinogenesis, Vol 19, 1931-1937, Copyright © 1998 by Oxford University Press
WE Glaab, JI Risinger, A Umar, JC Barrett, TA Kunkel and KR Tindall
Although the resistance to the cytotoxic response of certain DNA damaging
agents has been well characterized in cells deficient in mismatch repair,
little is known about how such resistance affects mutagenesis. Using human
cancer cell lines defective in mismatch repair (MMR) and complementary cell
lines in which the MMR defects were corrected by chromosome transfer, we
present the cytotoxic effect and the mutagenic response at the
hypoxanthine-guanine phosphoribosyl transferase (HPRT) locus following
exposure to the chemotherapeutic agent, 6-thioguanine (6-TG). Upon exposure
to 6-TG, there was a differential cytotoxic response. The MMR-deficient
cells were resistant to 6-TG exposure up to 5 microM, whereas the
MMR-proficient cell lines were significantly more sensitive at the same
levels of exposure. Furthermore, the mutagenic response at HPRT induced by
6-TG was substantially increased in the MMR-deficient lines relative to the
MMR- proficient cell lines. These findings support the notion that
cytotoxicity to 6-TG is mediated through functional MMR and that resistance
to the cytotoxic effects of 6-TG is directly associated with an increase in
induced mutations in MMR-defective cells. These data suggest that the use
of 6-TG as a chemotherapeutic agent may result in the selection of
MMR-defective cells, thereby predisposing the patient to an increased risk
for developing secondary tumors.
ARTICLES
Resistance to 6-thioguanine in mismatch repair-deficient human cancer cell lines correlates with an increase in induced mutations at the HPRT locus
Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
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