Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have previously described a unique molecular species of Interleukin 1 spontaneously produced by a human EBV-transformed B-cell line. This IL 1 shares a number of biological activities with monocytic IL 1 although its NH2-terminal amino-acid sequence is different from both IL 1 alpha and beta. In the present study we have investigated the activity of this B-cell IL 1 in two recently reported new assays for interleukin 1. We found that this B-cell IL 1 is able to promote the proliferation of the human astrocytoma cell line U373 in a dose dependent manner. We also describe that B-cell IL 1 is directly cytotoxic for a melanoma cell line, A375, but not for the tumor necrosis factor target cell, the murine transformed fibroblast line L929. These studies should prove useful in analysing structure-function relationships of the various IL 1 species, when the primary sequence of B-cell IL 1 becomes available.
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PMID:B-cell line-derived interleukin 1 is cytotoxic for melanoma cells and promotes the proliferation of an astrocytoma cell line. 349 9

Human recombinant interleukin 2 (IL-2) and tumor necrosis factor (TNF) were evaluated individually and in combination for their antitumor efficacy in vivo, using five s.c. murine tumors: L1210 leukemia, P815 mastocytoma, B16 melanoma, EL-4 lymphoma, and the methylcholanthrene-induced sarcoma, Meth A. While only the s.c. methylcholanthrene-induced tumor exhibited regression and/or cures in response to immunomodulatory therapy with either agent alone, the simultaneous administration of a maximally tolerated dose of TNF and IL-2 given daily from within 1 day (B16 melanoma), 3 days (L1210 leukemia and P815 mastocytoma) or 5 and 10 days (EL-4 lymphoma and methylcholanthrene-induced sarcoma) after tumor cell implant resulted in no tumor takes (growth). The TNF dose was apparently rate limiting in that reduction of the amount of TNF in the combination by 50% resulted in the loss of curative effects, while IL-2 doses could be reduced by 90% (depending upon tumor type) and still result in an efficacious combination. The synergy seen in combination IL-2 and TNF therapy appeared to be dependent upon tumor burden, but somewhat independent of tumor location. For example, no tumors were seen in the artificial pulmonary metastasis model of the B16 melanoma, and the percentage of extension of median lifetime (test versus control) greater than 150% was seen in the i.p. B16 melanoma, as well as several other i.p. models of the five tumor types. On the other hand, no significant extension of lifetime (greater than 150%) was seen with either lymphokine alone when administered i.p. at maximally tolerated dose for any of the five tumors tested here. Results are discussed in relation to potential immune modulatory events which may be occurring during combination treatments.
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PMID:Synergistic effects of combination therapy with human recombinant interleukin-2 and tumor necrosis factor in murine tumor models. 349 53

This investigation was designed to study the effects of relatively low doses of cyclophosphamide (CY) on monocyte function in patients with surgically resected melanoma. Monocytes taken from patients 3 days after receiving 300 mg, 150 mg, or 75 mg CY/m2 had decreased interleukin-1 (IL-1) production. Production of tumor necrosis factor (TNF)-like molecules by the same monocytes appeared to be enhanced following 300 mg/m2 CY but not after 150 or 75 mg/m2 CY. In vitro studies of the direct effects of CY metabolites (mafosfamide and 4-hydroperoxycyclophosphamide) on human monocytes showed only concomitant decreases in production of IL-1 and TNF-like molecules. This occurred at concentrations that did not obviously affect viability, although monocyte spreading was inhibited. No evidence was obtained for in vitro enhancement of TNF-production. We conclude that CY can affect monocyte function. In vivo it may have both direct effects leading to decreased TNF and IL-1 production and indirect effects through lymphocytic or haematopoietic systems that activate monocytes to enhanced TNF production. The effects are dose-dependent. These CY-induced changes could be responsible in part for some of the alterations in host immunity and tumor resistance that follows administration of the drug.
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PMID:Cyclophosphamide-induced alterations in human monocyte functions. 350 Feb 54

Recombinant human tumor necrosis factor (rHu-TNF) was found to exhibit potent antitumor activities not only against murine tumors, i.e. Meth A sarcoma, B 16 melanoma, colon 26 adenocarcinoma, Lewis lung carcinoma and MH134 hepatoma, transplanted in syngeneic mice but also against human tumors, i.e. HMV-2 melanoma, PC-10 lung carcinoma and GOTO neuroblastoma, heterotransplanted in nude mice. rHu-TNF caused necrosis of all tumors tested and inhibited their growth in a dose dependent manner. Complete regression of tumors was observed in mice bearing Meth A, B16, colon 26, MH134, HMV-2 and PC-10 but not in mice bearing Lewis lung carcinoma and GOTO neuroblastoma. The prolongation of survival time was also observed in syngeneic mice transplanted with murine tumors except Lewis lung carcinoma. The antitumor effect of rHu-TNF was more evident when it was given intratumorally than when given intravenously. The feasibility of rHu-TNF as a drug for cancer therapy is discussed.
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PMID:Recombinant human tumor necrosis factor--II. Antitumor effect on murine and human tumors transplanted in mice. 352 34

