Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0278883 (metastatic melanoma)
 6,224 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines are soluble mediators involved in cell-cell regulations in the immunological and the hematopoietic systems-genetic engineering now allows the characterization and the availability of recombinant molecules, some of them being recently introduced in clinical trials. Interleukin-2 (IL-2) is the first factor having demonstrated a reproducible therapeutic effect on human metastatic solid tumors, mainly chemo-resistant. High-dose IL-2 alone could achieve about 25% objective responses in metastatic renal cancers, with a low but significant number of complete, relatively long-lasting complete responses. Similar data are obtained in metastatic melanoma. IL-2 is probably acting through the activation of cytotoxic lymphocytes (LAK: lymphokine activated killers). The interest for simultaneous administration of autologous LAK cells generated through in vitro culture with IL-2 is discussed. Cytokine therapy is currently limited by important systemic toxicities, including mainly general symptoms with fever, and a capillary leak syndrome with weight gain, edema and functional renal failure-cardiac are respiratory troubles can be life-threatening. Future trends for cytokine therapy will be: The discovery of new cytokines, and a better knowledge of their synergies, allowing the design of rational associations. A letter understanding of the mechanisms of toxicities, allowing specific prevention of adverse effects not needed for efficient anti-tumor action. Gene therapy, which will lead to important and prolonged release of cytokines by the tumor cells themselves, or by infiltrating peri-tumoral cells, in order to achieve local efficacy and to circumvent systemic toxicities.
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PMID:[Immunotherapy: current problems and outlook]. 146 35

Expression of alpha and beta subunits of VLA and VNR integrins was analyzed by cytofluorimetric analysis on 6 different human primary and metastatic melanoma cell cultures. Marked inter-tumor heterogeneity was observed, and expression of VLA-alpha I, VLA-alpha 2 and VLA-alpha 6 was lower on primary melanomas than on metastatic lesions. The function of VLA products on melanoma cells was assessed by adhesion assays to extracellular matrix (ECM) proteins using a panel of melanoma clones previously characterized for the presence and heterogeneity of expression of the distinct VLA-alpha subunits. These experiments indicated that intra-tumor heterogeneity in the integrin profile can influence the interaction of neoplastic cells with ECM proteins. Inhibition of adhesion with antibodies to VLA-alpha subunits revealed that the presence on melanoma cells of VLA-alpha 2, VLA-alpha 5 and VLA-alpha 6 is relevant for the adhesion to type-IV collagen, fibronectin and laminin respectively. Culture of tumor cells in the presence of cytokines such as rIL-I beta, rTNF-alpha, rIFN-gamma or TGF-beta I could induce up- or down-modulation in the level of expression of multiple VLA integrins. Cytokine-mediated antigenic shifts in the VLA profile of melanoma cells were detected by cytofluorimetric analysis as early as 24 hr after cytokine exposure. The cytokine-dependent change in the matrix receptor profile of melanoma cells also affected the adhesion to ECM proteins as revealed by the enhanced adhesion of rTNF-alpha-treated cells to fibronectin. These data indicate that constitutive heterogeneity in the integrin profile or cytokine-mediated shifts in VLA expression can affect the ability of human melanoma cells to interact with different ECM components.
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PMID:Heterogeneity for integrin expression and cytokine-mediated VLA modulation can influence the adhesion of human melanoma cells to extracellular matrix proteins. 199 84

The purpose of this study was to determine the mRNA expression level of multiple cytokine and growth factor genes in human malignant melanoma. Melanoma cells were isolated from several surgical specimens, adapted to growth in culture, characterized for their ability to produce experimental metastases in nude mice, and assessed for cytokine and growth factor steady-state gene expression. Highly metastatic in vivo- and in vitro-derived variants isolated from a single melanoma, A375, were also analyzed. Northern blot analyses revealed that all melanomas analyzed constitutively expressed steady-state mRNA transcripts for the growth and angiogenic factors, basic fibroblast growth factor (bFGF), and transforming growth factor alpha (TGF-alpha), which correlated with metastatic propensity. Only one highly metastatic melanoma, TXM-1, originally isolated from a lymph node metastasis, expressed mRNA transcripts specific for monocyte chemotactic and activating factor (MCAF) and granulocyte-macrophage colony-stimulating factor (GM-CSF). Similarly, of the nine melanomas examined, only TXM-1 expressed interleukin (IL)-1 alpha, IL-1 beta, and IL-6, important immunomodulatory cytokines. These data demonstrate the differential and heterogeneous expression of cytokine and growth factor genes in human malignant melanoma.
J Interferon Cytokine Res 1995 Jan
PMID:Heterogeneity of cytokine and growth factor gene expression in human melanoma cells with different metastatic potentials. 764 37

