ANTITUMOR-ACTIVITY OF MYCOPHENOLATE MOFETIL AGAINST HUMAN AND MOUSE-TUMORS IN-VIVO

Cultured tumor cell lines, tumor xenografts grown in athymic nude mice , and a murine experimental metastasis model were used to assess the i n vitro and in vivo anti-tumor activity of the potent IMP dehydrogenas e (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-dry, mycophenolate mofetil (MM). The growth of all the cell lines tested was inhibited by MPA in vitro, with EC(50) values ranging from less than 0.1 mu M to 3.9 mu M. Mice were monitored for s.c. tum or outgrowth in the case of human tumor xenograft models or survival t ime for the murine experimental metastasis model. Treatment with MM p. o. was started 24 hr after tumor challenge of after tumors became palp able. Treatment of athymic nude mice bearing A3.01 (T-lymphoblast), Mo lt-4 (T-cell leukemia), CaPan-2 (pancreatic adenocarcinoma), CaLu-3 (n on-small-cell lung adenocarcinoma), LS174T and T84 (colon adenocarcino ma), and Daudi (B-cell lymphoma) human tumor xenografts with MM signif icantly inhibited s.c. tumor growth. Treatment of BALB/c mice with MM after i.v. injection of murine RAW117-H10 lymphoma cells in an experim ental metastasis assay resulted in increased survival time for treated animals. No significant inhibitory effect on s.c. tumor outgrowth was seen with MM treatment of SK-Hep-1, a human hepatic endothelioma, or Hep-3B, a liver adenocarcinoma, at any of the doses tested. (C) 1994 W iley-Liss, Inc.