We investigated optimal conditions for cytotoxicity to tumor cell lines by recombinant human tumor necrosis factor (rhTNF) and the effect of amino-terminal deletions on the bioactivity of the rhTNF molecule. Two of four deletion muteins (-4 and -7) of rhTNF exhibit 2- to 3-fold enhancement of cytotoxicity/cytostasis against a variety of human carcinomas, a fibrosarcoma, and a melanoma cell line with no toxicity on normal fibroblastic and epithelial cultures. Of the two other muteins the -8 displayed equivalent and/or increased cytotoxicity/cytostasis while the -10 was consistently less cytotoxic than the parent on the same cell lines. Continuous exposure to TNF for greater than or equal to 96 h led to maximal cytotoxicity to tumor lines (99.99% with L929 cells) with no evidence of recovery. Pretreatment with actinomycin D (0.003-10 micrograms/ml for 1 h) rendered 82% of rhTNF-resistant cell lines (both tumor and normal) susceptible to its cytotoxic action within 24 h. However, the highest nontoxic concentrations of Actinomycin D necessary for rendering normal cell lines susceptible to TNF action were about 10-3000-fold higher than those necessary for converting resistant tumor cell lines. Similarly, preinfection of L929 cells with vesicular stomatitis virus (multiplicity of infection, 10(-2)-10(-4) for 1 h) rendered the cells 2-10-fold more susceptible to the cytotoxic action of rhTNF in 18 h. Our data suggest that rhTNF and its muteins represent potentially useful anticancer agents; however, adequate dosing and prolonged exposure may be critical in demonstrating cytotoxicity/cytostasis. The data also show that although normal and tumor cell lines became susceptible to cytotoxicity by rhTNF and actinomycin D, combination therapy of the two agents may be possible at defined concentrations.
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PMID:Biological effects of recombinant human tumor necrosis factor and its novel muteins on tumor and normal cell lines. 379 Dec 1

Currently, the most probable theory of tumor surveillance is neither the existence of any tumor-specific, antigen-dependent, T-cell-mediated cytotoxic effect that could eliminate spontaneous tumors in man and that could be used for some kind of vaccination against tumors, nor the complete absence of any surveillance or defense systems against tumors. What is probable is the cooperation of a number of antigen-independent, relatively weakly cytotoxic or possibly only cytostatic humoral and cellular effects, including nutritional immunity, tumor necrosis factor, certain cytokines, and the cytotoxic effects mediated by macrophages, NK cells, NK-like cells, and certain stimulated T-cells. One question remaining to be solved is why these antigen-independent effects do not attack normal cells. A number of plausible hypotheses are discussed. The hypothetical surveillance system is modulated both by traditional cancer treatment and by attempts at immunomodulation. Radiotherapy reduced the T-helper cell function for almost a decade, but not those of macrophages or NK cells. T-cell changes have no prognostic implication, supporting, perhaps, the suggestion of a major role for macrophages and NK cells. Cyclic adjuvant chemotherapy reduces the peripheral lymphocyte population and several lymphocyte functions but not NK activity. Most of the parameters were normalized some years following treatment, but NK activity remained elevated and Th/Ts cell ratio was still decreased. This might possibly be taken to support the surveillance role of NK cells. Bestatin increases the frequency of lymphocytes forming rosettes with sheep red blood cells (but not their mitogenic responses), enhances NK activity, and augments the phagocytic capacity of granulocytes and monocytes (but not their cytotoxic activity). Improved survival with Bestatin treatment following chemotherapy has been observed in patients with melanoma Stages 1b and II and in patients with acute nonlymphatic leukemia, where BCG also seems active, although possibly only in patient groups with less than 49% complete remissions.
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PMID:Cells responsible for tumor surveillance in man: effects of radiotherapy, chemotherapy, and biologic response modifiers. 391 61

