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)

Cytotoxic activity of recombinant human TNF (rHu-TNF) on various human cell lines was examined in vitro. rHu-TNF exerted a cytostatic effect on various types of human tumor cells such as carcinoma, sarcoma, leukemia, melanoma and other types. When the cytocidal effect was examined on the tumor cells which were cytostatically susceptible to rHu-TNF, the cytocidal effect of rHu-TNF was also noticed on many of these tumor cells. However, some tumor cells were affected cytostatically only. Human diploid cells were not affected cytostatically or cytocidally by rHu-TNF. WI-38 VA13 cells which are an SV-40-transformed derivative of WI-38 diploid cells, were affected both cytostatically and cytocidally by rHu-TNF. These results suggest that rHu-TNF exerts cytostatic and cytocidal effects against a broad spectrum of human tumor cells, and its cytotoxic activity is tumor-specific.
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PMID:Recombinant human tumor necrosis factor--I. Cytotoxic activity in vitro. 352 33

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

A human IgM monoclonal antibody (B5) recognizing human TNF alpha was established from peripheral blood lymphocytes by transformation with Epstein-Barr virus and subsequent cell fusion. The B5 monoclonal antibody (mAb) binds to cell surface TNF alpha (csTNF alpha) on human T cells, B cells, and monocytes. In addition, this autoantibody binds to csTNF alpha on a variety of lymphoid and monocyte lineage cell lines of human origin, as well as astrocytomas, a breast carcinoma, and a melanoma. Interestingly, the B5 mAb also binds to chimpanzee lymphocytes and to mouse T lymphoma cell line csTNF alpha. Many neutralizing mouse anti-TNF alpha mAbs do not exhibit comparable binding to csTNF alpha. This is consistent with the previous demonstration that B5 recognizes an epitope on TNF alpha distinct from those recognized by three neutralizing mouse anti-TNF alpha mAbs. B5 binding to csTNF alpha is specific since it can be inhibited by TNF alpha. No inhibition of B5 binding was seen by a neutralizing mouse anti-TNF alpha mAb. The B5 autoantibody appears to recognize the transmembrane form of TNF alpha and most likely also recognizes TNF alpha associated with its receptor. The unique specificity of this B5 autoantibody provides some additional insight into the complex physiology of cell surface-associated TNF alpha.
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PMID:The B5 monoclonal human autoantibody binds to cell surface TNF alpha on human lymphoid cells and cell lines and appears to recognize a novel epitope. 750 82

Interleukin-2 (IL-2)-activated killer cells, also referred to as lymphokine-activated killer (LAK) cells, are stimulated by tumor cells to express cytotoxic activity and to also secrete cytokines such as interferon gamma (IFN gamma) and tumor necrosis factor alpha (TNF alpha). We previously reported that secretion of cytokines by IL-2-activated T cells (LAK-T cells) is dependent on the initial cross-linking of the T cell receptor (TCR)-CD3-molecular complex, but the cross-linking of accessory molecules, such as LFA-1, CD2, CD44 and CD45, on LAK-T cells can enhance this cytokine production. We have developed an approach involving interspecific gene transfer to define further the contributions of LFA-1 and CD2 to the activation of LAK-T cells. The genes for huICAM-1 (a ligand for LFA-1) and huLFA-3 (a ligand for CD2) were transfected singly and in combination into a null mouse melanoma background, and clonal populations of cells that stably express ICAM-1 and/or LFA-3 were derived. Expression of the introduced ICAM-1 and/or LFA-3 by transfected cells enhanced their ability to bind LAK-T cells; the LFA-1/ICAM-1-mediated binding was not further enhanced by activation with phorbol 12-myristate 13-acetate. ICAM-1- and/or LFA-3-transfected cells, in the presence of immobilized anti-CD3, exhibited a greater ability to stimulate IFN gamma secretion by LAK-T cells compared to the untransfected parental lines. This experimental system, which allows ICAM-1/LFA-1 and CD2/LFA-3 interactions to occur on the LAK-T cell at a site distal from the anti-CD3 signal, extends our understanding of LAK-T cell activation by establishing that both LFA-1/ICAM-1 and CD2/LFA-3 can mediate co-stimulation via adhesion and signaling events.
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PMID:ICAM-1 and LFA-3 enhance the ability of anti-CD3 mAb to stimulate interferon gamma production in interleukin-2-activated T cells. 751 26

