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)

Therapy with interleukin-2 (IL-2) achieves reproducible objective responses in 20%-30% of patients with malignant melanoma (MM) and renal cell carcinoma (RCC). This cytokine has significant dose and schedule dependence with regard to both clinical toxicity and biological activity. This article reviews the current status of clinical trials with IL-2 used as a single agent in a variety of doses and schedules or in combination with lymphokine-activated killer (LAK) cells in RCC and MM. The article also discusses the rationale, preclinical data, and preliminary clinical trial experience with IL-2 in combination with other cytokines such as IFN-alpha, monoclonal antitumor antibodies, and tumor infiltrating lymphocytes (TILs).
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PMID:The role of interleukin-2 in the biotherapy of cancer. 268 10

The prognosis of malignant melanoma (MM) depends on the level of invasion, vertical tumour size, location of the primary, clinical stage, and sex. Whereas MMs are potentially curable in the early stage of disease, the therapeutic possibilities are very limited in advanced and disseminated MM. Most chemotherapeutic agents lack sufficient activity in MM especially with regard to survival. Dacarbazine (DTIC) is the most effective drug in MM with response rates of 20-25% followed by other drugs such as melphalan with 15-20%, hydroxyurea and platin derivates. Multidrug regimens were not shown to be more effective than DTIC alone. Radiotherapy may be relevant in local treatment of metastases. With regard to the poor prognosis and limited therapeutic approaches in advanced and disseminated MM, new strategies are required. In this context immunotherapeutic strategies with biological response modifiers are of interest for adjuvant or palliative approaches. Earlier trials with Bacillus Calmette-Guerin (BCG) +/- DTIC as adjuvant or palliative treatment revealed no effect of BCG on the prognosis. Alpha-interferon (alpha-IFN) was shown to induce remissions in about 15% and gamma-IFN in about 10% of patients. A very interesting new approach is the induction and/or activation of autologous cytotoxic cells by systemic administration of recombinant interleukin-2 (rIL-2) with response rates of 20-25% and the in vivo propagation and transfer of so-called tumour infiltrating lymphocytes. Further trials combining rIL-2 with other cytokines, chemotherapy, tumour vaccination or monoclonals against melanoma cells are required.
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PMID:Malignant melanoma--prognosis and actual treatment strategies with chemotherapy and biological response modifiers. 269 76

Recombinant alpha-2a interferon (IFN alpha-2a; Roferon-A) was administered as adjuvant therapy in 21 patients with malignant melanoma stage IIa or IIb after surgical removal of all detectable metastases. Patients received 9 x 10(6) units of IFN alpha-2a s.c. 3 times weekly over 6 months. One patient was treated over 12 months. Relapses occurred in 5 of the 21 patients during therapy, and 10 patients developed new metastases a few weeks or months after the end of therapy. Of the 15 patients with recurrent disease, 9 have since died. One patient without any relapse died of a myocardial infarction 5 months after the start of therapy. Comparison of the 21 treated patients with an untreated historical matched control group did not show any prolongation of the recurrence-free period in the interferon-treated group.
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PMID:[Adjuvant therapy with recombinant interferon alfa-2a in metastasized malignant melanoma]. 273 1

We conducted a Phase I trial of interferon-alpha-2a (IFN-alpha-2a) plus combination chemotherapy consisting of cyclophosphamide, vincristine, prednisone, and doxorubicin (COPA) in order to determine the maximum dose of IFN-alpha-2a that could be administered without compromising the dose intensity of COPA. Twenty-one patients received IFN-alpha-2a intramuscularly on days 1-5, followed by 600 mg/m2 cyclophosphamide intravenously (i.v.) on day 8; 50 mg/m2 doxorubicin i.v. on day 8; 1.2 mg/m2 vincristine i.v. on day 8; and 100 mg/m2 prednisone orally on days 8-12. IFN doses were escalated between patient groups; 7 patients received 12 x 10(6) U/m2, 11 patients received 6 X 10(6) U/M2, and 3 patients received 12 X 10(6)/m2. Because 79% of the cycles of COPA administered at the third dose level required a delay for hematologic recovery, further patient accrual at this dose level ceased. Grade III or IV granulocytopenia occurred on day 1 in 6, 9, and 0 of the patients treated at the three dose levels. Granulocyte counts rapidly recovered, however, and did not result in a delay in chemotherapy administration on day 8 in 94% of the cycles at the first two dose levels. The mean hematocrit following five cycles of therapy dropped from 40 to 31%. Only two patients required dose reductions due to constitutional symptoms related to the IFN-alpha-2a. Eight responses were observed, including five of five patients with nonHodgkin's lymphomas, one of five with melanoma, one of six with renal cell carcinoma, and one of one with adenoid cystic carcinoma. One patient with metastatic melanoma remains in a complete response on maintenance IFN-alpha-2a for three years. We conclude that 6 X 10(6) U/m2 of IFN-alpha-2a can be administered to cancer patients without significantly compromising the dose intensity of COPA. This observation, and the demonstrated activity of IFN-alpha-2a plus COPA (I-COPA) in low and intermediate grade histology nonHodgkin's lymphomas, provides the basis for the randomized Phase III trial comparing COPA to I-COPA in these neoplasms, which is currently being conducted in the Eastern Cooperative Oncology Group.
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PMID:A phase I trial of interferon-alpha-2a plus cyclophosphamide, vincristine, prednisone, and doxorubicin. 274 97

