tacrolimus and Kidney-Neoplasms

Tacrolimus is used initially as an immunosuppressant drug in solid organ transplant population. This calcineurin inhibitor has also been recommended by KDIGO Clinical Practice Guideline for Glomerulonephritis for the treatment of nephrotic syndrome in children and adults. Tacrolimus is characterized by a narrow therapeutic index and large pharmacokinetic (PK) variations. Therefore, routine Therapeutic Drug Monitoring (TDM) is critical to keep tacrolimus blood levels within the therapeutic range. Tacrolimus is mainly metabolized by cytochrome P450 (CYP) enzymes 3A5 and 3A4. Actually, for pediatric patients, they are totally different to adults. Profound changes in CYP3A expression and activity occur throughout fetal life and in the neonatal and childhood periods thereby influencing their catalytic function. CYP3A7, CYP3A5, and CYP3A4 display an age-dependent maturation pattern. Notably, the CYP3A7-CYP3A4 switch taking place during the very early life will affect tacrolimus metabolism. Meanwhile, CYP3A isoforms are polymorphic enzymes, especially for CYP3A5. The guideline has recommended that the tacrolimus dosage should be adjusted according to the CYP3A5 genotype. Additionally, genetic CYP3A4 variation (e.g., CYP3A4*22) is also associated with interindividual variability of exposure level to tacrolimus. However, age (ontogeny) sometimes trumps genetics (genotype) in determining the enzymatic functions (phenotype) in pediatric patients. It's important to discriminate at what age the ontogeny plays key roles and at what age genetic variation become a major determinant. Thus, we need to better understand the mechanisms driving the CYP3A maturation and integrate ontogeny and genetics into the tacrolimus disposition, thereby tailoring the dosage individually for pediatric NS patients at different developmental stages.

Topics: Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Humans; Immunosuppressive Agents; Kidney Neoplasms; Nephrotic Syndrome; Tacrolimus

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Antineoplastic Agents; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Colitis; CTLA-4 Antigen; Cyclosporine; Diarrhea; Drug Eruptions; Humans; Immunosuppressive Agents; Infliximab; Ipilimumab; Kidney Neoplasms; Lung Neoplasms; Melanoma; Mycophenolic Acid; Neoplasms; Nivolumab; Pituitary Diseases; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus; Thyroiditis

Safety and efficacy of two sirolimus (SRL)-based regimens were compared with tacrolimus (TAC) and mycophenolate mofetil (MMF). Renal transplantation recipients were randomized to Group 1 (SRL+TAC; week 13 TAC elimination [n = 152]), Group 2 (SRL + MMF [n = 152]) or Group 3 (TAC + MMF [n = 139]). Group 2, with higher-than-expected biopsy-confirmed acute rejections (BCARs), was sponsor-terminated; therefore, Group 2 two-year data were limited. At 1 and 2 years, respectively, graft (Group 1: 92.8%, 88.5%; Group 2: 90.6%, 89.9%; Group 3: 96.2%, 95.4%) and patient (Group 1: 97.3%, 94.4%; Group 2: 95.2%, 94.5%; Group 3: 97.0%, 97.0%) survival rates were similar. One- and 2-year BCAR incidence was: Group 1, 15.2%, 17.4%; Group 2, 31.3%, 32.8%; Group 3, 8.2%, 12.3% (Group 2 vs. 3, p < 0.001). Mean 1- and 2-year modified intent-to-treat glomerular filtration rates (mL/min) were similar. Primary reason for discontinuation was adverse events (Group 1, 34.2%; Group 2, 33.6%; Group 3, 22.3%; p < 0.05). In Groups 1 and 2, delayed wound healing and hyperlipidemia were more frequent. One-year post hoc analysis of new-onset diabetes posttransplantation was greater in TAC recipients (Groups 1 and 3 vs. 2, 17% vs. 6%; p = 0.004). Between-group malignancy rates were similar. The SRL-based regimens were not associated with improved outcomes for kidney transplantation patients.

