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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A range of potent immunoregulatory molecules termed cytokines has become available for the therapy of human melanoma. Among the cytokines, the interferons (IFN) have been examined in great depth for the therapy of melanoma. IFN are able to modulate host effector cell function, including the tumor cytolytic function of lymphocytes and monocytes. IFN also have the capacity to regulate the distribution of circulating immunoregulatory (T) lymphocytes and the expression of tumor cell surface antigens, as well as class I and II products of the major histocompatibility locus. These activities of the IFN have led to their early application for treatment of human melanoma. The empirical evidence that IFN alpha exerts clinically significant anti-tumor effects against melanoma is reviewed, and evolving status of adjuvant trials of IFN alpha and gamma is noted. New indirect host-mediated anti-tumor activities that may potentially be manifest by IFN have yet to be fully harnessed. The opportunity to obtain meaningful anti-tumor activity in advanced disease or adjuvant settings, at dose ranges below those which are toxic (conventional maximal tolerable), are at hand. The U.S. cooperative groups [Eastern Cooperative Oncology Group (ECOG), Cancer and Leukemia Group B (CALGB), and South West Oncology Group (SWOG)] are studying IFN gamma in pursuit of this goal in advanced and adjuvant settings for melanoma and other tumors. The determination of the clinical role of IFN as biologic response modifiers demands equal commitment to the clinical assessment of immunobiologic mechanisms and anti-tumor effects. The immunologic assessment of IFN and a number of other cytokines is a major focus of the Pittsburgh Cancer Institute. Regional delivery of cytokines such as interleukin-2 (IL-2) may be the most appropriate and least toxic approach, given their half-life. Regional therapy by the intralesional route has yielded enhanced activity for a range of biologics, including bacillus Calmette-Guerin (BCG), IL-2, and tumor necrosis factor (TNF). Intralymphatic therapy with methanol extraction residue of BCG (MER-BCG) has been tested, and trials are now in progress with IL-2 to assess the optimal dosage by this route. It is likely that the optimal role of IFN and other cytokines will be found in combination with one another, and with different biologic modalities such as monoclonal antibodies and vaccines, to allow expansion and heightened activity of the desired effector cell populations in the host. Enhanced host toxicities, as well as anti-tumor effects, may require that special attention be devoted to optimal sequence of administration to enhance the therapeutic index.
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PMID:Role of interferons in the therapy of melanoma. 170 5

Activation of endothelial cells by the two inflammatory mediators interleukin-1 (IL-1) and tumor necrosis factor strongly increases tumor cell adhesion. We describe antibody inhibition studies showing that the endothelial leukocyte adhesion molecule-1 (ELAM-1), a cell-surface glycoprotein selectively expressed by cytokine-activated endothelial cells and responsible for neutrophil adhesion, is the major, if not the only, mediator of colon carcinoma cell adhesion to activated endothelial cells. Among the different tumor cell lines tested, seven colon carcinoma cell lines were sensitive to ELAM-1 antibodies. Adhesion of melanoma, osteosarcoma, and lung, cervix, or kidney carcinoma cell lines to IL-1-treated endothelial cells was not affected by the ELAM-1 antibody. This result suggests that ELAM-1 is selectively recognized by colon carcinoma cells and that adhesion of tumor cells to activated endothelial cells could be mediated by different and specific mechanisms.
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PMID:Tumor cell adhesion to endothelial cells: endothelial leukocyte adhesion molecule-1 as an inducible adhesive receptor specific for colon carcinoma cells. 171 24

Hematogenous metastasis involves adhesive interactions between blood-borne tumor cells and the vessel wall. By the use of in vitro assays, the adhesion of human melanoma, osteosarcoma, and kidney carcinoma (but not colon carcinoma) cell lines was shown to involve the cytokine-inducible endothelial cell surface protein inducible cell adhesion molecule 110 (INCAM-110) and the alpha 4 beta 1 integrin, molecules normally involved in endothelial-leukocyte interactions. Tumor adhesion to human endothelial cell monolayers was increased 1.9- to 8.2-fold by endothelial activation with the cytokine tumor necrosis factor (TNF) and inhibited by the anti-INCAM-110 monoclonal antibody (mAb) E1/6. Each of these tumor cells expressed members of the beta 1 integrin family of adhesion molecules, and antibodies to the alpha 4 and beta 1 integrin subunits inhibited tumor-endothelial adhesion (48-87% inhibition). A cDNA encompassing the three N-terminal Ig-like domains of vascular cell adhesion molecule 1 (VCAM-1) encoded a protein recognized by the anti-INCAM-110 mAb E1/6 and, when captured onto plastic, supported melanoma cell adhesion by an alpha 4 integrin-dependent mechanism. In contrast to mAb E1/6, a second anti-INCAM-110 mAb Hu8/4 neither inhibited adhesion to activated endothelium nor bound the first three Ig-like domains of INCAM-110/VCAM-1. These data indicate that the adherence of several human tumors to activated endothelium is mediated by an interaction of alpha 4 beta 1 integrin and the N-terminal Ig-like domains of endothelial INCAM-110/VCAM-1. Tumor acquisition of the alpha 4 integrin subunit and endothelial expression of INCAM-110 may affect the frequency and distribution of metastasis.
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PMID:Tumor cell surface alpha 4 beta 1 integrin mediates adhesion to vascular endothelium: demonstration of an interaction with the N-terminal domains of INCAM-110/VCAM-1. 171 64

