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Biomedical subjects

A Belldegrun

Publications and source records attributed to A Belldegrun.

At least 91 records · Page 5Linked to original sources
PubMed1994

In vitro modulation of the invasive and metastatic potentials of human renal cell carcinoma by interleukin-2 and/or interferon-alpha gene transfer.

BACKGROUND: Continuous local delivery of interleukin-2 (IL-2) and interferon-alpha (IFN-alpha) via gene transfer appears to be more effective than systemic therapy in preventing the growth of human renal cell carcinoma (RCC) in vitro and in vivo. To understand further if cytokine-gene transfection of RCC could alter certain cellular properties that are associated with the invasive and metastatic potentials of tumor, the authors characterized six cell lines that produce IL-2 and/or IFN-alpha in their expression of intercellular adhesion molecule-1 (ICAM-1) and CD44; binding affinity to extracellular matrix (ECM) components (fibronectin, laminin, type IV collagen, and vitronectin); and preference in forming homotypic aggregation and mRNA levels of c-myc, epidermal growth factor receptor (EGF-R), tumor transforming growth factor-beta (TGF-beta) and type IV collagenase. These six lines were compared with control vector transfected parental R11 line. METHODS: The expression of ICAM-1 and CD44 was determined by fluorescence-activated cell sorter (FACS) analysis, the tumor cell binding affinity to ECM components was measured by cell attachment assay, the degree of homotypic aggregation was quantified by cell aggregation assay, and the mRNA levels of c-myc, EGF-R, TGF-beta, and collagenase were analyzed by a quantitative polymerase chain reaction analysis. RESULTS: Both IL-2-gene- and IFN-alpha-gene-modified R11 exhibited enhanced expression of ICAM-1, suppression of CD44, and decreased binding affinity to ECM components, when compared with the R11-control vector. All cytokine-producing tumor lines showed a decreased preference to form homotypic aggregation. Interferon-alpha gene transfer downregulated c-myc, EGF-R, and type IV collagenase mRNA expression, whereas only the higher producers of IL-2 downregulated TGF-beta mRNA expression. Exogenous IL-2 and/or IFN-alpha treatment of a IFN-alpha-resistant RCC enhanced both HLA class I antigen and ICAM-1 expression and suppressed CD44 expression, but had no effect on tumor growth rate. CONCLUSIONS: The local production of high concentrations of IL-2 and IFN-a at the tumor site may directly alter tumor properties associated with invasive and metastatic phenotypes of RCC. Interleukin-2 and/or IFN-alpha gene therapy may be an effective strategy for treatment of patients with advanced renal cancer.

Base Sequence↗
PubMed1994

Patterns of cytokine release of unselected and CD8+ selected renal cell carcinoma tumor-infiltrating lymphocytes (TIL). Evidence for enhanced specific killing of tumor necrosis factor-secreting/IL-6 nonsecreting TIL in vitro and correlation with complete response in vivo.

Murine systems have demonstrated improved anti-tumor efficacy when tumor-infiltrating lymphocytes (TIL) are combined with interleukin-2 (IL-2). One goal of human adoptive immunotherapy is to identify and expand TIL with specific activity against autologous tumor. In this study we attempted to isolate and characterize such cells by phenotype and cytokine expression pattern. Fourteen unselected (bulk) TIL and 5 CD8+ selected cultures were established from primary renal cell carcinoma. All cultures were grown in the presence of IL-2; triplicate cultures of each TIL culture were grown in IL-2 alone or were intermittently cocultured with irradiated allogeneic or autologous tumor. The in vitro cytotoxicity, phenotype, and cytokine expression pattern as defined by the secretion of tumor necrosis factor-alpha (TNF-alpha), interferon-gamma, granulocyte-macrophage colony-stimulating factor, IL-4, IL-6, and IL-12 were evaluated for each culture. While there was significant heterogeneity among the cultures under differing culture conditions as characterized by cytotoxicity, phenotype, and cytokine secretion pattern, we identified 8 TIL cultures which demonstrated specific enhanced lysis of only autologous tumor upon exposure to irradiated autologous tumor in vitro. These cultures demonstrate a decreased proportion of cells expressing the phenotype CD11b+. More importantly, these cultures were defined by the cytokine secretion phenotype TNF(+)/IL-6(-) upon exposure to irradiated autologous tumor. When utilized in vivo in adoptive immunotherapy of metastatic renal cell carcinoma together with IL-2, complete resolution of all metastatic tumor has only been achieved in patients who received TIL with the cytokine profile TNF(+)/IL-6(-). These findings suggest that tumor-specific renal TIL with enhanced tumor-specific cytotoxicity can be generated in vitro and can be characterized by a specific pattern of cytokine secretion. In addition, patients who receive TIL characterized by the cytokine profile TNF(+)/IL-6(-) may have an improved outcome when receiving immunotherapy.