Topics: Adult; Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Middle Aged; Mycophenolic Acid; Sirolimus; Tacrolimus

Tacrolimus is widely used as prophylaxis for graft-versus-host disease (GVHD) in allogeneic stem cell transplantation (allo-HSCT). It has a narrow therapeutic index range; high tacrolimus concentrations are associated with toxicity, whereas low concentrations are associated with an increased risk of GVHD. Although dose adjustments based on therapeutic drug monitoring are performed, unexpected large variations in tacrolimus concentration are sometimes encountered. The available evidence suggests that the factors affecting tacrolimus concentration are not fully understood. This study was aimed primarily at investigating the factors affecting day-to-day variations in tacrolimus concentration in children and young adults who received continuous tacrolimus infusion after allo-HSCT. The secondary objective was to identify the factors causing large variations (>20%) in tacrolimus concentrations. This retrospective cohort study comprised 123 consecutive pediatric and young adult patients (age <25 years) who received continuous i.v. tacrolimus infusion after allo-HSCT at Shinshu University Hospital, Matsumoto, Japan, between January 2009 and December 2021. To compare day-to-day variations in tacrolimus concentration without consideration of the tacrolimus dose, 2 consecutive days when the tacrolimus dose was not changed were selected from between the first post-allo-HSCT day of a tacrolimus concentration >7 ng/mL and day 28 post-allo-HSCT. Subsequently, information for the subsequent 24 hours was collected along with the tacrolimus concentrations and hematocrit values. Tacrolimus concentration was determined using whole blood samples. Tacrolimus concentrations were significantly higher in patients who received red blood cell concentrate (RCC) transfusions (P < .0001) and methotrexate (P = .0162), patients with persistent fever (P = .0056), and patients with a decline in fever (P = .0003). In contrast, tacrolimus concentrations were significantly lower in patients who received platelet concentrate (PC) transfusions (P < .0001), who redeveloped fever (P = .0261), and who had a replaced tacrolimus administration route set (P = .0008). Variations in tacrolimus concentration were significantly correlated with variations in hematocrit (r = .556; P < .0001). Body weight (P < .0001), RCC transfusion (P < .0001), methotrexate use (P = .0333), persistent fever (P = .0150), and decline in fever (P = .0073) were associated with a sharp increase in tacrolimus concentration. In

Topics: Adult; Carcinoma, Renal Cell; Child; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Kidney Neoplasms; Methotrexate; Retrospective Studies; Tacrolimus; Young Adult

The safety of the coadministration of sunitinib with tacrolimus and everolimus with regard to therapeutic drug monitoring has not been demonstrated. Here, we report a patient who showed high sunitinib concentrations, in addition to pharmacokinetic changes in tacrolimus and everolimus after sunitinib therapy. A living-donor renal transplant patient treated with tacrolimus and everolimus was diagnosed with pulmonary and pleural metastases of renal cell carcinoma. The patient received sunitinib therapy (37.5 mg/day, 2 weeks on and 1 week off). This patient exhibited a high total sunitinib concentration (sunitinib, 105.8 ng/mL; N-desethyl sunitinib, 27.9 ng/mL) on day 10 postinitiation and experienced grade 3 diarrhea. The observed sunitinib concentrations were a little higher than those reported in the 421C>A polymorphism of the ATP-binding cassette subfamily G member 2 gene carrier. The observed concentrations of both tacrolimus and everolimus gradually decreased compared with the Bayesian-predicted values after the onset of sunitinib therapy, and the doses of tacrolimus and everolimus were increased. Careful therapeutic drug monitoring of sunitinib, tacrolimus, and everolimus concentrations is necessary during combination therapy, especially after episodes of diarrhea.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Renal Cell; Combined Modality Therapy; Everolimus; Humans; Kidney Neoplasms; Kidney Transplantation; Male; Sunitinib; Tacrolimus

The development of de novo renal cell carcinoma (RCC) in a transplanted kidney is a rare condition. Currently, this is the second case report of a 41-year-old man in whom carcinoma of a renal allograft was detected by contrast-enhanced ultrasound (CEUS). An abdominal CT scan was not conclusive enough to differentiate between septal enhancement of a cyst and a low vascularized tumor. CEUS confirmed a solid, homogeneously enhancing but hypoechoic and hypovascular lesion compared to the surrounding kidney parenchyma without septal enhancement. Therefore, the patient underwent nephron-sparing surgery (NSS), affirming papillary RCC type 2. Graft function remained unchanged postoperatively; 12 months after NSS, no local recurrence or distant metastasis was described. CEUS seems to be a minimally invasive and efficient imaging option if other diagnostic tools cannot clearly exclude RCC, with the advantage of wide-ranging use, especially in cases of impaired renal function.

