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)

B16-F10.9 is a highly metastatic clone of the B16-F10 melanoma line, that expresses low levels of MHC class-I antigens. F10.9 cells transfected with H-2Kb are highly immunogenic and consequently exhibit a low metastatic phenotype. Treatment with gamma-IFN elevated H-2Kb and H-2Db cell surface expression of F10.9 cells to levels much higher than did transfection of these genes. Yet, following intravenous injection, the gamma-IFN treated cells generated high loads of lung metastases. However, when tested for their immunogenic effect, they elicited CTL and were sensitive to CTL. Immunization with both the positive transfectant KI and the gamma-IFN-treated F10.9 cells protected in vivo against metastatic spread of a subsequent transplant of parental F10.9 cells. The protection elicited by KI transfectants was more effective than the protection by gamma-IFN-treated cells.
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PMID:Immunization by gamma-IFN-treated B16-F10.9 melanoma cells protects against metastatic spread of the parental tumor. 190 54

Murine monoclonal antibody ZME-018 recognizes a 240 Kda glycoprotein present on the surface of most human melanoma cells and on over 80% of human biopsy specimens tested. Gelonin is a ribosome-inactivating plant toxin similar in nature and rivaling the activity of ricin A chain. ZME-018 was coupled to purified gelonin using the reagents SPDP and 2-iminothiolane. The ZME-gelonin conjugate was purified by S-300 Sephacryl and Blue Sepharose chromatography, removing unreacted gelonin and antibody, respectively. PAGE analysis showed that ZME was coupled to 1, 2, or 3 gelonin molecules. The ZME-gelonin conjugate was 10(6)-fold more active than gelonin itself in inhibiting the growth of log-phase human melanoma cells in culture. The immunoconjugate was not cytotoxic to antigen negative T-24 (human bladder carcinoma) cells. Treatment of melanoma cells with recombinant IFN-alpha or TNF substantially augmented the cytotoxicity of the immunoconjugate while treatment with IFN-gamma had a minor effect. Using the human tumor colony assay of melanoma cells obtained from fresh biopsy specimens, greater than 90% growth suppression was observed in 2 of 4 samples tested at a concentration of 250 ng/ml. In addition, 25% growth suppression was observed with a third sample tested, and no growth suppression was observed in 1 sample. Thus, clonogenic melanoma cells are sensitive in vitro to the cytotoxic activity of this immunotoxin at concentrations which we presume are pharmacologically relevant.
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PMID:A specific and potent immunotoxin composed of antibody ZME-018 and the plant toxin gelonin. 190 86

Mouse B16 melanoma cells have been shown to rapidly develop resistance to the antiproliferative effects of MuIFN-alpha or MuIFN-beta when exposed to these interferons. In cloning studies, the maximal antiproliferative effects of MuIFN-alpha were seen with 2-4 days treatment. This resistance has been further characterized. The level of resistance which develops in B16 melanoma cells is dependent upon the concentration of MuIFN-alpha to which the cells are exposed. In addition, B16 melanoma cells which are resistant to the antiproliferative effects of MuIFN-alpha have greatly elevated levels of the interferon-induced enzyme 2',5'-oligoadenylate (2-5A) synthetase. Since it has previously been shown that B16 melanoma cells do not develop resistance to the antiproliferative effects of MuIFN-gamma, several experiments studied the influence of MuIFN-gamma on the development of resistance to MuIFN-alpha. Combinations of IFN-gamma and IFN-alpha have previously been shown to result in a synergistic enhancement of the antiproliferative effects. Kinetic studies show that the response of the cells to the MuIFN-gamma antiproliferative effect appears to be dominant over the development of resistance since no resistance develops in response to combination treatment. Not only is MuIFN-gamma able to prevent development of resistance when it is present continuously, but also when it is used for the sequential treatment of the cells before their exposure to MuIFN-alpha. A 2-day pretreatment with MuIFN-gamma is sufficient to prevent the development of resistance during later exposure of the cells to MuIFN-alpha alone for up to 6 additional days.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Resistance to the antiproliferative activity of IFN-alpha: further characterization and demonstration of antagonistic effects of IFN-gamma. 190 84

