Base excision repair as a therapeutic target in colon cancer.
Base excision repair (BER) is a fundamental cellular process used to reduce the cytotoxicity of alkylating agent chemotherapy. Heretofore, no therapeutic agents have targeted this DNA repair pathway. Methoxyamine (MX), which binds abasic sites, acting as an inhibitor of BER, was evaluated in combination with the methylating agent temozolomide (TMZ). Three human colon cancer cell lines were used, SW480 cells, which are wild-type for mismatch repair genes and have mutated p53, HCT116 cells, which are mutant in hMLH1 and wild-type for p53, and HCT15 cells, which are mutant in hMSH6 and mutant in p53 as well. Nude mice carrying these tumors received TMZ alone or in combination with MX or O(6)-benzylguanine (BG), an inhibitor of O(6)-alkylguanine DNA-alkyltransferase, daily i.p. for 5 consecutive days. At the highest tolerable dose of TMZ (120 mg/kg), a tumor growth delay of approximately 9.3 +/- 1.2 days was noted in SW480. Addition of BG resulted in a tumor growth delay of 25 +/- 2.4 days accompanied by significant weight loss (23%) and severe myelosuppression. In contrast, SW480 tumor-bearing mice treated with MX + TMZ had cessation of tumor growth for 50 +/- 13 days and very slow regrowth, yielding tumor growth delays of >70 +/- 14 days (P < 0.002) without additive systemic toxicity. HCT116 and HCT15 xenografts were completely resistant to treatment with TMZ alone or in combination with BG. However, treatment with MX + TMZ induced significant tumor growth delays (20 +/- 1.4 days in HCT116 and 14 +/- 3.1 days in HCT15 xenografts, P < 0.05). These studies demonstrate that a significant enhancement of the antitumor effect of TMZ by MX was observed in human colon cancer xenografts with mismatch repair proficiency and deficiency. DNA BER may be a useful pharmacological target through which tumor cells can be sensitized to alkylating therapeutic agents.
Liu
Lili
L
Division of Hematology and Oncology, Department of Medicine, Case Western Reserve University, Cleveland, Ohio 44106, USA.
Nakatsuru
Yoko
Y
Gerson
Stanton L
SL
D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000494:pharmacology* / Q000633:toxicity; D020137:Base Pair Mismatch / Q000187:drug effects; D001855:Bone Marrow Diseases / Q000139:chemically induced; D002869:Chromosome Aberrations / Q000187:drug effects; D003110:Colonic Neoplasms / Q000188:drug therapy* / Q000235:genetics; D018736:DNA Adducts; D004260:DNA Repair / Q000187:drug effects*; D004273:DNA, Neoplasm / Q000378:metabolism; D003606:Dacarbazine / Q000031:analogs & derivatives* / Q000494:pharmacology* / Q000633:toxicity; D003849:Deoxyguanosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D004357:Drug Synergism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005260:Female; D006801:Humans; D006898:Hydroxylamines / Q000494:pharmacology* / Q000633:toxicity; D051379:Mice; D008819:Mice, Nude; D019853:O(6)-Methylguanine-DNA Methyltransferase / Q000037:antagonists & inhibitors; D012854:Sister Chromatid Exchange / Q000187:drug effects; D000077204:Temozolomide; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism / Q000637:transplantation; D023041:Xenograft Model Antitumor Assays
D018906:Antineoplastic Agents, Alkylating; D018736:DNA Adducts; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D006898:Hydroxylamines; C035022:O(6)-n-butyldeoxyguanosine; D003606:Dacarbazine; C005214:methoxyamine; D019853:O(6)-Methylguanine-DNA Methyltransferase; D003849:Deoxyguanosine; D000077204:Temozolomide