We have reported that patients with metastatic melanoma treated with an autologous, dinitrophenol-modified vaccine develop inflammatory responses at tumor sites. Histologically, these inflamed lesions are characterized by T cell infiltration, which is sometimes associated with tumor cell destruction. We tested biopsy specimens of eight subcutaneous metastases that had developed inflammation following vaccine treatment for expression of mRNA for interferon gamma (IFN gamma), interleukin-4 (IL-4), tumor necrosis factor alpha (TNF alpha), and IL-10. Post-vaccine, inflamed biopsies contained mRNA for IFN gamma (5/8), IL-4 (4/8) or both (3/8), and for TNF alpha (4/7). In contrast, IFN gamma mRNA was detected in only 1/17 and TNF alpha mRNA in 2/16 control specimens (pre-treatment lymph node metastases or non-inflamed subcutaneous metastases). mRNA for IL-10, a cytokine with anti-inflammatory properties, was detected in 24/25 melanoma metastases and was independent of lymphoid content; in situ the reverse transcriptase/polymerase chain reaction confirmed that melanoma cells were the major source. These findings may provide a new parameter by which to measure the effects of cancer immunotherapy.
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PMID:Expression of cytokine mRNA in human melanoma tissues. 755 83

The matrix protein tenascin-C (TN-C) is present in the blood of healthy individuals at concentrations around 1 mg/l. Elevated serum levels have been reported in cancer patients. In this study we have measured the concentration of circulating TN-C in 40 patients with melanoma, soft-tissue sarcoma (STS) or squamous-cell carcinoma (SCC) of the limbs, and have found a minor increase in the mean concentration compared with healthy subjects. Only 10 patients had TN-C levels above the normal range. No correlation was observed between TN-C levels and tumor burden. Nineteen patients were treated by isolation limb perfusion (ILP) with TNF, IFN gamma, melphalan (11 melanoma, 2 SCC and I STS), melphalan alone (3 melanoma) or hyperthermia at 41.5 degrees C (2 melanoma). ILP with TNF, IFN gamma and melphalan induced a rapid increase in plasma TN-C levels, peaking in most patients between 24 or 48 hr after ILP. Two patients treated with hyperthermia only had a slow increase in TN-C concentration peaking at day 4, while the patients treated with melphalan alone had no significant change. In some cases elevated TN-C levels persisted for over 8 weeks after ILP. The early rise in TN-C concentration correlates with the increase in circulating C-reactive protein. Our findings suggest that circulating TN-C behaves, at least in part, as an acute-phase protein and that it may play a role in the inflammatory response.
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PMID:Rapid increase in plasma tenascin-C concentration after isolated limb perfusion with high-dose tumor necrosis factor (TNF), interferon gamma (IFN gamma) and melphalan for regionally advanced tumors. 759 Dec 83

Local administration of high-dose r-TNF alpha with IFN gamma in the limbs of melanoma patients has proved to be a very promising treatment. To understand the role played by the effect of TNF on melanoma cells in tumor destruction, we have investigated the expression of TNF-receptors in melanoma cells using monoclonal antibodies specific for the type-A (75-kDa) and the type-B (55-kDa) TNF receptors. Flow cytometric analysis of cultured melanoma cells indicated the presence of both types of receptor. Quantificative differences in the relative levels of receptors were observed for different cells lines, although the type-B receptor was generally more strongly expressed. Similar results were obtained by immunohistochemistry on cryosections from tumor samples. Positive staining of variable intensity was observed for the type-B TNF-receptor in a high percentage of tumor cells. The type-A TNF-receptor was also detected, but with a weaker staining. The total TNF-binding activity of cultured melanoma cells, as measured by binding of 125I-labeled TNF alpha, was up-regulated between 2- and 4-fold by incubation of cells with activators of protein kinase A or IFN gamma. Treatment of cultured melanoma cells with dbc-AMP resulted in a selective induction of type-A TNF-receptors, without affecting the type-B receptor level. In contrast, IFN gamma was able to induce either type of receptor in a cell-line-dependent fashion. Addition of TNF alpha to melanoma cells induced the activation of the nuclear transcription factor kappa B, as measured in an electrophoretic mobility shift assay, thus indicating the biological significance of the TNF-receptors on these cells.
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PMID:Expression of type A and B tumor necrosis factor (TNF) receptors on melanoma cells can be regulated by dbc-AMP and IFN gamma. 760 71

