Glucuronidation by human colorectal adenocarcinoma cells as a mechanism of resistance to mycophenolic acid.
Mycophenolic acid (MPA), a potent and specific inhibitor of IMP dehydrogenase, exerts its anti-mitotic action by a rapid depletion of the cellular content of guanine nucleotides. Although MPA is a potent inhibitor of GTP synthesis in the HT29 line of human colorectal adenocarcinoma cells in short-term culture, its ability to depress the cloning efficiency of these cells was found to be markedly less than against the mouse mammary carcinoma line, EMT6. In vivo, MPA is efficiently converted to the biologically inactive O-glucuronide derivative thereby limiting its effectiveness as an anti-tumor agent. Investigation of the fate of MPA incubated with monolayer cultures of HT29 and EMT6 cells revealed that the compound is rapidly converted to the O-glucuronide derivative by HT29 cells, but not by EMT6 cells. Confirmation of the identity of the glucuronide formed by HT29 cells was obtained by its conversion to MPA after incubation with beta-glucuronidase and by comparison of the mass spectrum of its HPLC peak with that of synthetic MPA O-glucuronide. Cultures of two other lines of human colorectal adenocarcinoma cells, Colo-205 and LoVo, also depleted their culture media of MPA although we have not yet established whether these cells also synthesize the glucuronide. The intrinsic partial resistance of HT29 cells to MPA appears to be associated with the ability of these cells to convert MPA to the biologically inactive glucuronide. These results, in conjunction with other reports of the capacity of colorectal cancer cells for Phase I and II metabolism of xenobiotics, may have implications for the design of drugs intended for the treatment of colorectal cancer.
Franklin
T J
TJ
Cancer Research Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, U.K.
Jacobs
V
V
Bruneau
P
P
Ple
P
P
D000230:Adenocarcinoma / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D005260:Female; D005965:Glucuronates / Q000378:metabolism*; D014453:Glucuronosyltransferase / Q000378:metabolism; D006160:Guanosine Triphosphate / Q000096:biosynthesis / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors; D007700:Kinetics; D008325:Mammary Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology; D051379:Mice; D009173:Mycophenolic Acid / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D005965:Glucuronates; D006160:Guanosine Triphosphate; D007168:IMP Dehydrogenase; D014453:Glucuronosyltransferase; D009173:Mycophenolic Acid