Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0677930 (primary tumor)
 20,210 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The effect of the administration of recombinant interferon-gamma (rIFN-gamma) and a synthetic lipid A subunit analog (GLA-60) on angiogenesis induced by B16-BL6 melanoma was examined in syngeneic C57BL/6 mice. Intravenous administration of rIFN-gamma followed by GLA-60 (referred to as rIFN-gamma/GLA-60) induced endogenous production of tumor necrosis factor (TNF). This treatment on day 3 after tumor inoculation caused a marked decrease in the number of vessels oriented towards the tumor mass (angiogenic response) and tumor size over a period of 9 days. In contrast, neither rIFN-gamma nor GLA-60 alone, nor GLA-60/rIFN-gamma (reverse sequence of administration), which is unable to induce the production of TNF in the serum, had any effect. Sera induced by the treatment with rIFN-gamma/GLA-60, and recombinant TNF, inhibited the in vitro growth of lung endothelial cells which is considered to be one of the essential events in tumor neovascularization. Multiple i.v. treatments with rIFN-gamma/GLA-60 on days 5, 8 and 11 after s.c. implantation of tumor significantly inhibited primary tumor growth by the amputation time (day 20) and lung metastasis of B16-BL6 cells on day 34, while other treatment modalities had no such effect. Our results indicate that inhibition of lung-tumor metastasis by rIFN-gamma/GLA-60 treatment may be partly due to the inhibition of tumor-associated angiogenesis.
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PMID:Inhibition of tumor-induced angiogenesis by the administration of recombinant interferon-gamma followed by a synthetic lipid-A subunit analogue (GLA-60). 137 2

Human leukocyte antigen (HLA) classes I and II molecules are essential for antigen presentation to cytotoxic T cells and helper T cells, respectively. Consequently, they may play a role in anticancer immunotherapy as well. We studied whether the pretreatment HLA phenotype of the tumor is predictive for response to interferon immunotherapy in vivo. Therefore, renal cell carcinoma (RCC) primary tumor lesions from 31 patients treated with interferon-alpha and interferon-gamma (13 responders and 18 nonresponders) were analyzed retrospectively for HLA antigen expression with immunohistochemical methods. Furthermore, from eight patients, pretreatment metastatic lesions were examined. In the primary tumors HLA class I expression was high: in 26 of 30 lesions more than 50% cells were stained. HLA class II expression was mostly low: in 14 of 31 primary tumors less than 5% cells were stained. A significant correlation was found between HLA phenotype of primary tumors and corresponding metastases. There was no association between tumor HLA classes I and II antigen expression and clinical response to interferon therapy. In conclusion, pretreatment HLA phenotype of RCC has no predictive value for outcome of interferon immunotherapy. A role for treatment-induced changes in HLA expression in vivo, however, can not be excluded. These findings do not provide indications for the working mechanism of interferon immunotherapy in vivo.
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PMID:Human leukocyte antigen expression in renal cell carcinoma lesions does not predict the response to interferon therapy. 163 84

Quantitative evaluation of the levels of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the extracts of tumors and their corresponding normal tissues resected from 43 patients with colorectal adenocarcinoma was done using solid-phase, sandwich radioimmunoassay. The levels of both IFN-gamma and TNF-alpha detected in the tumor tissues were higher than those in the corresponding normal colorectal tissues obtained from each patient. A significant negative correlation was observed between the level of IFN-gamma and TNF-alpha in each tumor extract. The decrease of the level of IFN-gamma in the tumor correlated with the advance of clinical stage, and the levels of IFN-gamma of the patients with distant metastases were significantly lower than those of the patients without distant metastases. However, an increase in the level of TNF-alpha correlated not only with an enlarged diameter but also with the extent of the primary tumor. Immunohistochemical staining of IFN-gamma and TNF-alpha producing cells in tumor tissues showed that IFN-gamma was mainly produced by CD4+ CD8- T-lymphocytes and TNF-alpha was mainly produced by CD11c+ cells with macrophage-like morphology. These results suggest that CD4+ T-lymphocytes that produce IFN-gamma might play an important role in the antitumor response against cancer progression in human colorectal adenocarcinomas.
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PMID:Functional evaluation of tumor-infiltrating mononuclear cells. Detection of endogenous interferon-gamma and tumor necrosis factor-alpha in human colorectal adenocarcinomas. 171 32

