Differential cytotoxicity of anticahcer agents in hMutSα-deficient and -proficient human colorectal cancer cells

Abstract

Mismatch repair (MMR)-deficient cells exhibit drug resistance to several anticancer agents including N-methyl-AP-nitro-N-nitrosoguanidine (MNNG), cisplatin, and adriamycin. Since these agents are potent mutagens, it is possible to select resistant clones of tumor cells during chemotherapy. Prior to determining whether drug cytotoxicity was altered by MMR-deficiency, mutation in the (A)₈ repeat region of the hMSH3 gene of the MMR-deficient human colorectal cancer cell line HCT116 and the MMR-proficient human chromosome 3-transferred HCT116(HCT116+ch3) was comfirmed. A screening method was then determined using MNNG cytotoxicity in both cell lines and 20 additional anticancer agents were examined. Clonogenic cytotoxic assay revealed in 8 anticancer agents (streptozotocin,5-fluorouracil, tegafur, bleomycin, mitomycin C, vinblastine, vincristine, and nidoran) maintaining the desired level of cytotoxicity required a higher concentration in HCT116 than in HCT116+ch3. Cytosine β-D-arabinofuranoside, chlorambucil, and epirubicin were more cytotoxic to HCT116. Dacarbazine, nitrogen mustard,3'-azido-3'-deoxythymidine, aclarubicin, neocarzinostatin, actinomycin D, and peplomycin possessed similar cytotoxicity. These results suggest that drugs with higher or uncompromised sensitivity can circumvent drug resistance due to MMR-deficiency in tumor cells.