mycophenolic-acid and Breast-Neoplasms

Mycophenolic acid is an antimetabolite used experimentally for the treatment of psoriasis. Thirty-eight patients were treated with mycophenolic acid. A double-blind, placebo-controlled study demonstrated the efficacy of mycophenolic acid (P less than .01). A long-term safety study showed the occurrence of hematologic abnormalities, viral infections, and carcinoma. The position of mycophenolic acid in the therapeutic treatment of psoriasis must await the results of a multicenter cooperative study.

Topics: Adolescent; Adult; Aged; Breast Neoplasms; Carcinoma, Squamous Cell; Clinical Trials as Topic; Double-Blind Method; Epiglottis; Female; Humans; Laryngeal Neoplasms; Male; Middle Aged; Mycophenolic Acid; Psoriasis; Virus Diseases

Breast cancer is the most commonly diagnosed cancer and the leading cause of cancer-related death. Drug therapy for breast cancer is currently selected based on the subtype classification; however, many anticancer drugs are highly cytotoxic. Since intracellular levels of GTP are elevated in many cancer cells that undergo a specific cell proliferation cycle, GTP has potential as a target for cancer therapy. The present study focused on nucleosides and nucleotides and examined intracellular GTP-dependent changes in cell proliferation rates in normal (MCF-12A) and cancer (MCF-7) breast cell lines. Decreased cell proliferation due to a reduction in intracellular GTP levels by mycophenolic acid (MPA), an inosine monophosphate dehydrogenase inhibitor, was observed in both cell lines. The inhibitory effects of MPA on cell proliferation were suppressed when it was applied in combination with Guanosine (Guo), a substrate for GTP salvage synthesis, while the single exposure to Guo suppressed the proliferation of MCF-7 cells only. Although the underlying mechanisms remain unclear, since the inhibitory effects of Guo on cell proliferation did not correlate with GTP or ATP intracellular levels or the GTP/ATP ratio, there may be another cause besides GTP metabolism. Guo inhibited the proliferation of MCF-7, a human breast cancer cell line, but not MCF-12A, a human normal breast cell line. Further studies are needed to investigate the potential of applying Guo as a target for the development of a novel cancer treatment system.

Topics: Adenosine Triphosphate; Antineoplastic Agents; Breast Neoplasms; Cell Proliferation; Female; Guanosine; Guanosine Triphosphate; Humans; MCF-7 Cells; Mycophenolic Acid

Mycophenolic acid (MPA) has promising anticancer properties; however, it has limited clinical applications in vivo due to hydrophobic nature, high first-pass metabolism, lack of targeting, etc. These associated problems could be addressed by developing a suitable delivery vehicle, inhibiting the first-pass metabolism and additive/synergistic pharmacodynamic effect. Thus, MPA loaded highly stable lipid polymer hybrid nanoparticles (LPNs) were developed and investigated with the combination of quercetin (QC), a CYP 450 inhibitor cum anticancer. LPNs of MPA and QC (size; 136 ± 12 and 176 ± 35 nm, respectively) demonstrated higher cellular uptake and cytotoxicity of combination therapy (MPA-LPN + QC-LPN) compared to individual congeners in MCF-7 cells. In vivo pharmacokinetics demonstrated 2.17 fold higher T

Topics: Animals; Antioxidants; Apoptosis; Breast Neoplasms; Cell Survival; Drug Delivery Systems; Female; Humans; Lipids; MCF-7 Cells; Mycophenolic Acid; Nanoparticles; Polymers; Quercetin; Spectroscopy, Fourier Transform Infrared