CD8 Antigens↗
PubMed1994

Inhibitory effect of locally produced and exogenous interleukin-6 on tumor growth in vivo.

In order to define the potential antitumor activity of the multifunctional cytokine interleukin-6 (IL-6), retrovirus-mediated gene transfer was used to introduce and express a cDNA encoding human IL-6 in the murine fibrosarcoma cell line Fsa-R. Although these genetically modified tumor cells appeared morphologically and phenotypically identical to control Fsa-R cells and had a similar plating efficiency in vitro, they were found to exhibit greatly reduced tumorigenicity in vivo following intravenous injection into syngeneic recipients. Exogenous IL-6 was shown to produce a similar inhibition of tumor growth in the lung if administered intraperitoneally. In contrast, tumor growth in subcutaneous sites was inhibited only if the tumor cells were engineered to express IL-6 locally, or if IL-6 was administered intratumorally. Intraperitoneal injection of IL-6 had no inhibitory effect. Tumors that did grow from IL-6-producing tumor cell inocula in subcutaneous sites were found to contain large numbers of macrophages. These results demonstrate that the antitumor activity of systemically administered IL-6 varies depending on the site of tumor growth and suggest an important role for IL-6 in the recruitment, proliferation and/or survival of tumor-associated macrophages.

Animals↗
PubMed1994

Management of disseminated kidney cancer.

The approach to disseminate renal cell carcinoma (RCC) has evolved significantly in recent years, largely owing to the progress of biologic therapy development. With increasing knowledge of biologic therapy come several dilemmas, including the choice of cytokine therapy, the appropriate mode of delivery, the selection of candidates for given therapeutic options, and the role of cytoreductive nephrectomy in immunotherapy protocols. This article reviews the historical development of immunotherapy and the lessons learned from previous experience and offers a logical approach to the patient with disseminated RCC.

Carcinoma, Renal Cell↗
PubMed1993

Erythropoietin production. A potential marker for interleukin-2/interferon-responsive tumors.

BACKGROUND: Interleukin-2 (IL-2) recently was approved by the Food and Drug Administration for the treatment of renal cell cancer. It is effective in a small minority of patients, but no markers identify individuals likely to respond to treatment. METHODS: Two polycythemic patients with erythropoietin-producing renal cell cancer and three other polycythemic patients with renal cell cancer were treated with the combination of IL-2 and alpha-interferon (alpha-IFN). RESULTS: All five patients achieved a partial or complete remission. In both patients in which it was measured, the erythropoietin level decreased significantly with treatment, and the polycythemia resolved in all patients. Hypothyroidism developed in two patients, and transient hyperthyroidism developed in another. CONCLUSION: These results contrast with those achieved with IL-2 alone or in combination with lymphokine-activated killer cells, for which a 15% response rate was seen in patients with renal cell cancer and polycythemia. Although less than 5% of renal cell tumors produce erythropoietin, its production may identify a subset of individuals with renal cell cancer responsive to IL-2 and alpha-IFN.

Adult↗
PubMed1993

Effect of L-buthionine sulfoximine on the radiation response of human renal carcinoma cell lines.