Interleukin 1 alpha (IL1 alpha) and tumor necrosis factor alpha (TNF alpha) have been successfully incorporated into specific phosphatidylcholine (PC) and phosphatidylserine (PS) multilamellar vesicle (MLV) liposomes by modifying the concentration of calcium ion and pH of the encapsulation buffer. Under these conditions, some of the cytokines may attach to the exterior surface of the MLV and therefore be readily accessible to target cells for receptor binding and signal transduction. These cytokine-associated liposomes are stable for up to 2 weeks in serum-free buffer, and leakage of cytokines into medium containing 10% fetal bovine serum was about 50% at the end of a 3-day incubation period at 37 degrees C. The biological activities mediated by liposomal IL1 alpha and TNF alpha were specific: the stimulation of thymidine uptake in T-helper D10 lymphocytes and the cytolysis of TNF alpha-sensitive L929 target cells could be blocked by specific neutralizing antibodies in a dose-dependent fashion. When administered intravenously into C57BL/6 mice bearing the syngeneic B16F10 murine melanoma cells, dual entrapment of liposomal IL1 alpha and TNF alpha significantly reduced the number of metastatic tumor nodules in the lungs and prolonged the life span of the animals. Thus, liposomal IL1 alpha and TNF alpha displayed significant in vivo antitumor activity against the IL1 alpha- and TNF alpha-resistant B16F10 metastatic murine melanoma.
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PMID:Antitumor effects of liposomal IL1 alpha and TNF alpha against the pulmonary metastases of the B16F10 murine melanoma in syngeneic mice. 760 87

The purposes of this study were to determine the maximally tolerated dose (MTD) of IL-2 when sequentially administered following TNF (at its MTD), to identify any unique toxicities, and determine the immunomodulatory effects of this combination. Patients with metastatic cancer were treated with 160 micrograms/ml rTNF by rapid i.v. infusion for 5 days, followed by rIL-2 therapy daily at doses up to 18 x 10(6) IU/m2/day for 5 days and 6 x 10(6) IU/m2/day for 7 days. Cycles were repeated at 3- or 4-week intervals until progressive disease or unacceptable toxicity developed. Fifteen patients received 46 cycles of therapy (range 1-8, median 3). Major toxicities included hypotension, weight loss, and decreased performance status comparable to that reported with rIL-2 alone. No novel toxicities were identified. Two of 14 patients who received two cycles of therapy had objective responses (1 complete, 1 partial). Both occurred in patients with malignant melanoma, lasted 30 and 75 weeks, respectively, and included a complete response in liver metastasis. Dosage reductions of IL-2 were necessary for 3 patients over 11 treatment cycles (23%), and rTNF in 1 patient for 1 cycle (2%). The MTD of 5-day infusional rIL-2 was determined at 18 x 10(6) IU/m2/day. rTNF did not augment natural killer/lymphokine-activated killer activities beyond that commonly seen with IL-2 infusions. We conclude that full doses of rTNF can be combined with escalating rIL-2 infusions in an outpatient setting without additive toxicity and with clinical activity in patients with malignant melanoma.
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PMID:Phase I study of sequentially administered recombinant tumor necrosis factor and recombinant interleukin-2. 761 42


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