A 66-year-old woman with hypopharyngeal cancer was treated with recombinant interferon-gamma (KW-2202). r-IFN-gamma was administered at a dose of 1-8 X 10(6) U/body every day for six weeks by i.v. drip infusion. After the start of the therapy both the primary tumor and metastatic lymph nodes showed remarkable regression and PR was obtained. Observed side effects, which included fever and hepatic function disorder, were slight and transient. Immunological studies were also carried out on the patients and the results were reported. Further investigation will be necessary in order to confirm the efficacy of the drug and to compile data on immunological parameters.
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PMID:[A case of hypopharyngeal cancer responding to recombinant interferon-gamma (KW-2202)]. 310 10

To examine the potential regulatory role of interferon-gamma in the cellular immune response to melanoma and its precursor lesions, we have tested the capacity of this lymphokine to enhance HLA class II antigen-dependent T lymphocyte blastogenesis, its in vitro production by autologous T cells stimulated by melanoma, and its presence in melanocytic lesions in situ. Cell lines derived from a dysplastic nevus, a radial growth phase primary tumor, a vertical growth phase primary, and metastatic lesions were induced by recombinant interferon-gamma to express increased amounts of HLA class II antigens. Such cells were then examined in radioimmunoassay for expression of HLA-DR antigens and in co-culture for their ability to stimulate proliferation of autologous T cells. Interferon-gamma treatment of melanocytic cells increased their expression of HLA-DR antigens threefold to sixfold. In parallel with these findings, co-culture of T cells with interferon-treated cells of a dysplastic nevus and a radial phase melanoma led to augmented T cell incorporation of tritiated thymidine, and this stimulation was inhibited with a monoclonal antibody to HLA-DR antigens. Despite augmented expression of HLA class II antigens (HLA-DR, -DQ, and -DP), vertical growth phase and metastatic melanoma cells failed to stimulate autologous T cells. When T cells were co-cultured with stimulating melanoma cells, culture supernatants contained significantly increased amounts of interferon-gamma (12 U/ml) in comparison with supernatants of T cells alone (4 U/ml). No interferon was detectable in cultures of melanoma cells alone. To link these in vitro phenomena to in situ events, we used murine monoclonal antibodies to interferon-gamma, the interleukin 2 receptor, and HLA-DR antigens in an immunoperoxidase system to detect interferon production and lymphocyte activation in frozen sections of lesions representative of melanocytic tumor progression. In these studies, precursor dysplastic nevi and radial phase melanomas contained the highest numbers of activated lymphocytes and stained positively for interferon-gamma. These results suggest that interferon-gamma plays a central role in the regulation of the cellular immune response to melanoma. It is produced by T cells, likely activated by tumor antigens seen in the context of HLA class II antigens. In turn, interferon-gamma production enhances expression of HLA class II antigens by melanoma and precursor cells, and such enhancement is associated with additional T cell activation in a positive feed-back loop.
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PMID:Interferon-gamma regulates the T cell response to precursor nevi and biologically early melanoma. 310 2

Interleukin-12 (IL-12) is a heterodimeric cytokine originally defined by its ability to induce the maturation of cytolytic lymphocytes and by its capacity to effectively synergize with IL-2 in the induction of cytolytic activity. Recent studies in mice have demonstrated the ability of IL-12 to cause tumor regression and stimulate long-term antitumor immunity in treated animals. To examine the antitumor effect of direct gene transfer of IL-12 into tumors, we have developed retroviral vectors that coordinately express both subunits of IL-12. An MFG-based retroviral vector was used to generate a recombinant retrovirus in which a long terminal repeat (LTR)-driven polycistronic transcript encodes both subunits of human IL-12: hp35 and hp40 cDNAs are linked and coexpressed using the internal ribosome entry site (IRES) from the encephalomyocarditis virus (DFG-hIL-12). In addition, two IRES sequences were used to express both subunits of IL-12 and a neomycin resistance (neoR) selectable marker gene from the same polycistronic message (TFG-hIL-12). The amphotropic DFG-hIL-12 and TFG-hIL-12 viruses were used to infect both human and murine cell lines as well as primary tumor cultures. The production of human IL-12 by the nonselected, infected cells was measured in both a PHA blast proliferation bioassay and an ELISA and ranged from 15 to 40 ng/10(6) cells per 24 hr. Following G418 selection of TFG-hIL-12-infected cells, the level of expression of IL-12 was significantly higher (up to 120 ng/10(6) cells per 24 hr). The IL-12 protein secreted by the infected cells exhibited all of the biologic activities of recombinant hIL-12: proliferation of activated natural killer (NK) and T cells, stimulation of interferon-gamma (IFN-gamma) induction by NK and T cells, and enhancement of lymphokine-activated killer (LAK) activity. These retroviral vectors expressing human IL-12 should be useful in evaluating the biological properties of IL-12 as well as for use in clinical trials for gene therapy of patients with cancer.
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PMID:Construction and characterization of retroviral vectors expressing biologically active human interleukin-12. 771 Nov 42

