mycophenolic-acid and Adenomatous-Polyposis-Coli

Familial adenomatous polyposis (FAP) was found to be completely reversed in a patient treated with mycophenolate mofetil (MMF) and tacrolimus following kidney transplantation. In this preliminary study, we assessed whether MMF and tacrolimus alone or in combination interfere with the cell cycle and proliferation in a human colonic adenocarcinoma cell line and in the colonic polyps of the patient with FAP.. Human colonic adenocarcinoma HT-29 cells were treated with tacrolimus and MMF alone and in combination at different concentrations. Cell viability and proliferation were assessed using the MTT assay. Cell-cycle distribution was analyzed by flow cytometry. Expression of Ki-67, a marker of mitotic activity, was evaluated in the patient's colonic polyps before and under drug treatment.. MMF in combination with tacrolimus induced S-phase cell-cycle arrest and markedly inhibited HT-29 cell proliferation. Ki-67 expression in the patient's colonic polyps was significantly reduced following combined tacrolimus and MMF treatment.. MMF and tacrolimus synergistically inhibited proliferation of a human colonic adenocarcinoma cell line and interfered with the expansion of colonic crypt proliferation in the polyp from a patient with FAP. The results confirm our clinical observation and indicate the possibility of novel approach to therapy of colorectal neoplasia.

Topics: Adenocarcinoma; Adenomatous Polyposis Coli; Antibiotics, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carcinogenesis; Cell Cycle Checkpoints; Cell Proliferation; Colon; Colonic Neoplasms; Drug Synergism; HT29 Cells; Humans; Immunosuppressive Agents; Ki-67 Antigen; Mycophenolic Acid; Tacrolimus

Numerous germline mutations in the adenomatous polyposis coli (APC) tumor-suppressor gene are responsible for development of multiple adenomatous colorectal polyps with their inevitable progression to cancer. Multiple attempts at dietary and pharmacological prevention of colorectal carcinoma development in patients with familial adenomatous polyposis (FAP) have provided conflicting results. Immunosuppressive treatment with tacrolimus is known to be associated with an increased risk of malignancy and should be avoided in patients with high propensity for development of neoplasia. We observed a complete reversion of FAP phenotype in a male teenager carrying a germline mutation in APC gene who underwent a kidney transplant due to end-stage kidney disease secondary to congenital dysplastic kidneys. The patient was treated with tacrolimus and mycophenolate mofetil after transplantation. The possible chemopreventative role of these agents should be evaluated and confirmed in a larger cohort. The elucidation of molecular mechanisms underpinning the observed chemopreventative effect of tacrolimus and mycophenolate mofetil might lead to the development of a novel colorectal cancer therapy.

Topics: Adenomatous Polyposis Coli; Adenomatous Polyposis Coli Protein; Adolescent; Adult; Antineoplastic Agents; Calcineurin Inhibitors; Colon; Drug Therapy, Combination; Female; Genetic Predisposition to Disease; Germ-Line Mutation; Heredity; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pedigree; Phenotype; Remission Induction; Tacrolimus; Treatment Outcome; Young Adult