Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0178874 (tumor progression)
 40,807 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.
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PMID:A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer. 211 71

The role of autochthonous IFN- production was evaluated in immune reactions to Moloney murine sarcoma virus (M-MSV)-induced tumors which are characterized by spontaneous regression mainly caused by virus-specific CTL activity. A functional IFN- depletion, induced by repeated administration of mAb anti-IFN- at the site of virus inoculation, prevented tumor regression in M-MSV-injected mice. Moreover, this antibody inhibited in vitro both proliferation and differentiation of M-MSV-specific T lymphocytes obtained in bulk cultures, but not growth and lytic activity of the already differentiated virus-specific CTL clone CHM-14 stimulated with rIL-2 and relevant tumor Ag. In addition, in mice receiving mAb treatment the frequency of M-MSV-specific CTL precursors, evaluated by means of limiting dilution analysis, was strongly reduced in comparison with that of control mice injected only with virus. Because CTL secrete IFN- following antigenic stimulation, the possibility that non-T effector cells recruited by this lymphokine might mediate tumor regression was also considered. Adoptive immunotherapy experiments, performed in T cell-deficient (Tx + BM) and in sublethally irradiated mice, demonstrated that transfer of CHM-14 CTL clone, which secretes IFN-, was able to counteract M-MSV tumor growth despite the local mAb anti-IFN- treatment which may have prevented host cell recruitment. Moreover, repeated local rIFN- inoculations in Tx + BM mice did not counteract M-MSV tumor progression, thus confirming that other IFN- properties such as non-T cell recruitment, antiviral or anti-proliferative IFN- activities have little or no relevance when M-MSV-specific CTL are lacking. On the whole, these results indicate that in M-MSV-injected mice, tumor enhancement after mAb anti-IFN- treatment is principally caused by impaired differentiation of virus-specific CTL precursors.
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PMID:Monoclonal antibody against IFN-gamma inhibits Moloney murine sarcoma virus-specific cytotoxic T lymphocyte differentiation. 283 Mar 39

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

We studied a series of 40 rats at various stages of colorectal carcinoma, as induced by N-methyl-N-nitro-Nitrosoguanidine. Lymphokine containing supernatants were obtained simultaneously from splenic and peripheral lymphocytes, after exposure to rat colon cancer antigen in vitro. The lymphokine was found capable of performing Macrophage Migration Inhibition (MIF) when obtained from rats with: carcinoma through serosa, carcinoma of submucosa, carcinoma of the mucosa and carcinoma in situ. All control rats were free of cancer and were MIF negative. The MIF response in this study was evaluated as a marker of chemically induced colorectal carcinoma in rats in order to better understand the lymphocyte response to tumor progression from atypia to adenocarcinoma of the colon.
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PMID:Colon cancer bearing rats produce a lymphokine which induces macrophage migration inhibition (MIF) in vitro. 328 27

The humoral interactions between three malignant glioma early-passage cell cultures and in vitro interleukin (IL)-1 alpha- and IL-2-activated autologous peripheral blood mononuclear cells (PBMC's) were investigated, employing standard and modified (separated by permeable membranes) mixed lymphocyte tumor cell (MLTC) cultures. In modified MLTC's, glioma cells clearly inhibit proliferation of PBMC's (up to 60%), whereas lymphokine-activated PBMC's enhance glioma cell growth up to 12-fold, as determined by 3H-thymidine incorporation assays. Glioma cells produce both stimulatory (IL-6) and inhibitory proteins (transforming growth factor-beta) for PBMC's. Lymphokine-activated PBMC's secrete IL-1 alpha, IL-2, IL-4, IL-6, interferon-gamma, and tumor necrosis factor-alpha, which may modulate glioma cell proliferation. None of these cytokines stimulated glioma cells as intensely as modified MLTC systems. These observations indicate that in vitro lymphokine-activated PBMC's, although suppressed by humoral glioma-derived factors, may enhance glioma cell proliferation with soluble factors secreted into the culture medium. The authors conclude that glioma-lymphocyte growth regulatory networks include stimulatory and inhibitory factors from both cell populations, which may modulate tumor progression. These observations may have relevance for adoptive immunotherapy in patients with gliomas.
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PMID:In vitro studies of cytokine-mediated interactions between malignant glioma and autologous peripheral blood mononuclear cells. 793 92