Gelatinases (GLs) belong to a family of enzymes known as matrix metalloproteinases (MMPs), which are produced by both normal and neoplastic cells. These enzymes have been implicated in tumor invasion and metastasis, although the mechanism of regulation of tumor MMP production is unknown. Since our previous studies have shown that numerous cytokines are present in the tumor microenvironment, our goal was to establish the effect of selected cytokines on GL production by both established tumor cell lines and primary cultures of head and neck squamous cell carcinoma (HNSCC). Supernatants of HNSCC cell lines SCC-25 and FADU stimulated with interleukin (IL)-1 alpha and IL-1 beta demonstrated modest induction of 92 kd GL production by zymogram analysis when compared with controls; IL-2, IL-6, and interferon-gamma had no consistent effect on MMP production. Stimulation of cell lines with tumor necrosis factor (TNF)-alpha (10(4) to 10 U/mL), however, dramatically enhanced production of 92 kd GL by both cell lines in a dose-dependent fashion, although tissue inhibitor of metalloproteinase (TIMP) expression was unaffected. Northern blot analysis showed that this enhancement of 92 kd GL occurred at the messenger RNA level. Stimulation of short-term primary tumor cultures with TNF-alpha resulted in significant enhancement of 92 kd GL expression in one of four cultures and enhancement of 72 kd GL expression in all cultures. The observed increase in GL expression by TNF-alpha suggests a role for this cytokine in the regulation of GL expression by tumor cells during invasion and metastasis.
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PMID:Cytokine regulation of gelatinase production by head and neck squamous cell carcinoma: the role of tumor necrosis factor-alpha. 787 3

Cytokines and immune cells are likely to be involved in the control of lung metastasis. We have therefore investigated the possibility of inhibiting lung metastases by the means of interferon-gamma (IFN-gamma) aerosolizations in a murine model of lung cancer. A Lewis lung carcinoma (3LL) was inoculated in the thigh of C57BL/6 mice. Randomized groups of 10 mice each were then treated by repeated aerosols of IFN-gamma (4,000 U/mouse) of aerosols of a Hanks' solution as controls. When the animals were killed at 18 days, the number of lung metastatic nodules was significantly reduced (by 50%; P < 0.01) after IFN-gamma aerosols, compared with controls. When the primary tumor was resected at 18 days and aerosols were continued, in the absence of local recurrence, mice treated by IFN-gamma aerosols survived longer than did controls (P < 0.05). In vitro, IFN-gamma exerted no direct antitumoral effect on 3LL cells in culture. Macrophages recovered from mice receiving IFN-gamma aerosols showed a higher antiproliferative effect on 3LL cells in vitro than did controls. Nevertheless, the higher antiproliferative effect of activated macrophages seems insufficient to explain the difference of survival that we observed between IFN-gamma-treated mice and controls.
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PMID:Antitumoral potential of aerosolized interferon-gamma in mice bearing lung metastases. 811 Apr 75