In this report we have examined the ability of tumor necrosis factor-alpha (TNF) to induce the activity of phospholipase A2 (PLA2) in the cell line C3HA, a murine 3T3-like cell line which is normally resistant to TNF-induced cytolysis but can be sensitized with inhibitors of transcription and translation. Our results show that TNF is normally unable to induce the activity of PLA2 in this cell, as measured by the release of [3H]arachidonic acid. We find, however, that in the presence of either actinomycin D (Act D) or cycloheximide (CHI), TNF is indeed able to induce phospholipase activity and that the TNF-induced activation of PLA2 occurs 2-4 h before the onset of 51Cr release. The release of [3H]arachidonic acid was inhibited by 40-50% by pretreatment with 1 microM dexamethasone. Treatment with dexamethasone also inhibited cytolysis by 40-50% indicating that the CHI-dependent, TNF-induced activation of PLA2 is a cause, not an effect of cytolysis. The ability of TNF to induce the activity of PLA2 was also tested in two other cell types which are resistant to TNF except in the presence of Act D or CHI: SK-MEL-28, a human melanoma-derived cell line, and pVBETK-1cl15.2, an SV40-transformed murine L cell line. Our results were the same, treatment with a combination of Act D and TNF or CHI and TNF was required to cause activation of PLA2.
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PMID:Inhibitors of transcription and translation act synergistically with tumor necrosis factor to cause the activation of phospholipase A2. 173 Jun 4

Our previous studies have demonstrated the production and release of a tumor-derived factor that promoted lipolysis in normal adipocytes. We further demonstrated that this in vitro lipolysis was correlated with the in vivo loss of total carcass lipids induced by the presence of the same tumor. This study identified and isolated this "lipolysis-promoting" factor (LPF), released into the extracellular environment (conditioned media) by the human A375 melanoma cell line, which appears to be responsible for the previously demonstrated induction of in vitro and in vivo lipolytic activity. Unlike previously described non-tumor-derived molecules, such as tumor necrosis factor-alpha/cachectin, which have been implicated in cancer cachexia, the LPF induces alterations in lipid metabolism similar to those observed in cancer patients. The biochemical nature of human tumor-derived LPF appears to be a heat-stable molecule with an apparent molecular weight of approximately 6000. The lipolysis-promoting activity was trichloroacetic acid precipitable, but not precipitable with protamine sulfate or extractable with chloroform:methanol. Its activity appears to be resistant to enzymatic treatments with protease K, trypsin, Pronase, RNase, and DNase, as well as to periodate oxidation. Immunochemically, LPF appears to be distinct from tumor necrosis factor-alpha/cachectin. Furthermore, in contrast to the mechanism of action of tumor necrosis factor-alpha/cachectin, the mechanism of "lipolysis promotion" by LPF appears to be by the induction of cellular lipase activity.
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PMID:Identification of a human tumor-derived lipolysis-promoting factor. 173 44

In light of in vitro and preclinical animal model data suggesting potential additive or synergistic antitumor effects from the combined use of interferon-gamma (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha), we conducted a phase I study employing escalating doses of each agent in 36 patients with solid tumors to determine the maximum tolerated dose (MTD). Patients were given an intramuscular (i.m.) injection of IFN-gamma, followed 5 min later by an i.m. injection of TNF-alpha, each agent in different sites, every other day for ten doses over 20 days. Patients received 10, 50, or 100 micrograms/m2 of each agent throughout the treatment course. No dose modifications were made. Patients suffering serious toxicity had therapy stopped and were considered to be off-study. All patients experienced fatigue, and 36% spent over half their time in bed on treatment days. Fever and chills were nearly universal. Mild to moderate elevations in serum transaminase levels were noted in 44% of patients, and 44% developed transient microscopic hematuria. Although 81% of patients had anorexia, only 17% of patients lost more than 3 kg of body wt during the 3 weeks of therapy. Because two of three patients receiving 100 micrograms/m2 of both agents developed serious toxicity (one fever greater than 105 degrees F, one thrombocytopenia 43,000/mm3), the MTD was established to be 100 micrograms/m2 of IFN-gamma plus 50 micrograms/m2 of TNF-alpha. The use of aspirin did not significantly alter the toxic effects of the agents. One patient with melanoma had a mixed response and one patient with mesothelioma transiently cleared his ascites of malignant cells.
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PMID:Phase I evaluation of recombinant tumor necrosis factor given in combination with recombinant interferon-gamma. 179 Jan 43

