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)

Human basophils possess receptors for interleukin-2 (IL-2) and IL-4. The effect of 3 days of intravenous administration of IL-2 and/or IL-4 on basophil histamine release was examined in three groups of patients receiving IL-2, IL-4, or the combination of agents as part of a protocol to treat malignant melanoma or renal cell carcinoma. Because all patients received ranitidine for control of side effects, a control group of patients receiving ranitidine for Zollinger-Ellison's syndrome was also studied. IL-4 significantly inhibited IgE-mediated histamine release, while there was a trend for enhancement of IgE-mediated histamine release by IL-2. Administration of the combination of IL-2 and IL-4 did not alter IgE-mediated basophil histamine release. Both IL-2 and IL-4, alone and in combination, enhanced basophil histamine release induced by histamine releasing factors in human nasal washings. The effect of IL-2 alone was significantly greater than that of IL-4 alone or the combination of IL-2 plus IL-4. Taken together, the data suggest that when coadministered, IL-4 may inhibit the effects of IL-2 on basophils. Neither cytokine exerted any effect on basophil histamine release induced by the calcium ionophore A23187, nor did ranitidine cause any effects on histamine release induced by any of the stimulants. Thus, human basophil reactivity can be affected by IL-2 and by IL-4. The role that these two cytokines play in basophil function in vivo is likely to be complex.
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PMID:Effects of in vivo administration of interleukin-2 (IL-2) and IL-4, alone and in combination, on ex vivo human basophil histamine release. 137 88

When lymphocytes from the lymph nodes draining the site of a progressively growing MCA-105 sarcoma are stimulated in vitro with autologous tumor and low-dose interleukin-2 (IL-2), they will grow and develop the ability to lyse autologous tumor cells in vitro; these lymphocytes can also eradicate tumor metastases in vivo. Phorbol esters and calcium ionophores activate signal transduction pathways in T cells and mimic the events triggered by antigen binding. We therefore sought to determine whether large numbers of MCA-105 tumor-specific, therapeutically active T cells could be obtained from MCA-105 draining lymph nodes (DLNs) following a brief exposure to phorbol dibutyrate (PDBu) and ionomycin (Io). DLN cells primarily stimulated with autologous tumor, followed by a secondary stimulation with PDBu-Io and cultured in 20 U/ml IL-2, demonstrated marked expansion of cell numbers during 3 weeks in culture, had moderate cytolytic activity [37% at effector:target ratio (E:T) = 80:1], and were all CD8+ T cells. In contrast, DLN cells stimulated primarily with PDBu-Io and cultured in 20 U/ml IL-2 demonstrated at least 8-10-fold greater growth than antigen-stimulated DLN cells during 3 weeks, were moderately cytolytic (31% at E:T = 80:1), and were a mixed population of CD8+ and CD4+ T lymphocytes. DLN cells that were expanded by either protocol, like cells stimulated repeatedly in vitro with tumor cells, could eliminate MCA-105 pulmonary metastases when given with IL-2 in an adoptive immunotherapy model. DLN cells stimulated primarily with PDBu-Io completely eradicated MCA-105 metastases but had no in vivo antitumor activity against the syngeneic B16 melanoma or MCA-203 sarcoma.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Activation of CD8+ murine T cells from tumor-draining lymph nodes by phorbol dibutyrate plus calcium ionophore. 138 51