Interferon-alpha (INF-alpha) has a documented activity against metastatic melanoma. To what extent an antiproliferative effect or tumor cell modulation or immunomodulation contributes to this antitumor effect is still uncertain. The role of immune mechanisms in the control of malignant melanoma is suggested by several studies. Therefore, this investigation used monoclonal antibodies, anti-CD4, anti-CD8, and anti-CD11c, to study the occurrence and distribution of tumor-infiltrating mononuclear cells in 10 untreated and 26 IFN-alpha-treated patients with regional metastatic malignant melanoma. IFN-alpha was given for 1-3 weeks before resection of the metastases. The infiltration of mononuclear cells in the stroma and close to tumor cells was studied. The duration of IFN-alpha treatment was found to be of importance for the immunomodulatory effect. In patients treated for < or = 1 week, tumor-infiltrating mononuclear cells were still mainly localized in the stroma, similar to the situation in untreated patients. The differences in CD4+ cells close to the tumor cells, comparing untreated patients and patients with various durations of IFN-alpha treatment, were highly significant (p = 0.009). Thus, IFN-alpha treatment resulted in recruitment of CD4+ cells close to the tumor cells. IFN-alpha had only a weak effect on the recruitment of CD8+ and CD11c+ mononuclear cells close to the tumor cells. Regressive changes in metastases were also analyzed and correlated to duration of treatment. Some of the criteria used for histopathologic regression in primary melanoma (distorted histologic architecture, low tumor cell density, and fibrosis) were applied to analyze the effect of IFN-alpha in metastatic melanoma. The tumor cell density was found to be significantly reduced in metastases with marked tumor regression compared with metastases with no, or only minor, regressive changes (p < 0.005). A chi-square analysis for trend, comparing untreated patients and patients with various durations of IFN-alpha treatment, showed that regressive changes of the tumor increased significantly during IFN-alpha treatment (p = 0.02).
J Interferon Cytokine Res 1998 Jan
PMID:Effect of IFN-alpha on tumor-infiltrating mononuclear cells and regressive changes in metastatic malignant melanoma. 947 65

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

Interferon-alpha (IFN-alpha) therapy induces a response in a proportion of patients with metastatic melanoma. However, the mechanism of the antitumor action and reason(s) for resistance to IFN therapy are not known. To investigate whether lack of clinical response may be due to resistance of the melanoma cells to IFN-alpha or to an inability of IFN-alpha to reach the tumor cells during treatment, we investigated the in vivo and in vitro susceptibility of primary tumor cells obtained through fine needle aspiration biopsies and peripheral blood mononuclear cells (PBMC) to the induction of the IFN-induced enzyme 2'5'-oligoadenylate synthetase (2'5'OAS) during initiation of IFN-alpha therapy in 10 patients with metastatic melanoma. None of the patients showed an objective response to IFN-alpha treatment. The melanoma cells from 2 of the 10 patients were resistant to IFN-induced enhancement of 2'5'OAS in vitro. This correlated well with the in vivo induction of 2'5'OAS in the malignant cells, as no in vivo induction was seen in the 2 patients whose malignant cells were resistant in vitro, whereas tumor cells from 7 of 8 of the remaining patients showed enhancement also in vivo. This study shows that it is possible to monitor the cellular susceptibility of tumor cells to IFN-alpha in vivo and that melanoma cells from a small percentage of patients are resistant to the cellular effects of IFN-alpha. Furthermore, the absence of a clinical response to IFN-alpha therapy in the majority of melanoma patients can be explained neither by impaired cellular susceptibility to IFN nor by an inability of IFN-alpha to reach the tumor.
J Interferon Cytokine Res 1998 Sep
PMID:In vivo induction of the interferon-stimulated protein 2'5'-oligoadenylate synthetase in tumor and peripheral blood cells during IFN-alpha treatment of metastatic melanoma. 978 7