Nineteen patients with advanced malignant melanoma were treated with a combination of recombinant alfa-interferon (alpha-IFN) and vinblastine (VBL). The alpha-IFN was administered subcutaneously daily at an initial dose of 3 X 10(6) IU escalating to a maximal dose of 9 X 10(6) U daily for the first 10 weeks followed by 3 X/week for 6 months. The VBL was given once every week at a dose of 0.025 mg/kg. Of the 19 patients 17 were evaluable for tumor response. Thirteen patients had received chemotherapy previously. Median performance status (World Health Organization) was 0, ranging from 0 to 2. One complete response and one partial response was observed. All patients experienced flu-like symptoms attributed to alpha-IFN. Leukopenia was observed in 12 patients and a planned dose escalation of VBL was undertaken for the patients only. It is concluded that combined alpha-IFN and VBL is only marginally effective in patients with advanced malignant melanoma who have had prior chemotherapy.
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PMID:Interferon in combination with vinblastine in advanced malignant melanoma. A phase I-II study. 279 Jun 73

The structure-function relationship of several recombinant human alpha interferons (IFN-alpha) (IFN-alpha 1, IFN-alpha 2, IFN-alpha 4, IFN-alpha 7, IFN-alpha 2/alpha 1 and IFN-delta 4 alpha 1) was investigated with respect to their ability to augment natural killer (NK) cytotoxicity of human peripheral blood mononuclear cells (PBMC) against hemopoietic tumor cell lines. Although all these IFNs significantly augmented NK cytotoxicity against the K562, Daudi and U937 targets, significant quantitave differences were observed in their ability to augment NK. INF-alpha 4, IFN-alpha 2 and IFN-alpha 2/alpha 1 were able to augment NK at low concentrations (less than 0.1 ng/ml), whereas IFN-alpha 7, IFN-alpha 1 and IFN-delta 4 alpha 1 required significantly higher concentrations (3 ng/ml or higher). The cumulative rank order of INFs on the basis of NK augmenting ability was found to be: IFN-alpha 4 approximately IFN-alpha 2 approximately IFN-alpha 2/alpha 1 greater than IFN-alpha 7 greater than IFN-alpha 1 approximately IFN-delta 4 alpha 1. To determine synergism or potentiation in the ability of IFNs to augment NK cytotoxicity, we investigated the effect of simultaneous, sequential and reversed order of treatment of human PBMC by these IFNs. Such potentiation or synergism was not observed. In addition, all these IFNs were able to augment NK cytotoxicity against targets from malignant melanoma cell lines. IFN-alpha 7 augmented regularly and reproducibly NK cytotoxicity in 15 of 19 normal donors examined (79%). This augmentation was blocked by an anti-IFN-alpha antibody. Concentrations of IFN-alpha 7 as low as 0.06 ng/ml were able significantly to augment NK cytotoxicity of PBMC after incubation for one hour at 37 degrees C. In contrast to these findings, IFN-alpha J, an interferon similar to IFN-alpha 7, has been report to be incapable of augmenting NK cytotoxicity and also of interfering with augmentation of NK by other IFNs. Sequential treatment of PBMC first with IFN-alpha 7 and then with other interferons did not prevent the augmentation of NK. Similarly, simultaneous treatment with IFN-alpha 7 and other interferons did not prevent augmentation of NK. In both treatments IFN-alpha J has been reported to prevent augmentation of NK. IFN alpha J and IFN-alpha 7 differ only by one amino acid, at position 107, where a lysine in IFN-alpha J has been replaced by a glutamic acid in the IFN-alpha 7.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Regulation of natural killer cytotoxicity by recombinant alpha interferons. Augmentation by IFN-alpha 7, an interferon similar to IFN-alpha J. 281 13