To report a case of local transmission of invasive lobular carcinoma from a donor to a recipient in a keratolimbal allograft after cessation of systemic immunosuppressive therapy.. This is a case report including the clinicopathologic findings. Sections of the donor breast tumor and recipient conjunctival lesions were stained with hematoxylin and eosin. Immunohistochemical studies were performed using pancytokeratin, CK7, CK20, CAM 5.2, CD138, TTF1, estrogen receptor, progesterone receptor, GATA-3, GCDFP-15, and mammaglobin. Polymerase chain reaction-based DNA profiling of tumor cells was performed.. Histopathologic examination revealed an infiltrate of atypical cells with large hyperchromatic nuclei consistent with carcinoma. Immunohistochemical analysis showed pancytokeratin, CK7, CAM 5.2, GATA-3, and estrogen receptor positivity and progesterone receptor absence, consistent with the previously determined phenotype of the donor's breast carcinoma. Results of polymerase chain reaction analysis were also consistent with the donor's tumor. After reduced dosing of tacrolimus and mycophenolate mofetil, 2 limbal tumors occurred in the recipient. The immunosuppressive treatment had been stopped completely before the appearance of the third lesion. The recipient had no history of malignancy, and she had routine screenings for breast cancer.. We report a case of donor-derived breast carcinoma in a keratolimbal allograft recipient. The grafted tissue harbored donor-derived tumor cells for more than 4 years after surgery even after systemic immunosuppression was discontinued. Although no similar reports of tumor transfer could be found in the literature, this case suggests the need for increased stringency in donor selection and heightened surveillance for such tumor transmission.

Topics: Aged; Allografts; Biomarkers; Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Lobular; Conjunctival Neoplasms; Corneal Diseases; DNA Fingerprinting; Female; GATA3 Transcription Factor; Humans; Immunohistochemistry; Immunosuppressive Agents; Keratin-7; Keratins; Limbus Corneae; Mycophenolic Acid; Polymerase Chain Reaction; Receptors, Estrogen; Stem Cell Transplantation; Tacrolimus; Tissue Donors

Trastuzumab has been successfully used as a first-line therapy specific for HER2-overexressing breast cancer patients. However, despite the effectiveness of trastuzumab, the occurrence of inherent and acquired resistance remains as the main challenge of the therapy. Thus, this has motivated efforts toward finding new therapeutic strategies including combining trastuzumab with other drugs to enhance its therapeutic efficacy. In that line, we investigated the capability of mycophenolic acid (MPA), an inhibitor of de novo guanine nucleotide synthesis with potential anti-cancer activity, on improving the response to trastuzumab among SKBR3 cells as well as trastuzumab resistant SKBR3-TR cells. Our data indicated that irrespective to trastuzumab sensitivity of cells, MPA effectively inhibited cell growth through inducing adipocyte-like cell differentiation as well as blocking cell cycle progression at G

Topics: Antineoplastic Agents; Apoptosis; Breast Neoplasms; Cell Line, Tumor; Cell Proliferation; Female; Forkhead Box Protein O1; Humans; Janus Kinase 2; Mycophenolic Acid; Oncogene Protein v-akt; Receptor, ErbB-2; Signal Transduction; STAT3 Transcription Factor; Trastuzumab

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

Mycophenolic acid (MPA) has been known for decades to be an anticancer and immunosuppressive agent and has significant anticancer properties, but its underlying molecular mechanisms are poorly characterized. Peroxisome proliferator-activated receptor gamma (PPARγ) has a central role in adipocyte differentiation, and MPA has been shown to be a potent PPARγ agonist. Whether PPARγ activation has a putative role in the anticancer efficacy of MPA via induction of adipocyte-like differentiation has not been elucidated. In the present study, MPA was demonstrated to dose-dependently activate PPARγ transcription in the GAL4-hPPARγ (LBD) chimeric receptor assay and PPRE-luc reporter gene assay with an EC(50) of 5.2-9.3 μM. Treatment of the breast cancer cell lines MDA-MB-231 and MCF-7 with MPA resulted in differentiation of adipose tissue that was characterized by accumulation of intracellular lipids, enlargement of cell volume, and permanent withdrawal from the cell cycle at the G1/G0 stage. At a molecular level, the expression of three adipocyte differentiation markers (PPARγ, adipsin D, and aP2) was remarkably induced in differentiated breast cancer cells. However, RNA interference experiments showed that PPARγ-knockdown cannot completely reverse the differentiated state of MDA-MB-231 cells after MPA treatment. These data suggest that the effects of MPA on adipocyte-like terminal differentiation of breast cancer cells are (at least in part) due to PPARγ activation, which is a novel anticancer mechanism of MPA.