BACKGROUND: Renal cell carcinoma (RCC) is a progressive and relatively radioresistant disease. Currently, no data are available on the in vitro radiobiologic characterization of renal tumor cells to the authors' knowledge. METHODS: Two RCC were cultured from specimens from previously untreated patients after either surgical resection of the primary tumor or from the malignant ascites. These two cell lines were characterized with respect to cytogenetic abnormalities, gamma radiation survival response, intracellular levels of glutathione and its related detoxification enzymes, and the effect of glutathione depletion on radiation toxicity. RESULTS: The two RCC grew as adherent monolayer cultures with a median doubling time of 29 hours and 37 hours, respectively. Histopathologic analysis of the tumor cells grown in the renal capsule of the athymic mice confirmed their epithelial neoplastic growth. Both cell lines were aneuploid (range, 65-100 chromosomes) and had several marker chromosomes, including those derived from chromosomes 3, 7, and 11. In vitro radiation survival analysis indicated the relative radioresistance (RR; Do, 2.35 Gy) and relative radiosensitivity (RS; Do, 1.42 Gy), respectively, of these tumor cell lines. The levels of intracellular glutathione (GSH) were higher in the RR cells compared with the RS cells. The enzymatic activities of GSH S-transferase, GSH reductase, and the levels of GSH peroxidase and superoxide dismutase were elevated in the RS cells compared with the RR cells. L-Buthionine sulfoximine (BSO) treatment (concentration, 20 microM, applied for 17 hours) resulted in 77% and 63% GSH depletion compared with the untreated RR and RS cells, respectively. Pretreatment with higher concentration of BSO (50 microM for 17 hours) caused a modest radiosensitization of the RR cells (Do, 1.78 Gy). CONCLUSIONS: RCC have a differential pattern of radiosensitivity. BSO treatment causes moderate radiosensitization of the relatively radioresistant renal tumor cells.

Animals↗
PubMed1993

Human renal carcinoma line transfected with interleukin-2 and/or interferon alpha gene(s): implications for live cancer vaccines.

BACKGROUND: Combination therapy with systemically administered interleukin-2 (IL-2) and interferon alpha (IFN-alpha) has resulted in long-term objective remissions in 30% of patients with metastatic renal cell carcinoma (RCC), but toxic effects are clinically significant. PURPOSE: We have thus investigated an alternative therapeutic approach--continuous intratumoral production of IL-2 and/or IFN-alpha by a cytokine-transfected human RCC tumor cell line. METHODS: Plasmid vectors were used to transfect the R11 RCC line with the genes for human IL-2 and/or IFN-alpha by the calcium phosphate precipitation method. Biologic characteristics of the cytokine-transfected tumor cells were determined by assays of thymidine incorporation and cytotoxicity, fluorescence-activated cell-sorter analysis, Northern blotting, and in vivo studies in C3Hf/Sed/Kam mice rendered T-cell deficient. RESULTS: The transfected cell lines produced the following amounts of cytokine per 10(6) cells per day: R11-IL-2 (220 U), R11-IFN-alpha (10,240 U), and R11-IL-2 + IFN-alpha (95 U + 1270 U, respectively). Gamma irradiation did not eliminate cytokine secretion. Morphology and growth rates were identical to those for the parental R11 cell line, except for IFN-alpha-producing clones, which showed significant growth inhibition. All cytokine-producing cells demonstrated increased susceptibility to cell killing by peripheral blood leukocytes (PBL). IFN-alpha producers exhibited enhanced HLA antigen expression and suppressed c-myc messenger RNA expression; when cocultured in vitro, they induced similar changes in parental R11 cells. IL-2 producers could stimulate growth and cytotoxicity of naive (i.e., freshly isolated, uncultured) and activated PBL. All cytokine-producing cells lost their tumorigenicity, as evidenced by failure to grow in the T-cell-depleted mice. When co-injected at a local site but not at a distant site, these cells prevented growth of parental R11 cells. Histologic examination of the injection sites revealed a substantial influx of macrophages. Intraperitoneal administration of IL-2 and/or IFN-alpha could not, however, prevent growth of the parental R11 tumors. CONCLUSION: Local production of high concentrations of IL-2 and IFN-alpha at the tumor site is more effective in preventing tumor growth than systemic administration. IMPLICATION: Continuous local delivery of cytokines via transfer of cytokine genes into tumor cells for use as live cancer vaccines is a novel strategy for manipulation of host-mediated antitumor immune response in patients with advanced RCC.

Animals↗
PubMed1993

Neoadjuvant hormonal deprivation in patients with locally advanced prostate cancer.