The binding of adrenocorticotropic hormone (ACTH) to B16/C3 murine melanoma cells was found to be specific and saturable. The binding capacity of the cells changed as a function of the age of the culture. Scatchard analysis revealed one class of high-affinity ACTH binding sites. The specificity of ACTH binding to the cells was tested by displacement experiments with human leukocyte interferon (alpha-IFN) and alpha-melanocyte stimulating hormone (alpha-MSH) as the competitors. Structure-activity relationship of ACTH, alpha-MSH and alpha-IFN was discussed.
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PMID:Adrenocorticotropin binding activity of B16/C3 melanoma cells. 285 10

Fifteen patients with metastatic malignant melanoma, including 10 who had not previously received systemic therapy, were treated with recombinant alpha2-interferon (IFN-alpha 2) in a dose of 20 million IU/m2 by 30-min i.v. infusion daily for 5 days each 14 days. Evaluable metastatic sites included lung, subcutaneous tissue, liver, nodes, adrenals, and bone. Subjective toxicity was generally mild to moderate, with fever (38.2-40.2 degrees C), occasional rigors, fatigue, myalgia, headache, and nausea. Objective toxicity included transient neutropenia and elevation of hepatic enzymes, particularly gamma-glutamyl transpeptidase. In 1 of the 10 patients receiving more than one cycle, IFN dosage was reduced because of toxicity, but later reescalated. All patients were evaluated for response. No overall partial or complete responses were observed, but two site responses (lung and subcutaneous tissue) were seen. Median survival from start of IFN treatment was 19 weeks. High doses of IFN were reasonably well tolerated in this study, but the results suggest little activity against malignant melanoma.
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PMID:Phase-II study of recombinant alpha 2-interferon in advanced malignant melanoma. 287 Nov 16

The combination of recombinant human fibroblast interferon (INF-delta) and the antileukemic compound mezerein (MEZ) results in a synergistic suppression in the growth of human melanoma cells and a concomitant increase in melanin synthesis. In the present study we have further analyzed this synergistic interaction and have also evaluated the effect of IFN-delta and MEZ, alone and in combination, on recombinant human gamma interferon (IFN-gamma) binding and Class I HLA and melanoma associated antigen (MAA) expression in the HO-1 human melanoma cell line. Single cell clones isolated from the HO-1 cell line varied in their sensitivity to the antiproliferative effects of IFN-delta and MEZ. With all twelve clones, however, the combination of IFN-delta plus MEZ was more growth inhibitory than either agent used alone, even in HO-1 subclones displaying relative resistance to IFN-delta. By continuous growth in gradually increasing concentrations of IFN-delta, a variant population of HO-1 cells, HO-1 delta R-D, was generated which was more resistant to the antigrowth effects of IFN-delta than the original HO-1 parental cell line. In the IFN delta R-D cell line the combination of IFN-delta plus MEZ synergistically suppressed growth. Exposure of HO-1 cells to 2500 units/ml IFN-delta or 50 ng/ml MEZ for 96 hr resulted in no change or an increase in the binding of labelled IFN-gamma to surface receptors, whereas the combination of IFN-delta plus MEZ increased IFN-gamma binding 2-to-4-fold in HO-1 cells. This increase was the result of an increase in the number of receptors on treated cells coupled with a protection against a decrease in receptors observed for confluent untreated cells. Changes in IFN-gamma binding resulting from treatment with IFN-delta plus MEZ were not associated with alterations in the binding affinity of INF-gamma to its receptor. Changes were also observed in the expression of HLA Class I antigens and MAAs following treatment of HO-1 cells with IFN-delta, MEZ or IFN-delta plus MEZ. IFN-delta and MEZ increased the expression of HLA Class I antigens a 96 kd MAA defined by MoAb CL203, a 100 kd MAA defined by MoAb 376.96 and a 115 kd MAA defined by MoAb 345.134 but decreased the expression of a high molecular weight-melanoma associated antigen (HMW-MAA) defined by MoAb 325.28S.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of recombinant human fibroblast interferon and mezerein on growth, differentiation, immune interferon binding and tumor associated antigen expression in human melanoma cells. 294 74

Human recombinant interferon-alpha A/D (IFN-alpha A/D) is known to be effective on murine cells. We studied the in vivo effects of pure IFN-alpha A/D on murine splenic natural killer (NK) activity and experimentally induced pulmonary metastasis of B16-F10 melanoma. Intraperitoneal injection of IFN-alpha A/D augmented splenic NK activity, and suppressed melanoma metastasis. This suppression was abrogated by pretreatment of mice with anti-asialo GMl, but not with silica or carrageenan, showing that the effect of IFN-alpha A/D was dependent on NK cells. The suppression was strongest when IFN-alpha A/D treatment was given 12 hrs before or at the same time as tumor injection, showing that NK cells are most effective in the early phase of melanoma metastasis.
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PMID:[Antitumor effect of human interferon-alpha A/D in mice (II). Activation of natural killer cells and suppression of metastasis]. 298 56


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