Topics: Adult; Carcinoma, Renal Cell; Contrast Media; Everolimus; Humans; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Kidney Transplantation; Male; Neoplasm Metastasis; Nephrons; Postoperative Period; Recurrence; Renal Insufficiency; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Ultrasonography

Topics: Adrenal Cortex Hormones; Adult; Atrophy; Biomarkers, Tumor; Carcinoma, Renal Cell; Glomerulonephritis, Membranous; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney; Kidney Diseases, Cystic; Kidney Neoplasms; Kidney Transplantation; Male; Mucin-1; Mycophenolic Acid; Nephrectomy; Postoperative Complications; Reoperation; Tacrolimus

Topics: Female; Humans; Immunosuppressive Agents; Kidney Neoplasms; Male; Mycophenolic Acid; Sirolimus; Tacrolimus

To evaluate the development of Walker 256 tumor in male Wistar rats treated with tacrolimus using an experimental kidney tumor model.. 40 male Wistar rats were divided into four groups: Tumor group (TU) (n=10), Tacrolimus-Tumor group (TT) (n=10), Tacrolimus group (TC) (n=10) and Control group (C) (n=10). Treatment with tacrolimus was performed in groups TT and TC. Under anesthesia, the right kidney of each animal of TU and TT was accessed through a supraumbilical incision and inoculated with a 0.1 mL solution containing 2 x 10(6) tumor cells (Walker 256 carcinosarcoma tumor cells). Group TC was treated with a saline solution. All the animals of groups TC and TT were treated with tacrolimus (5mg/kg/day) by gavage for 15 days. TU group animals received saline by gavage for 15 days. On the 15th postoperative day, all animals were submitted to euthanasia and blood sampling for analysis of serum creatinine (Cr) and blood urea nitrogen (BUN). Abdominal gross examination was performed, the right kidney removed and prepared for histological analysis by hematoxylin-eosin staining. The resulting data were submitted to statistical analysis by ANOVA.. Statistical significance was found when comparing creatinine level between groups TU, TT and TC -TT group culminated with a marked increased in creatinine levels (Cr=1.013 + or - 0.3028 mg/mL), TU group (Cr=0.5670 + or - 0.03536 mg/dL) P=0.00256, TC group (Cr =0.711 + or - 0.1653 mg/mL) P= 0.02832. Statistical significance was found when comparing BUN levels in TT group (71.32 + or - 17.14 mg/mL), compared with TU group (45.83 + or - 5.046 mg/dL), P=0.000318. There were no statistically significant differences between groups TT and TC (61.23 + or - 9.503 mg/mL) P=0.7242. Histological analysis showed a poor evolution in TT group with multiple foci of hemorrhage and cortical invasion by the Walker tumor.. The Tacrolimus-treated group developed a more aggressive tumor and a drug-related nephrotoxic effect.

Topics: Analysis of Variance; Animals; Blood Urea Nitrogen; Carcinoma 256, Walker; Creatine; Disease Models, Animal; Immunosuppressive Agents; Kidney; Kidney Neoplasms; Kidney Transplantation; Male; Neoplasm Transplantation; Random Allocation; Rats; Rats, Wistar; Tacrolimus

A 53-year-old man who underwent successful kidney transplantation for stage 5 chronic kidney disease presented to our clinic with intermittent painless gross hematuria. Urachal adenocarcinoma, stage III A by Sheldon system, was diagnosed after serial histopathologic and radiological studies. The patient was treated with extended partial cystectomy, en bloc resection of urachus and umbilicus, pelvic lymphadenectomy, and ileocystoplasty. There were no complications seen in this patient. Neither urachal adenocarcinoma recurrence, metastasis, nor de novo uroileal cancer developed during 48-month follow-up. His reconstructed bladder functioned efficiently, without compromising the transplanted kidney function. Our case demonstrated that conservative surgery and augmentation ileocystoplasty could be offered to kidney transplant recipients with localized urachal carcinoma.

