A forward genetic approach for analyzing the mechanism of resistance to the anti-cancer drug, 5-fluorouracil, using Caenorhabditis elegans.
Pyrimidine antagonists including 5-Fluorouracil (5-FU) have been used in chemotherapy for cancer patients for over 40 years. 5-FU, especially, is a mainstay treatment for colorectal cancer. It is a pro-drug that is converted to the active drug via the nucleic acid biosynthetic pathway. The metabolites of 5-FU inhibit normal RNA and DNA function, and induce apoptosis of cancer cells. One of the major obstacles to successful chemotherapy is the resistance of cancer cells to anti-cancer drugs. Therefore, it is important to elucidate resistance mechanisms to improve the efficacy of chemotherapy. We have used C. elegans as a model system to investigate the mechanism of resistance to 5-FU, which induces germ cell death and inhibits larval development in C. elegans. We screened 5-FU resistant mutants no longer arrested as larvae by 5-FU. We obtained 18 mutants out of 72,000 F1 individuals screened, and mapped them into three complementation groups. We propose that C. elegans could be a useful model system for studying mechanisms of resistance to anti-cancer drugs.
Kim
Seongseop
S
Cancer Experimental Resources Branch, National Cancer Center, Goyang 411-769, Korea.
Shim
Jaegal
J
D000818:Animals; D000964:Antimetabolites, Antineoplastic / Q000378:metabolism* / Q000627:therapeutic use; D017209:Apoptosis / Q000502:physiology; D017173:Caenorhabditis elegans / Q000033:anatomy & histology / Q000196:embryology / Q000502:physiology*; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D005472:Fluorouracil / Q000378:metabolism* / Q000627:therapeutic use; D005816:Genetic Complementation Test; D008040:Genetic Linkage; D005854:Germ Cells / Q000166:cytology / Q000502:physiology; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
D000964:Antimetabolites, Antineoplastic; D005472:Fluorouracil