A non randomized pilot study has been undertaken to evaluate the feasibility of local immunotherapy (IT) of recurrent glioblastoma multiforme (GM) by continuous intracerebral perfusion of recombinant interleukin-2 (rIL-2, Eurocetus) with and without lymphokine activated killer (LAK) cells. At time of surgical removal of the tumor, a catheter was implanted in the cavity left by tumor debulking allowing continuous perfusion of rIL-2. Five patients received 18 x 10(6) IU/day or rIL-2 for five days. At days 1, 3, and 5 after surgery, rIL-2 perfusion was briefly interrupted for the injection of LAK cells. Eight other patients received rIL-2 alone, either 24 x 10(6) IU/day (five patients) or 54 x 10(6) IU/day (three patients). Capillary leak syndrome, which is the main side effect of systemic infusion of rIL-2, was never observed, but local immunotherapy induced fever, confusion, and cerebral edema in all patients. Despite local IT, tumor progression was diagnosed by CT scan 4 to 12 weeks after the treatment.
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PMID:Local immunotherapy of recurrent glioblastoma multiforme by intracerebral perfusion of interleukin-2 and LAK cells. 811 34

IL-2 therapy can induce marked oxidative stress via reactive oxygen and nitrogen intermediates. Glutathione, the major intracellular reductant, may become rate limiting to cytotoxic lymphocyte activation and proliferation under these circumstances. N-Acetyl cysteine (NAc-cys) was used to increase intracellular glutathione levels during lymphokine-activated killer (LAK) cell activation by IL-2. Incubation of splenocytes with NAc-cys (0.6 to 1.0 mM) resulted in significant changes in intracellular reduced and total glutathione (92% and 58% increase, respectively) at 96 h. These levels correlated with markedly enhanced cell proliferation (threefold) and cytolytic effector cell generation (> fivefold increase in LU/10(6) cells) induced by the combination of NAc-cys with IL-2. IL-2 exposure by itself unexpectedly increased intracellular reduced glutathione by 43%. IL-2 and NAc-cys were synergistic in increasing glutathione levels (reduced glutathione: 292% increase; total: 251% increase). Inhibition of glutathione synthesis, using L-buthionine-(S,R)-sulfoximine reversed the effects of NAc-cys on intracellular glutathione, as well as cellular proliferation and cytotoxicity. This experiment established that the effects of NAc-cys required de novo glutathione synthesis. In conjunction with IL-2/LAK treatment, oral NAc-cys administration (260 to 900 mg/kg/day for 7 days) significantly decreased tumor progression in a refractory s.c. tumor model. A small fraction of mice (11 to 17%) had complete tumor regressions. NAc-cys may be useful as an adjunct to increase the antitumor activity of IL-2/LAK therapy.
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PMID:Use of N-acetyl cysteine to increase intracellular glutathione during the induction of antitumor responses by IL-2. 820 9