Topics: Adenocarcinoma; Hematuria; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Neoplasms; Kidney Transplantation; Magnetic Resonance Imaging; Male; Middle Aged; Mycophenolic Acid; Neoplasm Staging; Prednisolone; Tacrolimus; Urachus

Malignancy is a dreaded complication following organ transplantation. Immunosuppressive therapy-induced impairment of the host immune system is the prevailing hypothesis for the high incidence and aggressive progression of post-transplant neoplasm. We summarize our observations supporting an autonomous cellular mechanism for cyclosporine and tacrolimus associated metastases. Cyclosporine conferred tumor invasiveness by a direct effect on the tumor cells and promoted metastases in T-, B-, and NK cell deficient SCID- beige mice, and anti-TGF-beta antibodies reduced metastases. Tacrolimus, another calcineurin inhibitor widely used in transplantation, induced TGF-beta secretion by tumor cells and promoted metastases in the SCID- beige mice. The immunosuppressive macrolide rapamycin reversed an invasive phenotype to a non-invasive one, reduced circulating levels of TGF-beta1 and prevented tumor growth and metastases in the immocompetant BALB/c mice and in the SCID-beige mice. Our studies, in addition to demonstrating a cell autonomous mechanism for tumor progression, advance TGF-beta blockade as an anti-tumor strategy.

Topics: Adenocarcinoma; Animals; Antineoplastic Agents; Cell Line, Tumor; Cyclosporine; Humans; Immunosuppressive Agents; Kidney Neoplasms; Lung Neoplasms; Mice; Mice, Inbred BALB C; Mice, Inbred DBA; Mice, SCID; Neoplasm Invasiveness; Neoplasms; Organ Transplantation; Phenotype; Sirolimus; Tacrolimus

The development of cancer is a major problem in immunosuppressed patients, particularly after solid organ transplantation. We have recently shown that calcineurin inhibitors (CNI) used to treat transplant patients may play a critical role in the rapid progression of renal cancer. To examine the intracellular signaling events for CNI-mediated direct tumorigenic pathway(s), we studied the effect of CNI on the activation of proto-oncogenic Ras in human normal renal epithelial cells (REC) and renal cancer cells (786-0 and Caki-1). We found that CNI treatment significantly increased the level of activated GTP-bound form of Ras in these cells. In addition, CNI induced the association of Ras with one of its effector molecules, Raf, but not with Rho and phosphatidylinositol 3-kinase; CNI treatment also promoted the phosphorylation of the Raf kinase inhibitory protein and the downregulation of carabin, all of which may lead to the activation of the Ras-Raf pathway. Blockade of this pathway through either pharmacologic inhibitors or gene-specific small interfering RNA significantly inhibited CNI-mediated augmented proliferation of renal cancer cells. Finally, it was observed that CNI treatment increased the growth of human renal tumors in vivo, and the Ras-Raf pathway is significantly activated in the tumor tissues of CNI-treated mice. Together, targeting the Ras-Raf pathway may prevent the development/progression of renal cancer in CNI-treated patients.

Topics: Adaptor Proteins, Signal Transducing; Animals; Calcineurin; Calcineurin Inhibitors; Cell Growth Processes; Cell Line, Tumor; Cyclosporine; Down-Regulation; GTPase-Activating Proteins; Humans; Kidney Neoplasms; Mice; Mice, Nude; Mice, SCID; Proto-Oncogene Mas; raf Kinases; ras Proteins; Signal Transduction; Tacrolimus

Topics: Antilymphocyte Serum; Brain Neoplasms; Cytomegalovirus Retinitis; Epstein-Barr Virus Infections; Female; Ganciclovir; Graft Rejection; Herpesvirus 4, Human; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Neoplasms; Kidney Transplantation; Lymphoma, Large B-Cell, Diffuse; Middle Aged; Muromonab-CD3; Mycophenolic Acid; Postoperative Complications; Prednisolone; Radiography; RNA, Viral; Tacrolimus; Transplantation, Homologous

