tacrolimus and Colonic-Neoplasms

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

Inflammation contributes to colon cancer initiation. The disease along with allergy and autoimmunity has been on the rise in Western and more recently in developing countries. This shared rise may imply a shared cause. Streptomycetes are known as soil residents and produce numerous antiproliferative, anti-inflammatory/immunosuppressive compounds, e.g. rapamycin and tacrolimus. Recently, Streptomyces has been shown in gut microbiome with a lower prevalence in humans than nonhumans whose microbiomes might be more representative of past humans' in a hunter-gatherer and farming environment. It was previously suggested that Streptomyces producing antiproliferatives/immunosuppressants would be 'old friends' against allergy and autoimmunity as well as inflammatory bowel diseases. Here, it is suggested that these streptomycetes within gut microbiome have also been evolved as 'old friends' to suppress colon tumorigenesis through their numerous antiproliferatives/immunosuppressants. Subsequently, the shortage of exposure to nature in our current lifestyle has cost us the shortage of these friends and vulnerability to colon cancer. An attractive research area in the future would be whether the shortage of Streptomyces exposure can be the underlying reason for colon cancer, allergy and autoimmunity rise, and if the restoration of these 'old friends' through probiotics or more exposure to nature can prevent colon cancer.

Topics: Anti-Inflammatory Agents; Carcinogenesis; Colonic Neoplasms; Friends; Gastrointestinal Microbiome; Humans; Life Style; Microbiota; Probiotics; Sirolimus; Soil; Soil Microbiology; Streptomyces; Tacrolimus

We estimated the effect of various immunosuppressants (ISs) and metformin (M) to provide theoretical background of optimal therapeutic strategy for de novo colon cancer after liver transplantation (LT). Three colon cancer cell lines (HT29, SW620, and HCT116) were used in in vitro studies. HT29 was also used in BALB/c-nude mice animal models. Following groups were used in both in vitro and in vivo studies: sirolimus (S), tacrolimus (T), cyclosporin A (CsA), M, metformin/sirolimus (Met/S), metformin/tacrolimus (Met/T), and metformin/cyclosporin A (Met/CsA). 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay was performed and western blot analyses were performed for mTOR pathway proteins, apoptosis proteins, and epithelial-mesenchymal-transition (EMT) proteins. Tumor volume was measured for 4 weeks after inoculation. MTT-assay revealed significant cell viability inhibition in all 3 colon cancer cell lines in groups of S, M, and Met/S. Of note, group Met/S showed synergistic effect compare to M or S group. Western blot analysis showed significant low levels of all investigated proteins in groups of S and Met/S in both in vitro and in vivo experiment. Tumor growth was significantly inhibited only in the Met/S group. Combination of Met and S showed the most potent inhibition in all colon cancer cell lines. This finding might have application for de novo colon cancer.

Topics: Animals; Antineoplastic Agents; Apoptosis; Cell Line, Tumor; Colonic Neoplasms; Cyclosporine; Disease Models, Animal; Drug Synergism; Drug Therapy, Combination; HCT116 Cells; HT29 Cells; Humans; Metformin; Mice; Mice, Inbred BALB C; Mice, Nude; Ribosomal Protein S6 Kinases, 70-kDa; Signal Transduction; Sirolimus; Smad3 Protein; Tacrolimus; Transplantation, Heterologous

Topics: Adenocarcinoma; Aged; Colonic Neoplasms; Colostomy; Dermatitis; Diagnosis, Differential; Humans; Male; Postoperative Complications; Prednisone; Pyoderma Gangrenosum; Skin Neoplasms; Skin Ulcer; Surgical Stomas; Tacrolimus

With this study we aimed to research the effects of immunosuppressive drugs, their cumulative doses, and viral infections on development of malign tumors in patients who have undergone treatment for 5 years.. We examined 100 patients who underwent renal transplantation from 2004 to 2009. Patients had mycophenolate mofetil and steroid in addition to cyclosporine, sirolimus, or tacrolimus as immunosuppressive treatment. For malignancy screening, physical examination, radiologic and endoscopic screening were done, and immunosuppressive drugs and their cumulative doses, age, sex, body mass index (BMI), dialysis history, and viral infection history were investigated.. The mean age of patients was 42.03 ± 11.30 years. There were 1 colon cancer patient, 1 retroperitoneal liposarcoma, 1 renal oncocytoma, 3 Kaposi sarcoma patients treated with cyclosporine; in those treated with Tac there were 1 basal cell carcinoma, 1 Kaposi sarcoma, 2 thyroid carcinoma, 1 breast carcinoma, 1 bladder carcinoma, 1 renal cell carcinoma, and 1 colon carcinoma patients. The mean age of patients having carcinoma was statistically significant compared with those without cancer (P < .01). The prednisolone cumulative dose was significantly higher in carcinoma patients than in patients without carcinoma (P < .01).. The use of long-term chronic immunosuppressive therapy may increase the development of cancer. The risk of carcinoma increases with increasing drug dose and time period of the immunosuppressive drug. There was not a negative effect on cancer prevalence in patients with cyclosporine or tacrolimus. But the cumulative dose of steroids significantly increased malignancy occurence.

