Mycophenolate Mofetil Inhibits Tumor Growth and Angiogenesis In Vitro but Has Variable Antitumor Effects In Vivo, Possibly Related to Bioavailability

Abstract

Identifying immunosuppressive agents with antitumor effects could help address the problem of posttransplant malignancy. Here we tested for potential inhibitory effects of mycophenolate mofetil (MMF) on tumors in vitro and in vivo. Mouse CT26 colon adenocarcinoma, B16 melanoma, and human TMK1 gastric adenocarcinoma cells were tested for in vitro growth in the presence of MMF. In vitro angiogenesis was tested with a rat aortic-ring assay. Tumor cells were implanted into dorsal skinfold chambers (DSFC) to assess in vivo angiogenesis. Subcutaneous tumor growth was determined in mice receiving MMF. MMF caused a dose-dependent reduction in tumor cell numbers in vitro, starting between 0.1 to 1 microM. Vessel sprouting from aortic rings was markedly blocked by similar concentrations of MMF. In vivo, however, DSFC results showed a marginal reduction in CT26 tumor angiogenesis with MMF doses of 40 or 80 mg/kg/day, although MMF did inhibit TMK1 vascularity. Moreover, 80 mg/kg/day MMF did not reduce subcutaneous CT26 tumor volumes, but did slightly inhibit B16 and TMK1 expansion. Interestingly, the mycophenolic acid (MPA) blood level 2 hr after 80 mg/kg/day MMF bolus dosing was near 14 mg/L, but decreased dramatically thereafter, suggesting a drug availability issue. Indeed, intermittent 2-hr MMF pulses in tumor-cell cultures substantially reduced the antiproliferative effect of MPA. MMF strongly inhibits tumor cell growth and angiogenesis in vitro, but only marginally inhibits tumors in vivo. These contrasting results may relate to drug availability, where intermittent exposure of tumor cells to immunosuppressive doses of MMF substantially reduce its potential antitumor effects.