Topics: Adipocytes; Animals; Antineoplastic Agents; Breast Neoplasms; Cell Differentiation; Cell Line, Tumor; Cell Proliferation; CHO Cells; Cricetinae; Cricetulus; G1 Phase; Gene Knockdown Techniques; Humans; Mycophenolic Acid; PPAR gamma; Resting Phase, Cell Cycle; Transcription, Genetic

Inosine monophosphate dehydrogenase (IMPDH), a rate-limiting enzyme in the de novo synthesis of guanine nucleotides, is a major therapeutic target. A prototypic uncompetitive inhibitor of IMPDH, mycophenolic acid (MPA), is the active form of mycophenolate mofeteil (CellCept), a widely used immunosuppressive drug. We have found that MPA interacts with intracellular IMPDH in vivo to alter its mobility on SDS-polyacrylamide gels. MPA also induces a striking conformational change in IMPDH protein in intact cells, resulting in the formation of annular aggregates of protein with concomitant inhibition of IMPDH activity. These aggregates are not associated with any known intracellular organelles and are reversible by incubating cells with guanosine, which repletes intracellular GTP, or with GTPgammaS. GTP also restores IMPDH activity. Treatment of highly purified IMPDH with MPA also results in the formation of large aggregates of protein, a process that is both prevented and reversed by the addition of GTP. Finally, GTP binds to IMPDH at physiologic concentrations, induces the formation of linear arrays of tetrameric protein, and prevents the aggregation of protein induced by MPA. We conclude that intracellular GTP acts as an antagonist to MPA by directly binding to IMPDH and reversing the conformational changes in the protein.

Topics: Breast Neoplasms; Cell Line, Tumor; Drug Interactions; Enzyme Activation; Enzyme Inhibitors; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Triphosphate; Humans; IMP Dehydrogenase; Mycophenolic Acid; Protein Conformation

The incidence of breast cancer in renal transplant patients is similar to that of general population. But fibroadenomas may be seen as a result of exposure to cyclosporine (CyA). Herein we report the case of a 32-year-old woman who received a renal transplant and had a breast fibroadenoma. She had been prescribed CyA, azathioprine, and steroids for 4 years. At the end of the first year a palpable mass had been detected in her right breast; the pathologic diagnosis was fibroadenoma. At the 4th year after transplantation, immunosuppressive treatment was switched to CyA and mycopholate mofetil (MMF) because of an increased serum creatinine level. Two years later seven breast nodes from both breasts were detected by ultrasonography. Totally excision was performed revealing a histopathologic diagnosis of fibroademata as before. In this case, the combination of CyA and MMF administration seemed to cause an increase in the number of nodules in a short time. The cause of fibroadenomas may be related to drug-induced secretion of proliferative or anti-apoptotic cytokines.

Topics: Adult; Azathioprine; Breast Neoplasms; Creatinine; Cyclosporine; Female; Fibroadenoma; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Steroids

Some cytotoxic drugs cause translocation of nucleophosmin/B23 and other nucleolar proteins to the nucleoplasm. The present study shows that these drugs caused a similar translocation of RH-II/Gu, a nucleolar RNA helicase. Other nucleolar proteins including p120, UBF, RNA polymerase I large subunit, fibrillarin, p40, and Ren-1 did not translocate. A 2-h treatment of MCF-7 breast cancer cells with 0.008 or 0.16 microM actinomycin D resulted in translocation of RH-II/Gu to the nucleoplasm; these effects were not reversed by 100 microM guanosine. The effects of 0.008 microM actinomycin D, but not 0.16 microM actinomycin D, on the translocation of RH-II/Gu were reversed when the drug was removed. However, the effects of 0.008 or 0.16 microM actinomycin D on the translocation of nucleophosmin/B23 were not reversible. The translocation effects of 50 microM toyocamycin on RH-II/Gu were reversed when the drug was replaced with fresh medium. RH-II/Gu mostly relocalized to the nucleoli within 15 min after toyocamycin was withdrawn; only partial relocalization of nucleophosmin/B23 occurred 40 h after removal of the drug. The effects of toyocamycin were not blocked by 100 microM guanosine. Mycophenolic acid (50 microM, 2-h treatment) caused partial translocation of RH-II/Gu; this effect was slowly reversed upon drug removal and was inhibited by 100 microM guanosine, in a manner similar to the effects of mycophenolic acid on the localization of nucleophosmin/B23. This study shows similarities and differences in the drug-induced translocation and relocalization of RH-II/Gu and nucleophosmin/B23. Analysis of translocation of specific nucleolar proteins may offer a quantitative approach to assessment of potency and duration of effects of cytotoxic agents.