A total of 22 patients with locally advanced prostate cancer (stage B2 to C) was entered into a protocol for 3 months of preoperative hormonal deprivation. Of the patients 8 were judged to have clinical stage B2 and 14 to have stage C disease. The protocol regimen consisted of daily administration of flutamide (250 mg. orally 3 times per day) and leuprolide injection (7.5 mg. intramuscularly) every month. Patients with objective evidence of downstaging by prostate specific antigen (PSA) levels and transrectal ultrasound were offered surgical therapy. Of the 22 patients 20 have completed the protocol and are evaluable, and 2 of them did not show significant downstaging and elected radiotherapy. Preoperative hormonal therapy produced an average 33% downsizing of the prostate gland as determined by transrectal ultrasound volumetrics. Decreases in serum PSA values were demonstrated from a pre-hormonal average of 30 micrograms./l. (range 0.7 to 97.7) to an average of 0.53 micrograms./l. (range 0.2 to 5.7) after hormonal therapy. Of the 18 patients who underwent an operation after demonstrating significant downsizing 7 had pathologically confirmed stage B disease, 7 had stage C cancer and 4 had positive pelvic lymph nodes. Of the 8 clinical stage B2 cancer patients 3 had pathological stage B2 disease following the protocol. Of the 12 clinical stage C cancer patients 3 had pathological stage B disease, 4 had positive pelvic lymph nodes and the remainder had pathological stage C cancer. Thus, only 3 of 20 patients (15%) demonstrated pathological downstaging from the clinical stage. Downsizing the prostate volume and PSA changes with hormonal therapy were not predictive of patient outcome either alone or in combination. Preoperative hormonal therapy did not appear to facilitate the surgical procedure. Patients completing neoadjuvant hormonal therapy had an average estimated blood loss of 1,238 ml. and an average operating time of 183 minutes. A group of 20 consecutive patients with stage B2 prostate cancer who underwent radical prostatectomy without preoperative hormone therapy had an average estimated blood loss of 1,296 ml. and an average operating time of 171 minutes.

Administration, Oral↗
PubMed1993

Interferon-alpha primed tumor-infiltrating lymphocytes combined with interleukin-2 and interferon-alpha as therapy for metastatic renal cell carcinoma.

Murine models demonstrate therapeutic synergy for the combination of interleukin-2, interferon-alpha and tumor-infiltrating lymphocytes. We treated 11 patients with metastatic renal cell carcinoma with a novel regimen consisting of in vivo primed tumor-infiltrating lymphocytes, interferon-alpha and interleukin-2. Patients received interferon-alpha before radical nephrectomy; in vivo primed tumor-infiltrating lymphocytes were isolated and expanded in vitro. Low dose continuous infusion interleukin-2 at a dose of 2 x 10(6) units per m.2 per day was administered for 96 hours during each treatment week and interferon-alpha was administered as a subcutaneous injection at a dose of 6 x 10(6) units per m.2 per day on days 1 and 4 of the interleukin-2 infusion. No therapy was given during the last 3 days of a treatment week. One course of therapy consisted of 3 weeks of therapy followed by 3 weeks of rest. Patients were treated until maximal response, disease progression or dose limiting toxicity. A maximum of 6 courses of therapy were administered. Eleven patients underwent interferon-alpha priming and subsequent radical nephrectomy. In vivo primed tumor-infiltrating lymphocytes were successfully expanded in all 11 patients with an expansion index of greater than 170. In vivo primed tumor-infiltrating lymphocytes maintained their lytic activity for greater than 5 to 8 weeks in culture as demonstrated in the 4-hour 51chromium release assay. Ten patients underwent multimodality biological therapy and 3 (30%, 95% confidence interval 6 to 65%) have achieved complete response (2 clinical and 1 surgical) with durations of 24+, 23+ and 5+ months. Patients with stable disease received no additional therapy. No deaths and no grade 4 toxicities occurred. Immunotherapy using a combination of interferon-alpha primed tumor-infiltrating lymphocytes, low dose continuous infusion interleukin-2 and interferon-alpha can induce significant and durable antitumor responses in some patients with advanced renal cell carcinoma.

Adult↗
PubMed1993

Sensitivity of human renal cell carcinoma lines to TNF, adriamycin, and combination: role of TNF mRNA induction in overcoming resistance.