Topics: Adult; Breast Neoplasms; Carcinoma; Colonic Neoplasms; Cyclosporine; Early Detection of Cancer; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Neoplasms; Retroperitoneal Neoplasms; Sarcoma, Kaposi; Sirolimus; Steroids; Tacrolimus; Thyroid Neoplasms; Time Factors; Urologic Neoplasms

Posttransplantation lymphoproliferative disorder (PTLD) is a serious complication following solid organ transplantation that has been linked to Epstein-Barr virus (EBV) infection. The aim of this article was to describe a single-center experience with the multiplicity of clinical presentations of PTLD. Among 350 liver transplantations performed in 303 children, 13 survivor children displayed a histological diagnosis of PTLD (13/242 survivors; 5.4%). The age at diagnosis ranged from 12 to 258 months (median, 47), and the time from transplantation ranged from 1 to 84 months (median, 13). Ten of these children (76.9%) were EBV-naïve prior to transplantation. Fever was present in all cases. The clinical signs at presentation were anemia (92.3%), diarrhea and vomiting (69.2%), recurrent upper airway infections (38.4%), Waldeyer ring lymphoid tissue hypertrophy (23.0%), abdominal mass lesions (30.7%), massive cervical and mediastinal adenopathy (15.3%), or gastrointestinal and respiratory symptoms (30.7%). One child developed fulminant hepatic allograft failure secondary to graft involvement by PTLD. Polymorphic PTLD was diagnosed in 6 patients; 7 had the diagnosis of lymphoma. Treatment consisted of stopping immunosuppression as well as starting intravenous gancyclovir and anti-CD20 monoclonal antibody therapy. The mortality rate was 53.8%. The clinical presentation of PTLD varied from fever of unknown origin to fulminant hepatic failure. The other symptoms that may be linked to the diagnosis of PTLD are pancytopenia, tonsil and adenoid hypertrophy, cervical or mediastinal lymph node enlargement, as well as abdominal masses. Despite numerous advances, the optimal treatment approach for PTLD is not completely known and the mortality rate is still high.

Topics: Biliary Atresia; Child; Child, Preschool; Colonic Neoplasms; Cyclosporine; Drug Therapy, Combination; Epstein-Barr Virus Infections; Female; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Transplantation; Lymph Nodes; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Postoperative Complications; Prednisone; Retrospective Studies; Survivors; Tacrolimus

Liver transplant recipients are known to be at increased risk for the development of de novo neoplasms or the recurrence of preexisting malignancies, and this is possibly related to the use of immunosuppressive medication. Little is known about the effects of cytotoxic chemotherapy on graft function after transplantation. A retrospective chart and pathology database review was undertaken to identify post-liver transplant patients developing rejection during chemotherapy. All liver biopsies were reviewed by a hepatopathologist. Three patients were identified. All patients were diagnosed with cancer within 7 years of liver transplantation; two-thirds died soon after the diagnosis of malignancy. Rejection occurred soon after chemotherapy was started. All patients were receiving prednisone and tacrolimus (trough levels: 2.1-4.8 ng/mL). One patient developed plasma cell hepatitis (de novo autoimmune hepatitis). There was no histologic evidence of hepatotoxicity due to the chemotherapeutic agents. Cytotoxic chemotherapy should be used in liver transplant recipients with caution, and immunosuppressant doses should be maintained at therapeutic levels, as patients may be at risk for allograft rejection. Treatment of rejection or plasma cell hepatitis in this setting should be undertaken in a timely and aggressive fashion to prevent chronic ductopenic rejection.

Topics: Adult; Antineoplastic Agents; Biopsy; Cholangitis, Sclerosing; Colonic Neoplasms; Cytotoxins; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver; Liver Cirrhosis, Biliary; Liver Neoplasms; Liver Transplantation; Male; Middle Aged; Prednisone; Retrospective Studies; Risk Factors; Skin Neoplasms; Tacrolimus

Topics: Administration, Topical; Adult; Colectomy; Colitis, Ulcerative; Colonic Neoplasms; Fatal Outcome; Humans; Male; Pyoderma; Risk Assessment; Severity of Illness Index; Stomatitis; Tacrolimus; Treatment Outcome

Topics: Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Cetuximab; Colectomy; Colonic Neoplasms; Dermatologic Agents; Female; Humans; Skin Diseases; Tacrolimus