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Biological Transport; Breast Neoplasms; Cell Nucleolus; Dactinomycin; Guanosine; Humans; Mycophenolic Acid; RNA Helicases; RNA Nucleotidyltransferases; Toyocamycin; Tumor Cells, Cultured

The relationship between terminal cell differentiation and changes in the subcellular levels of the HER-2/neu antigen was investigated in cultured human breast cancer cells: AU-565 cells (which overexpress the HER-2/neu gene) and MCF-7 cells (which do not overexpress this gene). Differentiation was achieved by treating the cells with mycophenolic acid (MPA), phorbol 12-myristate 13-acetate (PMA), retinoic acid (RA), or the TA-1 monoclonal antibody to the extracellular domain of the HER-2/neu protein. Ten to twenty percent of the cells in untreated, sparsely growing AU-565 cultures exhibited morphological maturation characterized by large lacy nuclei surrounded by sizable flat cytoplasms. A fraction of these cells harbored milk factors such as casein and large lipid droplets. Treatment of the AU-565 cells for 4 d with 9 microM MPA, 1.6 nM PMA, 2.5 microM RA, or 1 microgram/mL TA-1 antibody resulted in cell growth inhibition and an increase in the percentage of cells (48-97%) that exhibit a mature phenotype. MCF-7 cells were also susceptible to differentiation by MPA and RA, but to a lesser degree than the AU-565 cells. Differentiation in the AU-565 and MCF-7 cells was associated with reduced immunostaining for the HER-2/neu protein at the cell surface membrane and with a transient increased diffuse immunostaining for this protein in the cytoplasm.

Topics: Blotting, Southern; Breast Neoplasms; Cell Differentiation; Cell Division; Cell Membrane; Cell Nucleus; Cytoplasm; Genes; Humans; Mycophenolic Acid; Proto-Oncogene Proteins; Receptor, ErbB-2; Tetradecanoylphorbol Acetate; Tretinoin; Tumor Cells, Cultured

The effect of the nucleoside anti-metabolite tiazofurin (TR) was examined on the growth and phenotypic alterations of MCF-7 breast cancer and HBL-100 normal breast cell lines. TR was shown to inhibit MCF-7 cell growth. This inhibition could be reversed by exogenous addition of guanosine. The anti-proliferative effect of TR is accompanied by phenotypic alterations that include lipid accumulation and an increase in alkaline phosphatase activity. In contrast to MCF-7 cells, the HBL-100 breast milk derived cell line is relatively resistant to inhibition by TR. Alkaline phosphatase is not affected by TR and untreated cells accumulate lipid droplets, similar to TR-treated MCF-7 cells. Determination of GTP and ATP pools in both cell lines revealed that TR markedly reduces GTP content in MCF-7 cells. In HBL-100 cells, TR induces only a small decrease in GTP and does not affect ATP levels. The prototypic IMP dehydrogenase inhibitor, mycophenolic acid (MA), markedly inhibits HBL-100 cell growth, similarly to its effect on MCF-7 breast cancer cells. These findings may suggest differential metabolism of TR in MCF-7 and HBL-100 cells.

Topics: Adenosine Triphosphate; Antimetabolites, Antineoplastic; Breast Neoplasms; Cell Division; Cell Line; Female; Guanosine Triphosphate; Humans; Milk, Human; Mycophenolic Acid; Ribavirin; Ribonucleosides; Tumor Cells, Cultured

Topics: Adenosine Triphosphate; Breast Neoplasms; Cell Survival; Dose-Response Relationship, Drug; Female; Guanosine; Guanosine Triphosphate; Humans; IMP Dehydrogenase; Ketone Oxidoreductases; Mitosis; Mycophenolic Acid; Phenotype; Tumor Cells, Cultured