We have examined 6 human renal cell carcinoma (RCC) cell lines for their sensitivity and resistance to the cytolytic effect of tumor necrosis factor (TNF) and adriamycin (ADR), alone or in combination. The results of cytotoxicity mediated by TNF and ADR showed no direct correlation as TNF resistant lines were sensitive to ADR while the TNF sensitive lines were resistant. The combination of TNF and ADR resulted in enhanced cytotoxicity against the tumor lines. Induction of TNF mRNA and protein has been suggested as a mechanism of resistance to TNF in certain tumors. Resistant and sensitive lines were capable of upregulating TNF mRNA after treatment with TNF or PMA+ionophore for periods as short as 1 hour, but only the resistant lines were able to secrete detectable levels of TNF protein. Therefore, a positive correlation existed between resistance to TNF and production and secretion of TNF by the cell lines. In the presence of the protein synthesis inhibitor cycloheximide (CHX), the TNF mRNA level in the TNF resistant lines was increased while the sensitive lines required an additional signal, such as exogenous TNF, to upregulate the mRNA. Due to the enhanced cytotoxicity seen with the combination of TNF and ADR, we determined the effect of this combination on the levels of TNF mRNA. As examined in a constitutively TNF expressing line, ADR alone reduced the constitutive mRNA level and, in combination with TNF, reduced the level of induction produced by TNF. This downregulation of TNF mRNA by ADR may play a role in the enhanced cytotoxicity seen with combined TNF and ADR treatment. The present study demonstrates that RCC cell lines differ in their sensitivity and/or resistance to TNF. Further, ADR and/or TNF resistant RCC lines can be rendered sensitive by combining TNF and ADR. The constitutive and/or inductive secretion of TNF by certain lines and its relationship to tumor pathogenesis as well as overcoming resistance are discussed.

Carcinoma, Renal Cell↗
PubMed1993

Transfusion-associated graft-versus-host disease in immunocompetent patients: report of a fatal case associated with transfusion of blood from a second-degree relative, and a survey of predisposing factors.

A patient without evident immune deficiency who received a transfusion of blood from a second-degree family member developed fatal transfusion-associated graft-versus-host disease (TA-GVHD). The donor was homozygous for an HLA haplotype for which the recipient was heterozygous (one-way HLA match). All 39 reported cases of TA-GVHD in immunocompetent patients were reviewed to ascertain the predisposing factors and to define the indications for irradiating blood for this population. HLA typing was described in 15 cases; in 13, including seven related and six unrelated donors, a one-way HLA match was present. Thirty-one (79%) of the 39 cases were reported from Japan (and 196 other cases are cited in the Japanese literature), but a one-way HLA match among unrelated donors at HLA-A, -B, -DR loci is only approximately two to four times more likely in Japanese persons than in whites. Fresh blood (< 96 hours old) was used in 29 (94%) of the 31 cases reported from Japan and in 33 (87%) of 38 cases overall (in one case, the age of the blood used was not reported). Thus, factors that appear to predispose to TA-GVHD in immunocompetent patients are a one-way HLA match, fresh blood, and, possibly, Japanese ancestry. Irradiating cellular blood components from all blood relatives of transfusion recipients will not completely eliminate the risk of TA-GVHD.

Aged↗
PubMed1993

Soluble tumor necrosis factor receptor expression in patients with metastatic renal cell carcinoma treated with interleukin-2-based immunotherapy.

Two distinct types of soluble tumor necrosis factor alpha receptors (sTNFRs), which are felt to represent proteolytic cleavage products of the extracellular domains of membrane-bound TNFRs of molecular mass, 55 and 75 kDa, are found in the serum and urine of humans. We have measured the serum concentrations of these receptors in eight patients with metastatic renal cell carcinoma during treatment with interleukin-2 (IL-2)-based immunotherapy. The mean pretreatment concentration of sTNFR-55 kDa (p < 0.05) but not sTNFR-75 kDa was significantly elevated prior to the onset of immunotherapy. In one patient the concentrations of both sTNFRs decreased dramatically following removal of the primary tumor. There were significant increases in the concentrations of both sTNFRs in patients treated with IL-2-based therapy that included in vivo primed tumor infiltrating lymphocytes (pTILs); some of these patients eventually achieved a complete response to therapy. These data demonstrate that sTNFR-55 kDa is elevated in patients with metastatic renal cell carcinoma prior to therapy and that IL-2-based therapy that included pTIL cells results in a further increase in sTNFRs.

Carcinoma, Renal Cell↗
PubMed1992

Regulatory effects of interleukin-7 on renal tumor infiltrating lymphocytes.