Interleukin 12 (IL-12) has a pivotal role in controlling cell-mediated immunity through a number of important biological activities, such as secretion of interferon-gamma (IFN-gamma). In this review, we report our recent results regarding the antitumor and antimetastatic effects of IL-12. Five intraperitoneal injections of recombinant IL-12 (rIL-12) into mice bearing subcutaneous tumors (CSA1M fibrosarcoma) induced complete tumor regression, irrespective of whether tumors were at early or late stages of growth. Furthermore, IL-12-treated mice that had rejected the primary tumor exhibited complete resistance to rechallenge with the same tumor but did not reject a second syngeneic tumor. Immunohistochemical analyses following IL-12 treatment revealed that CD4+ and CD8+ T-cells had infiltrated the tumor. More importantly, IFN-gamma mRNA expression was observed in fresh tumor masses from tumor-bearing mice receiving IL-12 treatment. The importance of IFN-gamma was further demonstrated by the observation that systemic administration of anti-IFN-gamma monoclonal antibody prior to IL-12 treatment completely abrogated the antitumor effect of IL-12. We next investigated the ability of rIL-12 to modulate the outgrowth of metastatic tumor cells in an ovarian carcinoma (OV-HM) model. This aggressive tumor showed rapid growth of the primary tumor mass, a high incidence of metastases to the lung and lymph nodes, and invasion from the primary subcutaneous site into the peritoneal cavity. At approximately 1 month after tumor implantation, primary tumors in animals without palpable lymph nodes were surgically resected. When examined 2 months later, most animals had developed lymph node and lung metastases. In contrast, rIL-12 injections following tumor resection inhibited the development of metastases in both the lung and lymph nodes. Even in mice showing signs of lymph node metastases or invasion of the abdominal wall before primary tumor resection, rIL-12 administration following tumor resection prevented further invasion into the peritoneal cavity and metastatic tumor cell growth in the lung. Our results demonstrate that administration of rIL-12 to tumor-bearing mice results in tumor regression through mechanisms involving efficient IFN-gamma production by antitumor T-cells at tumor sites in situ and the establishment of a tumor-specific protective immune response. The results also indicate that IL-12 can induce a curative immune response in the face of an aggressive micrometastasizing tumor.
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PMID:Antitumor and antimetastatic effects of interleukin 12. 876 11

Cytokine gene transfer into tumor cells has been shown to mediate tumor regression and antimetastatic effects in several animal models via immunomodulation. Therefore, clinical protocols have been developed to treat cancer patients with cytokine gene-modified tumor cells. We inserted the genes coding for the p35 and p40 chain of interleukin-12 (IL-12) in two independent eukaryotic expression vectors and transduced melanoma cells of 15 different primary tumor cultures with both plasmids by a ballistic gene transfer approach. Secreted IL-12 demonstrated strong bioactivity by inducing interferon-gamma release from peripheral blood lymphocytes upon coculture with cell culture supernatants after IL-12 gene transfer which could at least partly be blocked by IL-12-specific antisera. Further enrichment of transduced tumor cells by magnetic separation directly after gene transfer increased cytokine secretion from a mean of 119 pg in the unsorted to 507 pg IL-12 (24 h/10(8) cells) in the magnetically enriched cell fraction. Irradiation of these cells led to a further elevation of secreted IL-12 (mean 987 pg). Elevated IL-12 levels were detected over 7 days after irradiation in vitro. In a subsequent first clinical phase I study six patients with metastatic melanoma were vaccinated with autologous, interleukin-12 gene-modified tumor cells. Melanoma cells were expanded in vitro from surgically removed metastases, transduced by ballistic gene transfer, irradiated and were then injected subcutaneously (s.c.) at weekly intervals. Clinically, there was no major toxicity except for mild fever. All patients completed more than four s.c. vaccinations over 6 weeks and were eligible for immunological evaluation. Post-vaccination, peripheral mononuclear cells were found to contain an increased number of tumor-reactive proliferative as well as cytolytic cells as determined by a limiting dilution analysis in two patients. Two patients developed DTH reactivity against autologous melanoma cells and one had a minor clinical response. Biopsies taken from that patient's metastases revealed a heavy infiltration of CD4+ and CD8+ T lymphocytes. In conclusion, vaccination induced immunological changes even in a group of advanced, terminally ill patients. These changes can be interpreted as an increased antitumor immune response.
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PMID:Vaccination with IL-12 gene-modified autologous melanoma cells: preclinical results and a first clinical phase I study. 961 72


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