Multiple administration of sublethal doses of recombinant murine tumor necrosis factor (TNF), e.g., 2 micrograms i.p. twice daily for 4 to 6 consecutive days, produces tachyphylaxis to the anorectic effects of TNF and tolerance towards a lethal challenge with recombinant murine TNF. The objective of this study was to examine whether the antitumor efficacy of TNF was retained in mice made tolerant. We treated tolerant and nontolerant C57BL/6 mice bearing a syngeneic B16BL6 melanoma tumor with repeated administrations of recombinant murine TNF (5 to 12.5 micrograms/injection) alone or in combination with recombinant murine gamma-interferon (5,000 to 50,000 units/injection). When the paralesional administration route was used, the tolerance-inducing pretreatment protected mice against the lethal outcome of both the single and the combination treatments (100% versus 40% survival in the former case; 80% versus 0% survival in the latter case) and still allowed complete regression of the tumor. When the i.p. route of administration was used, the final outcome was less positive; nevertheless, a significant protection against the lethal effects of the treatment was achieved without reduction of the antitumor efficacy. It is concluded that the toxic and antitumor activities of TNF are not inevitably linked and that their separation is an achievable research and perhaps a clinical goal.
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PMID:Induction of tolerance allows separation of lethal and antitumor activities of tumor necrosis factor in mice. 182 31

Nicotinamide methyltransferase (Nmd CH3transferase) activity increased in the liver of mice after i.p. transplantation of Ehrlich ascites tumor (ascitic form), but not in the liver of mice with acute inflammation induced by the i.p. administration of D-galactosamine, and it rather showed a decrease together with necrosis after carbon tetrachloride administration. When Nmd CH3transferase activity of rat hepatocytes in primary culture was investigated with the addition of dexamethasone, epidermal growth factor, transforming growth factor-beta, tumor necrosis factor-alpha and N1-methylnicotinamide (1-CH3Nmd), changes in activity were not correlated with DNA synthesis, suggesting that the increase of this enzyme activity in the tumor host liver was not directly related to liver cell proliferation. Thus, in order to make use of the increase of this enzyme activity as a tumor burden marker, a procedure for its estimation by measuring the blood level of 1-CH3Nmd, a metabolite of Nmd produced by Nmd CH3transferase, was established. The 1-CH3Nmd level in the blood of mice bearing Ehrlich ascites tumor 4 h after s.c. loading of Nmd (500 mg/kg body weight) was closely correlated with this enzyme activity in the liver (r = 0.835, P less than 0.00001) from the early to the terminal stage of tumor development. Furthermore, similar correlations were seen in the animal groups bearing various other tumors, such as s.c. implanted Ehrlich ascites tumor (solid form) and i.p. implanted sarcoma S-180, hepatoma MH-134, Yoshida ascites sarcoma and leukemia L-1210, but not solid tumors such as Lewis lung carcinoma and melanoma B-16, although almost all of the animals bearing these tumors showed a higher enzyme activity than their control normal animals.
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PMID:N1-methylnicotinamide level in the blood after nicotinamide loading as further evidence for malignant tumor burden. 183 57

Recent papers dealing with the effect of biologic response modifiers on the therapeutic activity of anticancer drugs are reviewed. Preclinical findings indicate that both interferons and tumor necrosis factor-alpha are able to synergize with different cytotoxic drugs in increasing both tumor cytotoxicity or cytostasis in vitro and the therapeutic effect in animal models in vivo. The mechanism of such a synergy, however, has not been definitively worked out. Several clinical phase I and II trials have assessed the interactions of biologic response modifiers (mainly interferons and interleukin-2) with anticancer drugs, particularly in melanoma and renal cancer patients. Evidence of a therapeutic synergism is limited with most of the studies, indicating a lack of synergic or additive effects of the combination compared with single agents. Few phase III studies provided conflicting results. It is concluded that further studies on the combination of biologic response modifiers and chemotherapy both at preclinical and clinical levels are necessary to establish the possible synergistic or additive therapeutic effect of such a therapeutic approach.
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PMID:Biologic agents as modifiers of chemotherapeutic effects. 184 10

Recombinant human tumor necrosis factor and recombinant human interleukin 2 were administered in a sequential schedule to 30 dogs with a variety of spontaneous neoplasms. Dose escalation of both drugs was performed, and a maximally tolerated dose of recombinant human tumor necrosis factor of 125 mg/m2 i.v. for 3 days, followed by 1.5 x 10(6) units/m2 of recombinant human interleukin 2 s.c. for 9 days, was derived. Dose-limiting toxicities were primarily gastrointestinal; however, weakness and malaise were seen during therapy at doses higher than the maximally tolerated dose. No clinically significant hematological toxicities were seen at any dose level. Objective tumor responses were seen in dogs with oral mucosal melanoma and cutaneous mastocytoma. Because of the histological, behavioral, and epidemiological similarities between human and canine tumor types, the canine cancer patient provides a unique model for the preclinical evaluation of recombinant cytokine therapy.
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PMID:Preclinical study of sequential tumor necrosis factor and interleukin 2 in the treatment of spontaneous canine neoplasms. 189 40


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