Proline oxidase is a p53-induced redox gene that can generate reactive oxygen species (ROS) and mediate apoptosis in tumor cells. We report that proline oxidase is a downstream effector in p53-mediated activation of the calcium/calmodulin-dependent phosphatase calcineurin in lung, renal, colon, and ovarian carcinoma cells. The activation of calcineurin by p53 and proline oxidase was detected by activation of the nuclear factor of activated T cells (NFAT), an established indicator of activated calcineurin. Both proline oxidase- and p53-induced activation of NFAT were sensitive to the calcineurin inhibitors cyclosporin A and FK-506, to scavengers of ROS, and to inhibitors of calcium mobilization. A proline oxidase antisense vector suppressed the ability of p53 to up-regulate proline oxidase, activate calcineurin, and induce apoptosis. Moreover, two renal carcinoma-derived mutant p53 proteins were deficient in inducing proline oxidase expression and in activating calcineurin. Inhibitors of calcineurin and calcium mobilization abolished proline oxidase-mediated apoptosis and reduced p53-induced apoptosis. Treatment of colon and ovarian carcinoma cells with the anticancer genotoxic agent etoposide up-regulated both p53 and proline oxidase, activated calcineurin, and induced apoptosis. The etoposide-mediated activation of calcineurin and induction of apoptosis was markedly suppressed by FK-506 calcineurin inhibitor. We propose that proline oxidase mediates apoptosis through the generation of proline-dependent ROS, which then mobilize calcium and activate calcineurin. The activation of calcineurin-regulated transcription factor pathways by proline oxidase might affect gene expression events important to p53 regulation of cell growth and apoptosis.

Topics: Apoptosis; Blotting, Western; Calcineurin; Calcium; Carcinoma, Renal Cell; Cell Line, Tumor; Cyclosporine; DNA-Binding Proteins; Dose-Response Relationship, Drug; Enzyme-Linked Immunosorbent Assay; Etoposide; Genes, Reporter; Green Fluorescent Proteins; Humans; Kidney Neoplasms; Luciferases; NFATC Transcription Factors; Nuclear Proteins; Nucleic Acid Synthesis Inhibitors; Oligonucleotides, Antisense; Plasmids; Proline Oxidase; Reactive Oxygen Species; Tacrolimus; Transcription Factors; Transfection; Tumor Suppressor Protein p53; Up-Regulation

Programmed cell death 4 (Pdcd4), originally identified as an inhibitor of murine cellular transformation, inhibits protein synthesis by directly interacting with eukaryotic initiation factor 4A (eIF4A) of the translation initiation complex. The relevance of Pdcd4 to a broad range of human cancers derived from multiple tissue sites is unknown. Protein expression patterns from the National Cancer Institute drug-screening panel of 60 human cancer cells (NCI60) were analyzed by Western blot methods and revealed frequent reduction of Pdcd4 protein levels in renal-, lung-, and glia-derived tumors. Greater than mean Pdcd4 protein levels correlated with the antitumor activity of geldanamycin and tamoxifen. Stable expression of antisense PDCD4 significantly reduced the sensitivity of MCF-7 breast cancer cells to geldanamycin and to tamoxifen. Sensitivity to geldanamycin significantly increased in UO-31 renal cancer cells expressing sense PDCD4 cDNA. Increased geldanamycin sensitivity was accompanied by enhanced cell cycle arrest and apoptosis. One primary mode of inactivation of Pdcd4 in human cancers appears to involve down-regulated expression, and this down-regulation causes a decreased sensitivity to geldanamycin cytotoxicity. Thus, up-regulating Pdcd4 expression may be promising for geldanamycin-based combination therapy.

Topics: Antineoplastic Agents; Apoptosis Regulatory Proteins; Benzoquinones; Cell Division; Cell Line, Tumor; Drug Screening Assays, Antitumor; G2 Phase; Humans; Kidney Neoplasms; Lactams, Macrocyclic; Mitosis; Neoplasms; Prognosis; Quinones; Retinoblastoma Protein; RNA-Binding Proteins; RNA, Messenger; Tacrolimus; Tamoxifen

While most BK virus infections are asymptomatic, immunosuppression has been associated with BK virus reactivation and impaired graft function or ureteric ulceration in renal transplant patients and hemorrhagic cystitis in bone marrow transplant patients. Oncogenicity is also postulated and this is the first report of a child with a carcinoma of the donor renal pelvis following BK virus allograft nephropathy. Removal of the primary tumor and cessation of immunosuppression led to regression of secondary tumors and a return to health.

