Anti‐tumor activity of mycophenolate mofetil against human and mouse tumors in vivo

Abstract

Cultured tumor cell lines, tumor xenografts grown in athymic nude mice, and a murine experimental metastasis model were used to assess the in vitro and in vivo anti-tumor activity of the potent IMP dehydrogenase (IMPDH) inhibitor, mycophenolic acid (MPA), and its morpholinoethyl ester pro-drug, mycophenolate mofetil (MM). The growth of all the cell lines tested was inhibited by MPA in vitro, with EC50 values ranging from less than 0.1 microM to 3.9 microM. Mice were monitored for s.c. tumor outgrowth in the case of human tumor xenograft models or survival time for the murine experimental metastasis model. Treatment with MM p.o. was started 24 hr after tumor challenge or after tumors became palpable. Treatment of athymic nude mice bearing A3.01 (T-lymphoblast), Molt-4 (T-cell leukemia), CaPan-2 (pancreatic adenocarcinoma), CaLu-3 (non-small-cell lung adenocarcinoma), LS174T and T84 (colon adenocarcinoma), and Daudi (B-cell lymphoma) human tumor xenografts with MM significantly inhibited s.c. tumor growth. Treatment of BALB/c mice with MM after i.v. injection of murine RAW117-H10 lymphoma cells in an experimental 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.

Dietary Immunosuppressants Do Not Enhance UV-Induced Skin Carcinogenesis, and Reveal Discordance between p53-Mutant Early Clones and Carcinomas

“…However, not all immunosuppressants necessarily promote cancer development. While mycophenolate mofetil has some capacity to reduce tumor cell proliferation (15,16), rapamycin exhibits impressive inhibitory effects on cancer development. Rapamycin inhibits angiogenesis and tumor cell proliferation (15,17,18), leading to impaired inoculated tumor growth in mice and de novo tumor development in a p53-null mice (19).…”

“…While mycophenolate mofetil has some capacity to reduce tumor cell proliferation (15,16), rapamycin exhibits impressive inhibitory effects on cancer development. Rapamycin inhibits angiogenesis and tumor cell proliferation (15,17,18), leading to impaired inoculated tumor growth in mice and de novo tumor development in a p53-null mice (19). Interestingly, azathioprine-treated transplant recipients have more mutant p53-overexpressing cell clusters in precursor skin lesions than immunocompetent patients with skin carcinomas (20); this finding contrasts with results in rapamycin-fed mice that develop fewer mut-p53 cell clusters than control mice (21).…”

Inhibition of T lymphocyte activation in mice heterozygous for loss of the IMPDH II gene

“…It has been shown that administration of IMPDH inhibitors to cultured cells results in inhibition of DNA synthesis (11) and cellcycle arrest at the G1-S boundary (12,13). Inhibitors of IMPDH have also been shown to possess antineoplastic (14,15), antiviral (16), antiparasitic (17), and immunosuppressive (18,19) activities, and to induce Inosine 5′-monophosphate dehydrogenase (IMPDH) is the rate-limiting enzyme in the de novo synthesis of guanine nucleotides, which are also synthesized from guanine by a salvage reaction catalyzed by the X chromosome-linked enzyme hypoxanthine-guanine phosphoribosyltransferase (HPRT). Since inhibitors of IMPDH are in clinical use as immunosuppressive agents, we have examined the consequences of knocking out the IMPDH type II enzyme by gene targeting in a mouse model.…”

Differential Sensitivities of Fast- and Slow-Cycling Cancer Cells to Inosine Monophosphate Dehydrogenase 2 Inhibition by Mycophenolic Acid

“…Cells were incubated overnight to attach to the bottom of the wells, and then treated with serials dilutions of MPA (1,5,10,15,20,25 and 30 μg/mL). Cell viability was analyzed by adding 5 mg/mL MTT (Sigma-Aldrich) and 150 μL DMSO.…”

“…Mycophenolic acid (MPA) acts as a nonnucleoside, noncompetitive, reversible inhibitor of IMPDH with fivefold higher potency of inhibiting IMPDH2 than IMPDH1. It has been reported to be able to inhibit cancer cell proliferation and induce apoptosis in several experimental models of human solid tumors and hematological malignancies by depleting guanine nucleotide pools (5,(8)(9)(10).…”