Lymphokine production by human melanoma tumor-infiltrating lymphocytes (TIL) was studied. Uncultured TIL produced interferon gamma (IFN gamma), but not interleukin-2 (IL-2) or IL-4, in response to anti-CD3 mAb or IL-2. In bulk cultures, IL-2-activated TIL displaying autologous tumor-specific cytotoxicity (CTL-TIL) produced IFN gamma in culture with medium alone, whereas IL-2-activated noncytotoxic TIL did not. Addition of anti-CD3 mAb or autologous tumor cells up-regulated IFN gamma production in IL-2-activated TIL from 10 of 12 or 6 of 12 cases respectively. Those from 4 of 12 cases (2 CTL-TIL and 2 noncytotoxic TIL) produced IL-2 in culture with medium alone. At the clonal level, 5 (4 CD4+ and 1 CD8+) of 7 autologous tumor-specific CTL clones derived from TIL and 3 (2 CD4+ and 1 CD8+) of 7 noncytotoxic TIL clones produced IFN gamma in culture with medium alone, which was up-regulated by adding anti-CD3 mAb. Two IFN gamma-producing CTL clones tested produced IL-2 in 4x-concentrated supernatants from a 3.5-h culture with medium alone. Furthermore, 2 IFN gamma-producing CTL clones tested expressed mRNA for both IFN gamma and IL-2. IL-2 production and its mRNA expression were up- or down-regulated, respectively, by adding anti-CD3 mAb or autologous tumor cells. IL-4 production was not observed in culture either with medium alone or with IL-2 in any of the cells described above. Anti-CD3 mAb was required for IL-4 production in 3 of 12 IL-2-activated TIL, 2 of 6 CTL clones, and none of 5 noncytotoxic TIL clones. In summary, IFN gamma production was characteristic of melanoma TIL. Some autologous tumor-specific CTL in TIL are suggested to be productive of IL-2 and IFN gamma under unstimulated conditions, both being required for self-activation in an autocrine loop.
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PMID:Lymphokine production by human melanoma tumor-infiltrating lymphocytes. 138 86

Interferon-alpha and dacarbazine combination is a milestone in the treatment of metastatic malignant melanoma. Objective response rate ranged from 3% to 25%. Our phase II study included 34 patients; the overall response was 29.4%. Median time of survival of the responders was significantly longer than that of the nonresponders. Nine of the 34 patients had previously progressed on interleukin-2 (IL-2) and dacarbazine treatment, or had been withdrawn because of unacceptable toxicity. Two patients (22.2%) achieved partial responses. There seemed to be no cross-resistance between the two biologic response modifiers. Successful treatment of melanoma patients by interferon resulted in complete disappearance of all extracerebral lesions, but left the brain vulnerable to involvement by metastases, and was frequently a site of relapse. Brain irradiation is suggested by several investigators to prevent cerebral involvement. Ongoing protocols are an adjuvant treatment for high-risk patients and combination of interferon-alpha, IL-2, dacarbazine and cisplatinum for metastatic melanoma after failure of interferon-dacarbazine regimen.
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PMID:Our experience with interferon alpha: metastatic malignant melanoma. 144 67

Cytokines are important modulators of host antitumor responses. Two of these cytokines, interleukin-2 (IL-2) and interferon gamma (IFN-gamma), are produced after antigen-induced activation of helper lymphocytes. The cytokines are released into the immediate vicinity where they either interact with the appropriate receptors on effector cell populations or are rapidly degraded. To mimic this physiologic release of cytokines at the effector-target site, we used retroviral vectors to transduce melanoma cells with the IL-2 or IFN-gamma cDNA. Five melanoma cell lines were transduced with IL-2- or IFN-gamma-containing vectors and secreted IL-2 at 1 to 40 U/mL/10(6) cells/24 h or IFN-gamma 1 to 8 U/mL/10(6) cells/24 h, respectively. After gamma irradiation, these cells continued to secrete cytokines for about 3 to 4 weeks. Secretion of IFN-gamma induced upregulation of major histocompatibility complex class I molecules in a subset of melanoma cell lines. IL-2 production by human melanoma xenografts induced tumor rejection in BALB/c nu/nu mice, showing the in vivo effect of this cytokine. This study shows that (1) human melanoma cells can be stably transduced with cytokine-containing retroviral vectors; (2) cytokines are secreted constitutively by the transduced tumor cells and have the expected biologic effects in vitro and in vivo; and (3) after gamma irradiation, cytokines continue to be secreted for several weeks. These data suggest that irradiated cytokine-secreting allogenic or autologous tumor cells can be used in vaccination protocols for cancer patients.
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PMID:Retroviral gene transfer induced constitutive expression of interleukin-2 or interferon-gamma in irradiated human melanoma cells. 145 Apr 8