Topics: Adenocarcinoma; BK Virus; Child; Genetic Diseases, X-Linked; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Diseases; Kidney Neoplasms; Kidney Transplantation; Male; Polyomavirus Infections; Renal Insufficiency; Tacrolimus; Tumor Virus Infections

Immunosuppressive therapy is a risk factor for the increased incidence and metastatic progression of malignancies in organ graft recipients. Transforming growth factor (TGF)-beta(1) has been associated with tumor invasion and metastasis, and we have implicated cyclosporine-associated TGF-beta(1) hyperexpression in tumor progression in mice.. BALB/c mice or severe combined immunodeficient-beige mice were treated with 2 or 4 mg/kg of tacrolimus, and the effect of treatment on mouse renal cancer cell pulmonary metastasis was investigated. We also determined whether tacrolimus induces TGF-beta(1) expression. Spleens from tacrolimus-treated mice were analyzed for level of expression of TGF-beta(1) mRNA with the use of competitive-quantitative polymerase chain reaction assay, and circulating levels of TGF-beta(1) protein were measured with the use of an enzyme-linked immunosorbent assay.. Treatment with tacrolimus resulted in a dose-dependent increase in the number of pulmonary metastases in the BALB/c mice (197+/-16 in untreated mice, 281+/-26 in mice treated with 2 mg/kg of tacrolimus, and 339+/-25 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, Bonferroni's P<0.001) and in the severe combined immunodeficient-beige mice (117+/-18 in untreated mice, 137+/-19 in mice treated with 2 mg/kg of tacrolimus, and 216+/-29 in mice treated with 4 mg/kg of tacrolimus; no treatment vs. 4 mg/kg tacrolimus, P<0.05). Treatment with 4 mg/kg but not 2 mg/kg of tacrolimus resulted in a significant increase in the levels of expression of TGF-beta(1) mRNA and circulating levels of TGF-beta(1) protein.. Tacrolimus has a dose-dependent effect on tumor progression and TGF-beta(1) expression, and tacrolimus-induced TGF-beta(1) overexpression may be a pathogenetic mechanism in tumor progression.

Topics: Animals; Carcinoma, Renal Cell; Disease Progression; Dose-Response Relationship, Drug; Immunosuppressive Agents; Kidney Neoplasms; Lung Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, SCID; Neoplasm Metastasis; Neoplasms; Spleen; Tacrolimus; Transforming Growth Factor beta; Transforming Growth Factor beta1

Malignancy is a dreaded complication of organ transplantation. Immunosuppressive drug therapy-induced impairment of the organ graft recipient's immune surveillance is considered to be the mechanism for the heightened incidence and metastatic progression. We identified a cell-autonomous and host-immunity independent mechanism for cyclosporine-associated tumor progression. In this study, we investigated the effect of rapamycin on tumor progression, in the presence and absence of cyclosporine.. A spontaneously arising renal adenocarcinoma (renal cancer) of BALB/c origin was used as the model tumor. The effect of rapamycin on renal cancer cell phenotype, molecules (E-cadherin, p27 kip1, cyclin D1) implicated in tumor progression, and the effect of rapamycin on in vivo tumor progression were explored in BALB/c mice and in T-cell, B-cell, and natural killer (NK) cell-deficient severe combined immune deficiency (SCID)-beige mice. In the SCID-beige mice, T24 human bladder transitional cell carcinoma also was used as the tumor inoculum.. Rapamycin conditioning of renal cancer cells upregulated E-cadherin expression and induced phenotypic transition from invasive spindle, or dome-shaped cells, with exploratory pseudopodia to noninvasive cuboidal cells that formed cell-to-cell adhesions. Rapamycin increased p27 kip1, reduced cyclinD1, and arrested the growth of renal cancer cells in G1/S phase. In vivo, rapamycin prevented tumor growth and metastatic progression in syngeneic BALB/c or SCID-beige mice, and in BALB/c or SCID-beige mice treated with cyclosporine. Rapamycin treatment alone, or with cyclosporine, prolonged the survival of mice inoculated with renal cancer cells or T24 human bladder cancer cells.. Our findings, in addition to unlinking mechanisms of immunosuppression from that of tumor progression, suggest that rapamycin may be of value for the management of posttransplant malignancy.

Topics: Adenocarcinoma; Animals; Antibiotics, Antineoplastic; B-Lymphocytes; Cadherins; Carcinoma, Renal Cell; Cell Cycle Proteins; Cyclin D1; Cyclin-Dependent Kinase Inhibitor p27; Disease Progression; DNA Primers; Genes, Tumor Suppressor; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Neoplasms; Killer Cells, Natural; Mice; Mice, Inbred BALB C; Mice, SCID; Sirolimus; T-Lymphocytes; Tacrolimus; Tumor Cells, Cultured; Tumor Suppressor Proteins