This study was undertaken to define the maximum tolerated dose (MTD) of recombinant interleukin-2 (IL-2) that could be combined with a fixed dose of alpha-2a-interferon (alpha-IFN) in an outpatient setting. The schedule called for IL-2 to be given by a 2-hour intravenous infusion 5 days a week for 4 weeks. The alpha-IFN was given at a dose of 6 x 10(6) U/m2/d intramuscularly 3 days per week (Monday, Wednesday, and Friday). The IL-2 dose was escalated in four dose levels from 1 to 4 x 10(6) U/m2/d. The MTD in this study of 17 patients was at the fourth dose level of IL-2 (4 x 10(6) U/m2/d). In addition to the usual IL-2 toxicities, debilitating fatigue limited outpatient administration of this dose. Although the response rate was low, with partial responses seen in only 1 of 15 patients, 2 of 5 patients with melanoma treated at the higher dose levels had objective tumor shrinkage with one partial and one minor response. Thus, an IL-2 dose of 3 x 10(6) U/m2/d combined with a recombinant alpha-2a-IFN dose of 6 x 10(6) U/m2/d is recommended for Phase II studies.
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PMID:A phase I study of an outpatient regimen of recombinant human interleukin-2 and alpha-2a-interferon in patients with solid tumors. 191 12

Any attempt to eradicate the heterogeneous cell population of a tumour mass would require the use of appropriate combination treatment protocols. The antitumour effects of interferon alpha (IFN alpha) in combination with AS2-1, the hydrolysis product of 3-phenylacetyl-amino-2,6-piperidinedione, were examined using several human tumour cell lines as a model. These included the malignant melanoma A375, adenocarcinoma of the prostate PC3 (hormone-insensitive bone metastasis), and the erythroleukaemia line K562. AS2-1 suppressed tumour growth through non-toxic mechanisms, with 1 mg/ml causing approximately 50% inhibition of the melanoma and prostate tumour cell proliferation. By contrast, primary normal human skin fibroblasts were significantly less sensitive to the antiproliferative effect of AS2-1. Suppression of tumour growth was seen also with AS2-1 treatment of the erythroleukaemia K562; in these cultures the drug also induced dose-dependent differentiation, as indicated by the increased haemoglobin production. Interestingly, addition of low doses of IFN alpha markedly enhanced the antitumour and differentiating effects observed with AS2-1. Treatment with 200-300 IU/ml of IFN (which caused about 20% inhibition of growth) together with 1 mg/ml of AS2-1 resulted in over 80% inhibition of the melanoma and prostate cancer cell proliferation, suggesting a synergistic activity of the two agents. This was substantiated by quantitative analysis of the differentiation induced in K562 erythroleukaemia. It appears, therefore, that IFN alpha and AS2-1 may act through synergistic mechanisms to effectively inhibit tumour growth and promote differentiation in a variety of human malignant cell lines.
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PMID:Interferon in combination with antitumourigenic phenyl derivatives: potentiation of IFN alpha activity in-vitro. 193 16

Bradykinin was found to induce production of IL-6 in human diploid fibroblasts, as well as in a hepatoma-derived cell line, but not in a human melanoma or an osteosarcoma cell line. With the exception of the melanoma cell line, these cells were also found to be responsive to IL-1 beta. The response to bradykinin was faster but less high than that induced by IL-1. Experiments in which IL-1 (-alpha or -beta) and bradykinin were applied simultaneously revealed a synergistic interaction. Of the other cytokines tested, TNF-alpha and IFN-gamma weakly induced IL-6. Neither IL-2, IFN-alpha, nor IFN-beta was able to induce IL-6, either in the absence or the presence of bradykinin. These observations constitute further evidence for the existence of interactions between cytokine and noncytokine peptides, thus linking the neuroendocrine and immune systems.
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PMID:Bradykinin induces interleukin-6 and synergizes with interleukin-1. 193 73

