Franklin T J, Jacobs V, Jones G, Plé P, Bruneau P
Cancer Research Department, Zeneca Pharmaceuticals, Macclesfield, Cheshire, England.
Cancer Res. 1996 Mar 1;56(5):984-7.
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.
抗肿瘤、免疫抑制性抗生素霉酚酸的体内疗效已知受其快速转化为无生物活性的7-O-葡糖醛酸苷的限制，这种转化由UDP-葡糖醛酸基转移酶活性催化，该酶广泛分布于包括肠上皮在内的正常组织中。我们发现，包括HT29、Lovo和Colo-205在内的几株人结肠癌细胞系也能将霉酚酸转化为其葡糖醛酸苷。相比之下，非结肠来源的恶性细胞系，包括EMT6、HeLa和SKOV3，没有代谢霉酚酸的能力。霉酚酸的7-氨基衍生物未被HT29细胞代谢。该化合物对EMT6和HeLa细胞的效力低于霉酚酸，但对HT29细胞显示出与母体抗生素相当的抑制活性。与缺乏显著葡糖醛酸化能力的细胞相比，HT29细胞对霉酚酸的快速代谢与其对该药物抗增殖活性和抑制GTP合成能力的敏感性显著降低有关。在霉酚酸诱导HT29细胞内GTP最初下降后，随着抗生素的代谢，GTP在48小时内逐渐恢复。在EMT6细胞中未观察到这种恢复过程。提示葡糖醛酸基转移酶活性可能在结肠癌细胞中广泛存在，并可能导致对易被葡糖醛酸结合失活的药物产生耐药性。
