Resistance to cytotoxic drugs in DNA mismatch repair-deficient cells.
Loss of DNA mismatch repair is a common finding in many types of sporadic human cancers as well as in tumors arising in patients with hereditary nonpolyposis colon cancer. The effect of the loss of DNA mismatch repair activity on sensitivity to a panel of commonly used chemotherapeutic agents was tested using one pair of cell lines proficient or deficient in mismatch repair due to loss of hMSH2 function and another due to loss of hMLH1 function. 6-Thioguanine and N-methyl-N'-nitro-N-nitrosoguanidine, to which these cells are known to be resistant, were included in the panel as controls. The results were concordant in both pairs of cells. Loss of either hMSH2 or hMLH1 function was associated with low level resistance to cisplatin, carboplatin, and etoposide, but there was no resistance to melphalan, perfosfamide, 5-fluorouracil, doxorubicin, or paclitaxel. The results are consistent with the concept that the DNA mismatch repair proteins function as a detector for adducts produced by 6-thioguanine, N-methyl-N'-nitro-N-nitrosoguanidine, cisplatin, and carboplatin but not for melphalan and perfosfamide. They also suggest that these proteins play a role in detecting the DNA damage produced by the binding of etoposide to topoisomerase II and propagating signals that contribute to activation of apoptosis.
Aebi
S
S
Department of Medicine and the Cancer Center, University of California at San Diego, La Jolla, California 92093-0812, USA.
Fink
D
D
Gordon
R
R
Kim
H K
HK
Zheng
H
H
Fink
J L
JL
Howell
S B
SB
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000473:pathology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D016190:Carboplatin / Q000494:pharmacology; D002352:Carrier Proteins; D002945:Cisplatin / Q000494:pharmacology; D015179:Colorectal Neoplasms / Q000473:pathology; D003520:Cyclophosphamide / Q000031:analogs & derivatives / Q000494:pharmacology; D018736:DNA Adducts / Q000032:analysis; D004249:DNA Damage; D004260:DNA Repair / Q000235:genetics; D004273:DNA, Neoplasm / Q000032:analysis / Q000187:drug effects; D004268:DNA-Binding Proteins; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D016889:Endometrial Neoplasms / Q000473:pathology; D005047:Etoposide / Q000494:pharmacology; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D006801:Humans; D008558:Melphalan / Q000494:pharmacology; D008769:Methylnitronitrosoguanidine / Q000494:pharmacology; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D016296:Mutagenesis; D009363:Neoplasm Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D009687:Nuclear Proteins; D017239:Paclitaxel / Q000494:pharmacology; D011518:Proto-Oncogene Proteins / Q000172:deficiency* / Q000235:genetics / Q000502:physiology; D013866:Thioguanine / Q000494:pharmacology; D014407:Tumor Cells, Cultured / Q000187:drug effects
D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D002352:Carrier Proteins; D018736:DNA Adducts; D004273:DNA, Neoplasm; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; D008769:Methylnitronitrosoguanidine; D005047:Etoposide; D004317:Doxorubicin; D003520:Cyclophosphamide; D016190:Carboplatin; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D013866:Thioguanine; D017239:Paclitaxel; D002945:Cisplatin; D008558:Melphalan; D005472:Fluorouracil; C011272:perfosfamide