Vascular endothelial growth factor (VEGF), the most potent angiogenic factor identified to date, is associated with growth and metastasis of solid tumours, including melanoma. It has been shown in vitro that melanoma cells produce raised concentrations of VEGF. We examined the VEGF concentrations in plasma of 20 patients with primary melanoma, local recurrence and metastatic melanoma. We also studied the inhibiting effect of one antioxidant, N-acetylcysteine, on VEGF production in three human melanoma cell lines. We found elevated levels of VEGF (median 205 pg ml; 95 percent confidence interval, 80-414) in metastatic melanoma, with respect to primary and locally recurrent melanoma (75 pg/ml; 95 percent confidence interval, 35-130). The health control patients had levels of 25 pg/ml (95 percent confidence interval, 10-35). Human melanoma cell lines secreted VEGF in basal conditions (550-963 +/- 125 pg/ml) and N-acetylcysteine (0.5-20 mM) significantly decreased the VEGF production in a dose-dependent manner. VEGF concentrations were found to be raised in patients with primary melanoma, local recurrence, and above all, metastatic melanoma (P=0.008). N-acetylcysteine inhibits VEGF production in three human melanoma cell lines. This antioxidant might have therapeutic applications in metastatic melanoma in combination with other cytotoxic drugs.
Cytokine 2000 Apr
PMID:Vascular endothelial growth factor (VEGF) and melanoma. N-acetylcysteine downregulates VEGF production in vitro. 1080 19

A 10-year-old male cross-breed dog was referred for investigation of oral malignant melanoma. Fine-needle aspirates were taken from the draining submandibular lymph node. The presence of metastatic melanoma cells was confirmed by cytological examination and reverse transcription polymerase chain reaction (RT-PCR) using primers for the melanoma-associated antigens: tyrosinase and mart-1/melan A. Cytokine expression in the lymph node was evaluated by multiplex RT-PCR, which demonstrated the presence of mRNA for IL-10 and TGF-beta1. However, IL-2, IL-4 and IFNgamma mRNA could not be detected, suggesting a lack of immune activation. Thoracic radiographs showed a lesion within the caudal lung fields suggestive of pulmonary metastasis. The dog developed signs of dyspnoea and collapse and was euthanased four days later. This case illustrates that molecular techniques can be used to aid clinical staging of canine oral malignant melanoma, and suggests that immunosuppressive cytokines could be involved in the pathogenesis of disease.
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PMID:Immunosuppressive cytokines in the regional lymph node of a dog suffering from oral malignant melanoma. 1240 Jun 46

Recently, it has been demonstrated that a number of novel thalidomide analogs possess anti-cancer properties due to their T cell co-stimulatory, anti-angiogenic and/or anti-inflammatory effects. Based on such effects, a class of thalidomide analogs known as Immunomodulatory Drugs (IMiDs) have recently entered into phase I clinical trials for the treatment of a number of cancers. The lead IMiD CC-5013 (referred to clinically as REVIMID) is now entering phase III clinical trials for multiple myeloma and metastatic melanoma, while CC-4047 (ACTIMID) is currently under investigation in phase I/II and II trials for multiple myeloma and prostate cancer, respectively. The other group of compounds, classified as Selective Cytokine Inhibitory Drugs (SelCIDs), do not co-stimulate T cells, but have anti-inflammatory and anti-angiogenic properties. Moreover, a subset of SelCIDs has been found to possess direct anti-tumor activity both in vitro and in vivo. This minireview highlights the various mechanisms of action associated with these compounds and their subsequent clinical development. The enhanced efficacy and lower side-effect profiles of the analogs in comparison to thalidomide make the use of these agents very attractive as novel anti-cancer agents.
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PMID:Thalidomide analogs as emerging anti-cancer drugs. 1278 37

The combination of temozolomide (TEM) and interferon-alpha (IFN-alpha) previously demonstrated a 30% response rate in metastatic melanoma. A single institution, phase II trial evaluating the efficacy of TEM/IFN in patients with advanced renal cell carcinoma (RCC) was conducted. Safety and tumor response were the main outcomes. Eligible patients received 200 mg/m(2)/day TEM orally on days 1-5 every 28 days, with IFN 2.5 million U/m(2)/day subcutaneously (s.c.) three alternate days/week for days 1-15 first cycle, then 5 million U/m(2)/day s.c. 3 alternate days/week throughout each 28-day cycle. Efficacy was evaluated every 8 weeks, and dose-limiting toxicities (DLTs) were treated with dose reductions of the culprit drug. Sixteen patients (ages 37-67) were initially enrolled. Of the 14 evaluable patients, there was one minor response. Best response was stable disease, with 7 patients remaining on study for > or =6 months. Five were alive for more than 2 years, and 2 remain alive at 45 and 50 months after enrollment. DLTs included TEM-induced myelosuppression and IFN-induced fever/chills. Other toxicities were mild to moderate (grades 1-3). The combination of TEM/IFN proved quite tolerable. This regimen appears inactive in terms of response in this population with poor prognosis, but the patients with stable disease > or =6 months remain of interest.
J Interferon Cytokine Res 2004 Jan
PMID:A phase II trial of temozolomide and IFN-alpha in patients with advanced renal cell carcinoma. 1498 83


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