Resistance to 6-thioguanine in mismatch repair-deficient human cancer cell lines correlates with an increase in induced mutations at the HPRT locus.
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.
Glaab
W E
WE
Laboratory of Environmental Carcinogenesis and Mutagenesis, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
Risinger
J I
JI
Umar
A
A
Barrett
J C
JC
Kunkel
T A
TA
Tindall
K R
KR
D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology*; D002352:Carrier Proteins; D002470:Cell Survival / Q000187:drug effects; D002874:Chromosome Mapping; D004260:DNA Repair; D004268:DNA-Binding Proteins; D019008:Drug Resistance, Neoplasm; D005656:Fungal Proteins / Q000235:genetics; D006801:Humans; D007041:Hypoxanthine Phosphoribosyltransferase / Q000235:genetics*; D000070957:MutL Protein Homolog 1; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D013866:Thioguanine / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D048868:Adaptor Proteins, Signal Transducing; D000964:Antimetabolites, Antineoplastic; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; D005656:Fungal Proteins; C501486:MLH1 protein, human; C098790:MSH6 protein, S cerevisiae; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D029701:Saccharomyces cerevisiae Proteins; D007041:Hypoxanthine Phosphoribosyltransferase; D000070957:MutL Protein Homolog 1; D013866:Thioguanine