IL-2 activated natural killer (A-NK) cells have the capacity to infiltrate metastatic tumors and lyse tumor cells. Nevertheless, adoptive immunotherapy with lymphokine-activated killer cells has been only modestly effective in the clinic and has not routinely provided long-term survival in patients with established cancer metastases. This may indicate the need for more carefully investigating the role of effector cells of the immune response, including A-NK cells, in models of tumor progression. Herein we describe the use of the MMTV/v-Ha-ras transgenic mouse model as a system for exploring the role of NK cells during tumor progression. We have examined the lytic capacity of A-NK cells generated from tumor-free and tumor-bearing transgenic oncomice against standard A-NK cell targets (YAC-1 and P815) in addition to tumor cells isolated from these animals. A-NK cells generated from mice without obvious tumor burden show higher lytic activity than A-NK cells generated from mice with evident tumors, i.e., those at a more advanced stage of tumor progression. Only long term (8-day) cultures of late passage A-NK cells generated from tumor-bearing mice showed significant increases in lytic activity over those generated from tumor-free mice. These results suggest that experimental protocols using transgenic oncomice at various stages of tumor growth may constitute a novel model for testing the role of A-NK cells for their capacity to interfere with cancer progression.
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PMID:Cytolytic activities of IL-2 activated NK cells from MMTV/v-Ha-ras transgenic oncomice during tumor progression. 989 Dec 21

The presence of alpha1,2-fucosylated glycans at the surface of rat colon carcinoma cells has been associated with an increased tumorigenicity and resistance to natural killer/lymphokine activated killer (NK/LAK) cytotoxicity. We now report that transfection of rat alpha1,2-fucosyltransferases cDNA (FTA and FTB) into REG cells, which are spontaneously devoid of this enzymatic activity, allows expression of histo-blood group H antigen and increases their resistance to LAK, but not NK cell lysis. Conversely, transfection of PRO cells, which spontaneously express alpha1, 2-fucosyltransferase activity, with the FTA cDNA in the antisense orientation decreases expression of the H antigen together with their resistance to LAK cell lysis, but again, not to NK cell lysis. Furthermore, REG cells that are rejected by immunocompetent syngeneic rats are similarly rejected by rats depleted of NK cells by antibody 3.2.3, directed against the NKR-P1 molecule. Thus, the rejection of REG cells by immunocompetent rats and their earlier reported increased tumorigenicity after transfection with an alpha1, 2-fucosyltransferase cDNA cannot be ascribed to NK cell sensitivity or resistance, respectively. The increased resistance to LAK cell lysis, however, may be relevant to tumor progression.
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PMID:Susceptibility of rat colon carcinoma cells to lymphokine activated killer-mediated cytotoxicity is decreased by alpha1,2-fucosylation. 1079 95

The intercellular adhesion molecule-1 (ICAM-1, CD54) serves as a counter-receptor for the beta2-integrins, LFA-1 and Mac-1, which are expressed on leukocytes. Although expression of ICAM-1 on tumor cells has a role in tumor progression and development, information on ICAM-1 expression and its role in oral cancer has not been established. Normal human oral keratinocytes (NHOK), human papilloma virus (HPV)-immortalized human oral keratinocyte lines (HOK-16B, HOK-18A, and HOK-18C), and six human oral neoplastic cell lines (HOK-16B-BaP-T1, SCC-4, SCC-9, HEp-2, Tu-177 and 1483) were used to study ICAM-1 expression and its functional role in vitro. Our results demonstrated that NHOK express negligible levels of ICAM-1, whereas immortalized human oral keratinocytes and cancer cells express significantly higher levels of ICAM-1, except for HOK-16B-BaP-T1 and HEp-2. Altered mRNA half-lives did not fully account for the increased accumulation of ICAM-1 mRNA. Adhesion of peripheral blood mononuclear cells (PBMC) to epithelial cells correlated with cell surface ICAM-1 expression levels. This adhesion was inhibited by antibodies specific for either ICAM-1 or LFA-1/Mac-1, suggesting a role for these molecules in adhesion. In contrast, lymphokine-activated-killer (LAK) cell cytotoxic killing of epithelial cells did not correlate with ICAM-1 levels or with adhesion. Nonetheless, within each cell line, blocking of ICAM-1 or LFA-1/Mac-1 reduced LAK cell killing, suggesting that ICAM-1 is involved in mediating this killing.
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PMID:Increased ICAM-1 expression in transformed human oral epithelial cells: molecular mechanism and functional role in peripheral blood mononuclear cell adhesion and lymphokine-activated-killer cell cytotoxicity. 1093 87


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