Role of DNA mismatch repair in apoptotic responses to therapeutic agents.
Deficiencies in DNA mismatch repair (MMR) have been found in both hereditary cancer (i.e., hereditary nonpolyposis colorectal cancer) and sporadic cancers of various tissues. In addition to its primary roles in the correction of DNA replication errors and suppression of recombination, research in the last 10 years has shown that MMR is involved in many other processes, such as interaction with other DNA repair pathways, cell cycle checkpoint regulation, and apoptosis. Indeed, a cell's MMR status can influence its response to a wide variety of chemotherapeutic agents, such as temozolomide (and many other methylating agents), 6-thioguanine, cisplatin, ionizing radiation, etoposide, and 5-fluorouracil. For this reason, identification of a tumor's MMR deficiency (as indicated by the presence of microsatellite instability) is being utilized more and more as a prognostic indicator in the clinic. Here, we describe the basic mechanisms of MMR and apoptosis and investigate the literature examining the influence of MMR status on the apoptotic response following treatment with various therapeutic agents. Furthermore, using isogenic MMR-deficient (HCT116) and MMR-proficient (HCT116 3-6) cells, we demonstrate that there is no enhanced apoptosis in MMR-proficient cells following treatment with 5-fluoro-2'-deoxyuridine. In fact, apoptosis accounts for only a small portion of the induced cell death response.
Meyers
Mark
M
Department of Radiation Oncology, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Hwang
Arlene
A
Wagner
Mark W
MW
Boothman
David A
DA
D000477:Alkylating Agents / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D020137:Base Pair Mismatch / Q000502:physiology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000494:pharmacology; D002945:Cisplatin / Q000494:pharmacology; D018736:DNA Adducts / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D005467:Floxuridine / Q000494:pharmacology*; D005472:Fluorouracil / Q000494:pharmacology; D006150:Guanine Nucleotides / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D000077146:Irinotecan; D011839:Radiation, Ionizing; D013873:Thionucleotides / Q000494:pharmacology
D000477:Alkylating Agents; D000970:Antineoplastic Agents; D018736:DNA Adducts; D006150:Guanine Nucleotides; D013873:Thionucleotides; D005467:Floxuridine; C003964:6-thioguanylic acid; D000077146:Irinotecan; D002945:Cisplatin; D005472:Fluorouracil; D002166:Camptothecin