Biological therapy using a combination of lymphokine and tumor infiltrating lymphocytes (TILs) is a new approach to the treatment of patients with advanced cancer. To improve the potency of TILs, new cytokines with T-cell stimulatory effects used alone or in combination with interleukin-2 (IL-2) are currently being investigated. We have studied the effect of interleukin-7 (IL-7) on TILs derived from renal cell carcinoma. Our data demonstrated that five of ten TILs proliferated in response to IL-7 alone. This proliferative response was 73-90% less than that obtained with IL-2 alone. The use of IL-7 plus IL-2 resulted in a 1.2- to 4.7-fold increase in proliferation of six of ten TILs compared with IL-2 alone. IL-7-driven TIL growth was consistently blocked by anti-IL-2, anti-IL-2R and anti-IL-7 antibodies (37.2%, 41.6% and 82.2% suppression, respectively). The expression of IL-2 receptors was also significantly increased in the presence of IL-7 or IL-7 phytohemagglutinin (40.6 + 3.8 and 72.5 + 1.5). In comparison with IL-2, IL-7 treatment was associated with a decrease in CD56 (46.3% +/- 19 vs 10% +/- 4.9) and increase in CD3 (29.3% +/- 12 vs 73% +/- 6.4) and CD4 (19.3% +/- 15 vs 58% +/- 10). These studies suggest that in some renal TILs, IL-7 and IL-2 can have a synergistic proliferative effect. The IL-7 stimulatory effect appears to be mediated via both an IL-2 pathway and an IL-7-independent pathway.

Antigens, CD↗
PubMed1992

Regulatory effects of interleukin-4 on tumor-infiltrating lymphocytes derived from human renal cell carcinoma.

We have studied the effects of interleukin-4 (IL-4) on the expansion, proliferation, phenotype, and antitumor activity of tumor-infiltrating lymphocytes (TIL) derived from human renal cell carcinoma. Cultures were obtained from three primary renal tumors and one group of tumor-invaded, regional lymph nodes. IL-4 induced a significant increase in lymphocyte expansion and proliferation, but the response was dependent on the concurrent dose of IL-2 in culture. Increased growth activity was only observed in those cultures receiving low doses (20 U/ml) of IL-2 (average increase of fold expansion of 6.5, P < 0.01) with no changes in growth activity in the high dose (1000 U/ml) cultures. The combination of low dose IL-2 and IL-4 (200 U/ml) promoted lymphocyte growth significantly better than high dose IL-2 alone, the current standard growth regimen for in vitro expansion of TIL. TIL grown in the presence of IL-4 significantly reduced the level of non-specific, non-major histocompatibility complex-restricted antitumor activity (P < 0.01 for allogeneic renal, nonrenal, and NK-sensitive K562 cells), while exhibiting no effect on the level of autologous killing. This is in contrast to previous findings of significant enhancement of autologous antitumor activity using IL-4 on tumor-specific, melanoma-derived TIL. We also evaluated the effects of irradiated autologous tumor stimulation (TIL:tumor ratio, 10:1) on TIL cultures. Addition of autologous tumor cells increased expansion and proliferation of all cultures regardless of concurrent lymphokines present in the culture media (average increase fold expansion of 2.21, P < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Carcinoma, Renal Cell↗
PubMed1992

The expression of C-jun and junB mRNA in renal cell cancer and in vitro regulation by transforming growth factor beta 1 and tumor necrosis factor alpha 1.

The proto-oncogene C-jun acts as a transcriptional activator or repressor for numerous cellular genes, and the overexpression of these genes may cause malignant transformation. JunB inhibits c-jun's transforming activities. We investigated the expression of jun genes in renal cell cancer (RCC) and their regulation by cytokines and transforming growth factor beta 1 (TGF-b1). The constitutive expression of c-jun was detected in 39 of 43 fresh frozen RCC, 5 of 10 normal kidneys, and the expression of junB detected in 28 of 34 RCC, 5 of 6 normal kidneys. C-jun was also found expressed in all 10 RCC tumor lines examined and junB was expressed at low levels in 6 of 10 renal tumor lines. TGF-b1 and tumor necrosis factor alpha (TNF-a) have been shown to alter the expression of jun genes in other tissue types. Additionally, TGF-b1, TNF-a, and gamma interferon (g-IFN) were shown to inhibit the growth of RCC. We found that TGF-b1 highly augmented the expression of junB (mean of 34 folds, p less than .05), but did not significantly alter the expression of c-jun, the transforming gene. In contrast, TNF-a significantly enhanced the expression of both c-jun (mean fold enhancement of 2.1, p less than .05) and junB (2.2 folds, p less than .05). Interleukin-2 (IL-2), interleukin-4 (IL-4) and g-IFN did not significantly alter jun expression. The findings presented suggest that c-jun may have a role in inducing malignant transformation in RCC and a novel mechanism by which TGF-b1 may exert its anti-tumor effects, via the activation of junB. Additionally, although TGF-b1, TNF-a, and g-IFN all have anti-proliferative actions on RCC in vitro, they were found to have different effects in altering jun expressions.

Carcinoma, Renal Cell↗