Topics: Adult; Antiviral Agents; Colonic Neoplasms; Cyclosporine; Esophageal Neoplasms; Female; Ganciclovir; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Neoplasms; Liver Transplantation; Lymphoproliferative Disorders; Middle Aged; Pharyngeal Neoplasms; Survival Analysis; Tacrolimus; Time Factors

Patients with stomas face a variety of problems, such as skin breakdown or ulceration at the peristomal site, that can complicate care. Topical steroids are frequently used to treat various inflammatory conditions that affect peristomal skin with good results, but chronic use can lead to undesirable side effects. Tacrolimus ointment 0.1%, a nonsteroidal immunosuppressant, could offer a more favorable alternative to topical steroids. We present 3 cases of peristomal skin disease that were successfully treated with tacrolimus ointment 0.1%.

Topics: Administration, Topical; Aged; Aged, 80 and over; Colonic Neoplasms; Dermatitis; Female; Humans; Immunosuppressive Agents; Male; Ointments; Surgical Stomas; Tacrolimus; Treatment Outcome; Urinary Bladder Neoplasms

1. Certain chemicals and drugs in addition to metabolically activated carcinogens are substrates for intestinal cytochrome P450s (CYPs) and a number of cell lines are available which could be used in metabolism studies. These include the rat duodenal cell line IEC 6, rat ileal IEC 18, foetal human HuTu 80, foetal human small intestinal FHS 74, human duodenal HCT 8 and human colon CaCo-2 cells, but they lack thorough biochemical characterization. 2. The aim of the present study was therefore to investigate the mRNA and protein expression of CYP1A1, CYP1A2, CYP2C9/10, CYP2E1 and CYP3A. In addition, the metabolism of the immunosuppressant drug tacrolimus and of the procarcinogen 7,12-dimethyl-benz[a]anthracene (DMBA) was studied to obtain information on the functional activity on these cell lines. 3. Of all the cell lines tested only CaCo-2 cells expressed CYP1A1 at the protein and mRNA level, but the CYP2E1 and CYP3A protein was also detected in CaCo-2 and FHS 74 cells. It is of considerable interest that none of the other cell lines expressed CYP1A1, CYP1A2, CYP2C9/10 or CYP3A4 at the protein and mRNA level. 4. When the metabolism of DMBA (a model carcinogen) was studied, CaCo-2 cells produced the following metabolites: 7,12-dihydroxymethylbenz[a]anthracene, 7,12-dimethylbenz-[a]anthracene-di-hydrodiol, 7-methyl-12-hydroxymethylbenz[a]anthracene, 7-hydroxy-methyl-12-benz[a]anthracene and possibly the dihydrated product of the latter two derivatives. 5. CaCo-2 cells also catalysed the metabolism of the immunosuppressant drug tacrolimus resulting in the formation of 13-O-demethyl-tacrolimus bisdemethyl-hydroxy-tacrolimus and demethyl-dihydroxy-tacrolimus. Neither the foetal human small intestinal FHS 74 cell line nor any of the other cell lines were able to catalyse the biotransformation of tacrolimus. 6. In conclusion, only CaCo-2 cells were able to produce metabolites similar to those observed in in vivo metabolism studies, whereas all other cell lines were metabolically incompetent. Therefore, this cell line may be used in studies of intestinal biotransformation.

Topics: 9,10-Dimethyl-1,2-benzanthracene; Animals; Biotransformation; Catalysis; Cell Line; Cells, Cultured; Colonic Neoplasms; Cytochrome P-450 Enzyme System; Duodenum; Fetus; Humans; Ileum; Intestine, Small; Isoenzymes; Kinetics; Microsomes; Microsomes, Liver; Protein Biosynthesis; Rats; RNA, Messenger; Substrate Specificity; Tacrolimus; Transcription, Genetic; Tumor Cells, Cultured

Topics: Adenocarcinoma; Animals; Colonic Neoplasms; fas Receptor; Gene Expression Regulation, Neoplastic; Genes, p53; Immunosuppressive Agents; Male; Mice; Mice, Inbred C57BL; Tacrolimus; Tumor Suppressor Protein p53