Melanoma does not respond meaningfully to systemic chemotherapy. No significant improvement in overall survival has been observed with any therapy in the setting of advanced disease, nor in the adjuvant setting. The most active single drugs achieve 14% to 22% response rates in larger phase II series, and drug combinations have not in general improved true response rates by 15% or more. Experience with recombinant interferon alpha-2 (rIFN alpha 2) administered by a variety of schedules and routes has demonstrated tumor response rates of 12% to 22% in advanced melanoma. Administered combined with chemotherapy, rIFN alpha 2 has improved response rates in some, but not all trials to date. On the basis of increased responsiveness noted to be inversely related to tumor size, IFN alpha has been explored over the past 7 years as an adjuvant to definitive surgery for melanoma. The North Central Cancer Treatment Group (NCCTG) and Eastern Cooperative Oncology Group (ECOG) have recently completed trials of 3 and 12 months' duration of maximal dosages of rIFN alpha 2 in subjects with high-risk resected deep primary or lymph node metastatic melanoma. These randomized controlled studies completed accrual in 1990. The ECOG trial EST 1684 has tested the effect of rIFN alpha 2b, given intravenously daily for 5 days per week for 4 weeks at 20 x 10(6) IU/m2/d, then subcutaneously three times a week at 10 x 10(6) IU/m2/d for 11 months. A series of three analyses is planned for the ECOG trial, and the first of these interim analyses was reported to the ECOG in June, 1990, revealing an encouraging divergence of survival curves that does not achieve statistical significance at this early time. A randomized controlled study of 3 months' duration of rIFN alpha 2a at 12 x 10(6) IU/m2/d intramuscularly three times a week performed by the NCCTG is also in too early a stage to allow definitive conclusions yet. The toxicity of IFN alpha administered at maximum tolerated doses has been significant in terms of constitutional symptoms and organ dysfunction. There have been two instances of fatal toxicity observed in the ECOG study (286 subjects). Consideration of lower, more tolerable dosage regimens has been derived from the desire to evaluate longer periods of IFN alpha 2 therapy, and long-term maintenance treatment with IFN alpha 2 in adjuvant melanoma therapy. In addition, immunologic studies suggest that dosages of 3 x 10(6) IU/m2/d may be more immunologically active in vivo.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Studies of interferons in the therapy of melanoma. 194 34

Systemic chemotherapy may be used in locally advanced or metastatic soft tissue sarcoma for palliation. Malignant melanoma shows objective responses in about 20% of patients treated with chemotherapy or with cytokines (IL-2, alpha-IFN). Adjuvant chemotherapy has not proven to be effective in either of these entities. The risk of local recurrences in limbs however can be reduced by hyperthermic perfusion with cytotoxic agents. Neoadjuvant (preoperative) treatment of locally advanced tumors needs to be prospectively evaluated. Symptomatic Kaposi sarcoma can be effectively treated with alpha-IFN or chemotherapy.
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PMID:[Chemotherapy of skin and soft tissue tumors]. 198 79

In vivo administration of escalation doses of recombinant alpha-interferon (IFN-alpha) during a phase I trial in malignant melanoma patients caused dose-dependent increases in the mRNA accumulation, synthesis, steady state cellular content, and plasma membrane expression of class I major histocompatibility complex molecules in peripheral blood mononuclear cells. In addition, circulating levels of class I molecules were also enhanced. These findings show that (a) antigenic enhancement by biomodifiers may occur in vivo, in humans and (b) the mechanism of class I major histocompatibility complex enhancement by IFN-alpha is similar in vitro and in vivo. Furthermore, because peripheral blood mononuclear cells of different melanoma patients display different susceptibility to IFN-alpha, the entity of their antigenic modulation may represent a useful parameter to evaluate the efficacy of different therapeutic regimens and/or assess the individual susceptibility to the molecular changes induced by IFN-alpha.
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PMID:Class I major histocompatibility complex enhancement by recombinant leukocyte interferon in the peripheral blood mononuclear cells and plasma of melanoma patients. 198 82

Sixty-two patients with biopsy-proven, measurable disseminated malignant melanoma received either the combination IFN-alpha 2A with BCNU (30 patients) or the combination cimetidine with BCNU (32 patients) in parallel noncomparative Phase II trials. From patients receiving IFN-alpha 2A plus BCNU, we observed a 7% response rate: 1 complete response (CR) and 1 partial response (PR) (soft tissue disease with durations of 6.9 and 11.5+ months, respectively). Median time to progression (MTP) was 1.8 months and median survival time (MST) was 3.8 months. Myelosuppression and a flu-type illness were the most common toxicities. From patients receiving cimetidine plus BCNU, the response rate was 16%: 4 PRs (soft tissue disease, 3.8 months; visceral, 2.1, 4.0+, and 9.7 months) and 1 CR (soft tissue, 14.3+ months). MTP and MST were 1.9 and 5.5 months, respectively. Myelosuppression and nausea/vomiting were the most common side effects. Although each of these regimens had great conceptual allure, neither offered any durable impact on the natural history of disseminated malignant melanoma. Nevertheless, alternative combinations of biological response modifiers (BRMs) and BRMs with biochemical modulators or cytotoxic agents may provide some useful alternatives for further clinical investigations.
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PMID:Phase II trial of recombinant leukocyte A interferon (IFN-alpha 2A) plus 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) and the combination cimetidine with BCNU in patients with disseminated malignant melanoma. 202 22


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