Interleukin-2 is a glycoprotein physiologically produced by human lymphocytes which is capable of mediating some still unknown immunologic reactions. In vitro, interleukin-2 was seen to induce a lytic reaction against tumor cells through the activation of a cytolytic system of natural killer cells. If administered to man in heavy doses, it causes a clinical response in the treatment of metastases from melanoma and renal cell carcinoma in 20-40% of cases. However, the clinical use of the drug, in therapeutic doses, is prevented by the occurrence of several side-effects, the major one being increased permeability of alveolar vessels with capillary leak and interstitial pulmonary edema (Vascular Leak Syndrome in the English literature). Thus, this work was aimed at evaluating chest radiographs during interleukin-2 treatment to detect, in the pulmonary district, the early stages of the vascular leak syndrome--i.e., pulmonary edema, pleural and pericardial effusions. Forty-three patients had been treated for metastases from renal cell carcinoma and melanoma November 1989 through September 1991: standard chest radiographs demonstrated 26 cases (60%) of pulmonary edema, 14 cases (32%) of bilateral pleural effusions and 12 cases (27%) of pericardial effusions. Daily chest films of the patients undergoing interleukin-2 therapy allowed the early stage of the vascular leak syndrome to be depicted, thus enabling the physician to use the highest tolerated doses and eventually to stop infusion before marked respiratory distress develops.
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PMID:[Radiologic characteristics of the thorax during therapy with interleukin-2]. 145 17

Recombinant interleukin-2 (IL-2) produces clinical responses in approximately 20% of adult patients with renal cell carcinoma and melanoma, with both high-dose bolus and continuous infusion regimens. Because of the lower toxicity of continuous infusion, we elected to investigate in a Phase I trial a 5-day continuous infusion repeated for three weeks in children with malignancies refractory to standard therapy. Nineteen children with solid tumors and eight children with hematologic malignancies were entered into the study. The maximum tolerated dose was 3 x 10(6) U/m2/day, with dose-limiting toxicities occurring in five of seven patients treated at the 5 x 10(6) U/m2/day dose level. Dose-limiting toxicities included hypotension, hyperbilirubinemia, thrombocytopenia, pulmonary/pleural effusion, and nephrotoxicity. Serum IL-2 levels were detectable at the higher dose levels and were comparable to those observed in adult patients. Hematologic changes at the higher dose levels included rebound lymphocytosis occurring within 48 h of discontinuation of IL-2, eosinophilia, and decreased platelet counts. No objective responses to therapy were seen. We have identified a dose and schedule of administration for IL-2 in pediatric patients that can be given without intensive care unit support. Pediatric Phase II trials examining the anti-tumor activity of IL-2 given by this schedule are in progress.
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PMID:A phase I study of interleukin-2 in children with cancer. 145 95

Between April 1988 and December 1990, 37 patients with progressive histologically proven metastatic melanoma were treated with interleukin-2 according to three multicentric successive protocols. Eighteen males and 19 females entered the trial. Mean age was 44 years (range 20-66); none of the patients had severe visceral disease or brain metastasis. Superficial and visceral metastatic sites were equally distributed. Interleukin-2 was administered as a 3 to 5 day continuous intravenous infusion, at a dose varying from 16 to 24 million international units/m2/day, as previously described by West. The second course was given after a 9 to 16 day free interval and one to seven courses were administered (mean three courses). A total of 132 courses has been given to the 37 patients. All are evaluable for toxicity and efficacy. Toxicity was tolerable and not different from that presented in recent reports. Only four patients had to definitively stop therapy for toxicity, one of them for cardiotoxicity; a dose modification or a transient suspension of therapy occurred in 18% of treatment cycles. One hypothyroidism with anti-thyroglobulin and anti-microsome antibodies was observed. We observed eight major responses (21.6%), usually of short duration (2-6 months). Most responses occurred in superficial lesions. One patient remains in complete remission, as therapy is stopped for 40 months. Immunological parameters, although demonstrating induced immunostimulation, did not correlate with clinical outcome. With an overall response rate of 21.6%, we confirm the activity of interleukin-2 in melanoma, as previously reported by others.
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PMID:[Treatment of metastatic malignant melanoma with interleukin-2]. 146 1