The antitumor activity of highly purified tumor necrosis factor (TNF) was tested against eight kinds of murine tumor and five kinds of human tumor heterotransplanted into nude mice. Mice were treated by intravenous or intratumoral injection of TNF, commencing when the tumors were well established. TNF showed an excellent curative effect against all kinds of murine and human tumors tested. Meth A sarcoma, Colon 26, Ehrlich, sarcoma 180, MM 46, MH 134, B16 melanoma, and Lewis lung tumors transplanted into mice underwent tumor necrosis and regression following a single injection of TNF. Sometimes a complete cure was observed in Meth A sarcoma, sarcoma 180, Ehrlich, and MM 46 tumors. Human cancers, SEKI, HMV-I, KATO-III, MKN 45, or KB, heterotransplanted into nude mice, also exhibited tumor necrosis and regression in size following several intratumoral injections of TNF. A great difference in curative effects of TNF was observed in Meth A sarcomas between those transplanted into BALB/c nu/+ and into BALB/c nu/nu mice: following a single intravenous administration the effect was stronger in BALB/c nu/+ than in nu/nu mice. In contrast, tumor necrosis was almost the same in nu/+ and nu/nu mice following intratumoral administration. The present results thus indicate that TNF from mice had an antitumor activity against not only murine tumors but also human tumors. In addition to direct cytotoxicity against tumor cells, TNF induced a host-mediated factor which contributed to the antitumor effects.
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PMID:Antitumor activity of murine tumor necrosis factor (TNF) against transplanted murine tumors and heterotransplanted human tumors in nude mice. 646

The purpose of these studies was to determine whether the induction of NO synthase activity in murine K-1735 melanoma cells correlated with their metastatic potential. Nonmetastatic, metastatic, and somatic cell hybrids (produced by fusion of nonmetastatic and metastatic cells) were injected i.v. into syngeneic C3H/HeN mice. Metastatic cells survived to produce experimental lung metastases, whereas nonmetastatic cells did not. The various clones and somatic cell hybrids were incubated in vitro with combinations of tumor necrosis factor, interleukin 1, gamma-interferon, and lipopolysaccharide. Nonmetastatic cells exhibited high levels of inducible NO synthase activity and NO, whereas metastatic cells did not. Both the cytotoxic effects of the cytokines and NO production were inhibited by the addition of NG-monomethyl-L-arginine, a specific inhibitor of NO synthase. These data demonstrate an inverse correlation between production of endogenous NO and the ability of K-1735 cells to survive in syngeneic mice to produce lung metastases.
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PMID:Inverse correlation between expression of inducible nitric oxide synthase activity and production of metastasis in K-1735 murine melanoma cells. 750 36

Angiogenesis depends on the adhesive interactions of vascular cells. The adhesion receptor integrin alpha v beta 3 was identified as a marker of angiogenic vascular tissue. Integrin alpha v beta 3 was expressed on blood vessels in human wound granulation tissue but not in normal skin, and it showed a fourfold increase in expression during angiogenesis on the chick chorioallantoic membrane. In the latter assay, a monoclonal antibody to alpha v beta 3 blocked angiogenesis induced by basic fibroblast growth factor, tumor necrosis factor-alpha, and human melanoma fragments but had no effect on preexisting vessels. These findings suggest that alpha v beta 3 may be a useful therapeutic target for diseases characterized by neovascularization.
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PMID:Requirement of vascular integrin alpha v beta 3 for angiogenesis. 751 51

The effect of cytokines with human recombinant interleukin-2 (rIL-2) on cytolytic T cell (CTL) generation was studied. Lymphocytes were isolated from involved lymph nodes of melanoma patients and expanded in medium containing rIL-2 alone or in combination with other human cytokines (rIL-1, rIL-4, rIL-6, and recombinant human tumor necrosis factor-alpha (rTNF alpha)). Lymphocytes incubated with rIL-2 alone did not grow, whereas addition of the other cytokines augmented IL-2-mediated lymphocyte proliferation. In all cultures, the majority of expanded lymphocytes were CD3+, CD56- T cells. Lymphocytes cultured with rIL-1, rIL-2, rIL-4, and rIL-6 exhibited cytolytic activity specific for autologous melanoma, which increased during the culture period (24.08 and 58.18% at 16 and 30 days in culture, respectively) without detectable changes in cell surface phenotype and remained high even after 100 days in culture. Moreover, the cytolytic activity was inhibited by monoclonal antibodies (mAbs) against HLA-class I, CD3, and CD8 molecules but not by mAbs against HLA-class II or CD4 molecules. Lymphokine-activated killer (LAK) activity was detected in lymphocytes cultured with rIL-1, rIL-2, and rIL-6 in the presence or absence of rTNF alpha. These data indicate that lymphocytes derived from melanoma-invaded lymph nodes and cultured in the presence of rIL-1, rIL-2, rIL-4, and rIL-6 offers an efficient system to expand CD8+ CTLs with HLA-restricted cytolytic specificity against autologous tumor cells.
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PMID:In vitro expansion of tumor-specific, HLA-restricted human CD8+ cytolytic T lymphocytes. 751 62


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