We examined alterations in cell morphology and expression of adhesion molecules in response to a general protein kinase inhibitor K252a treatment of non-adherent colon adenocarcinoma Colo201 cells. K252a induced rapid cell adhesion and spreading with concomitant formation of actin stress fibers. A protein kinase A inhibitor KT5720 also induced cell adhesion, but the rate of spread was slower than that seen with K252a. These adhesions were mediated by integrin molecules since cell adhesion required Mg2+, Mn2+ or Ca2+, and was inhibited by monoclonal antibodies for integrins alpha2 and beta1. Indirect immunofluorescence microscopic observations revealed that integrin alpha2 and beta1 molecules in K252a-treated cells were concentrated at sites of focal adhesion, but expressions of integrin molecules were not modulated. Tyrosine phosphorylation of focal adhesion kinase (FAK) and paxillin increased during K252a- or KT5720-induced cell adhesion. Immunosuppressants FK506 and cyclosporin A suppressed the K252a-induced cell adhesion and abolished tyrosine phosphorylation of cellular proteins including FAK and paxillin. Furthermore, W7 and calmidazolium, inhibitors of calmodulin, also inhibited the cell adhesion. Based on findings that FK506 and cyclosporin A are inhibitors of the calcium calmodulin-dependent protein phosphatase, calcineurin, this phosphatase may regulate integrin-dependent cell adhesion and spread of Colo201 cells. This Colo201 cell model provides a pertinent system for studying molecules involved in signal transduction pathways and can shed light on mechanisms of metastasis and invasion of colon carcinoma cells.

Topics: Adenocarcinoma; Carbazoles; Cell Adhesion; Cell Adhesion Molecules; Colonic Neoplasms; Cyclosporine; Cytoskeletal Proteins; Enzyme Inhibitors; Extracellular Matrix; Focal Adhesion Kinase 1; Focal Adhesion Protein-Tyrosine Kinases; Humans; Immunosuppressive Agents; Indole Alkaloids; Indoles; Integrins; Neoplasm Metastasis; Paxillin; Phosphoproteins; Phosphorylation; Protein Kinase C; Protein-Tyrosine Kinases; Pyrroles; Sulfonamides; Tacrolimus; Tumor Cells, Cultured; Tyrosine

Xenobiotics frequently induce proteins involved in their detoxification. Because many drugs that are metabolized by human cytochromes P450 (CYP) 3A4 and 3A5 are also transported by the drug efflux pump P-glycoprotein, we determined whether expression of these proteins was altered by a variety of drugs in a cell line derived from a human colon adenocarcinoma, LS180/WT, and its adriamycin-resistant subline, LS180/AD50. P-glycoprotein and CYP3A4 were constitutively expressed in both LS180/AD50 and LS180/WT cells, and both proteins were up-regulated after treatment with many drugs, including rifampicin, phenobarbital, clotrimazole, reserpine, and isosafrole. However, there were some exceptions because P-glycoprotein was up-regulated by midazolam and nifedipine, whereas CYP3A4 was not. CYP3A5, which is also constitutively expressed in these cells, remained unchanged with most drug treatments but was up-regulated by reserpine and clotrimazole. The apparent coordinated coexpression of the CYP3A gene family and P-glycoprotein in the LS180 cells suggests that for common orally administered drugs, P-glycoprotein may play an important role in net drug absorption and drug/drug interactions of shared CYP3A4/P-glycoprotein substrates.

Topics: Adenocarcinoma; ATP Binding Cassette Transporter, Subfamily B, Member 1; Base Sequence; Blotting, Northern; Cell Line; Clotrimazole; Colonic Neoplasms; Cytochrome P-450 CYP2E1; Cytochrome P-450 Enzyme System; Dexamethasone; DNA Primers; Doxorubicin; Gene Expression Regulation, Neoplastic; Humans; Midazolam; Mixed Function Oxygenases; Molecular Sequence Data; Multigene Family; Phenobarbital; Phenytoin; Polymerase Chain Reaction; Rifampin; Tumor Cells, Cultured; Verapamil

We show that cell lines derived from childhood alveolar rhabdomyosarcoma (RMS) are very sensitive to the growth-inhibitory effects of the immunosuppressive agent rapamycin (RAP), compared to other human cell lines (50% inhibitory concentration range of 0.1-8 ng/ml, compared to 1280 to > 10,000 ng/ml). Our data suggest that the sensitivity of RMS lines is due to RAP inhibition of insulin-like growth factor 1 receptor-mediated signaling, which is essential for continued proliferation of RMS cells. The embryonal RMS line Rh1, which was resistant to RAP in serum-containing medium (50% inhibitory concentration, 4180 ng/ml), was highly sensitive under autocrine conditions of growth, indicating that resistance was due to paracrine signaling pathways insensitive to RAP action. FK506 reversed RAP action in all cell lines, indicating a dependence on complexing with the cytosolic FK506-binding protein for activity.

Topics: Carrier Proteins; Cell Division; Child; Colonic Neoplasms; Heat-Shock Proteins; Humans; Immunosuppressive Agents; Polyenes; Receptor, IGF Type 1; Rhabdomyosarcoma; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins; Tumor Cells, Cultured

Topics: Animals; Colonic Neoplasms; Cyclosporine; Humans; Immunosuppressive Agents; Male; Mice; Mice, Nude; Neoplasm Transplantation; Sarcoma 180; Subrenal Capsule Assay; Tacrolimus