Chemoresistant melanoma cells are known to be susceptible in vitro to lymphokine activated killer (LAK) cells. To obtain a high LAK/tumour cell ratio in vivo and avoid systemic toxicity due to interleukin-2 (IL-2), we used IL-2 plus LAK cells in the treatment of in transit melanoma metastases of the limbs by isolation perfusion (IP). In vivo immunological modifications induced by this immunotherapeutic approach were also analysed. Six patients previously treated with IP in extracorporeal circulation with tumour cytotoxic drugs and presently relapsing or not responding, were submitted to locoregional adoptive therapy consisting of 5 days systemic administration of IL-2 (Proleukin, EuroCetus) (9-12 x 10(6) IU/m2/day c.i.). Autologous LAK cells were derived from leukapheresis and subsequent in vitro stimulation with IL-2; LAK cells were then given along with IL-2 (120-2400 IU/ml of perfusion priming) to the affected limb by IP. In addition, 7-16 x 10(9) LAK cells were administered by systemic infusion the day after together with IL-2 (9-12 x 10(6) IU/m2/day) by c.i. for 5 days. All patients concluded the treatment without major toxicity. The analysis of circulating lymphocytes obtained from extracorporeal circuit at different times revealed rapid disappearance of LAK cells, suggesting their extravasation and/or endothelial adhesion in perfused tissues. Clinical responses included four partial and one complete response; another patient had stable disease. All patients are presently alive. Follow-up after IP ranges from 8 to 22 months.
Melanoma Res 1992 Nov
PMID:Treatment of recurrent in transit metastases from cutaneous melanoma by isolation perfusion in extracorporeal circulation with interleukin-2 and lymphokine activated killer cells. A pilot study. 149 Jan 14

The aim of this phase I study was to exploit the potential efficacy of an alpha-2a-interferon (alpha-2a-IFN)-subcutaneous interleukin-2 (IL-2) combination, bypassing the toxicity usually associated with bolus or continuous infusion of IL-2. Therefore, nineteen patients with metastatic malignancies (7 melanomas, 6 renal cell carcinomas and 6 soft tissue sarcomas) were treated according to a dose escalating schedule of subcutaneous IL-2 combined with intramuscular alpha-2a-IFN for 5 days/week for 3 consecutive weeks. Cycles were repeated every 2-4 weeks unless disease progressed. Alpha-2a-IFN (3 MU/die) was given continuously, including during the rest weeks. IL-2 doses were started at 2 MIU/day/sqm and the MTD of 6 MIU/day/sqm was progressively reached. The dose of IL-2 was given twice daily every 12 hours. Both of the cytokines were administered in an outpatient setting. The main side effects were fever, chills, fatigue, hypotension, nausea and vomiting. Toxicity was correlated with IL-2 dose level. It was found to be mild at 2 and 4 MIU/day/sqm, while, in contrast, grade III toxicity was observed only at the highest dose of 6 MIU/day/sqm. However, this grade III toxicity was manageable and did not prevent continuation of the treatment as long as the dose was not increased above 6 MIU/day/sqm. Three patients, one with melanoma and two with renal cell carcinomas, obtained clinical partial responses. In eight patients, stable disease, and in the remaining eight, progression, were observed. The data suggest that the combined use of the two BRMs has manageable side effects and would seem to be efficacious. A phase II study at the recommended dose of 6 MIU/day is now necessary.
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PMID:An outpatient phase I study of a subcutaneous interleukin-2 and intramuscular alpha-2a-interferon combination in advanced malignancies. 149 78


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