Glucuronidation associated with intrinsic resistance to mycophenolic acid in human colorectal carcinoma cells.
The in vivo efficacy of the antitumor, immunosuppressive antibiotic mycophenolic acid is known to be limited by its rapid conversion to the biologically inactive 7-0-glucuronide, catalyzed by UDP-glucuronosyl transferase activity, which is widely distributed among normal tissues, including intestinal epithelium. We have found that mycophenolic acid is also converted to its glucuronide by several lines of human colorectal carcinoma cells, including HT29, Lovo, and Colo-205. In contrast, malignant cell lines not of colorectal origin, including EMT6, HeLa, and SKOV3, showed no ability to metabolize mycophenolic acid. The 7-amino derivative of mycophenolic acid was not metabolized by HT29 cells. This compound was less potent than mycophenolic acid versus EMT6 and HeLa cells but showed inhibitory activity against HT29 cells comparable with the parent antibiotic. The rapid metabolism of mycophenolic acid by HT29 cells was associated with a markedly lower sensitivity to both the antiproliferative activity of the drug and to its ability to inhibit GTP synthesis, compared with cells lacking the capacity for significant glucuronidation. After an initial decline in cellular GTP in HT29 cells induced by mycophenolic acid, there was a progressive recovery in GTP over 48 h, accompanying the metabolism of the antibiotic. This recovery process was not observed in EMT6 cells. It is suggested that glucuronosyl transferase activity may occur widely in colorectal cancer cells and could contribute to resistance to drugs that are susceptible to inactivation by glucuronide conjugation.
Franklin
T J
TJ
Cancer Research Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, England.
Jacobs
V
V
Jones
G
G
Plé
P
P
Bruneau
P
P
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000378:metabolism / Q000494:pharmacology*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D002455:Cell Division / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000378:metabolism* / Q000473:pathology; D004351:Drug Resistance; D005965:Glucuronates / Q000378:metabolism*; D006801:Humans; D051379:Mice; D009173:Mycophenolic Acid / Q000378:metabolism / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D005965:Glucuronates; D009173:Mycophenolic Acid