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)

Congenitally immune-deficient bg/nu/xid (BNX) mice are severely compromised in their ability to mount T-cell, B-cell, and lymphokine-activated killer (LAK) cell responses. Successful engraftment of BNX mice with human hematopoietic stem cells has been demonstrated recently. We have investigated the potential use of BNX mice for studies relating to the biology and immunotherapy of human malignant melanoma. The intravenous injection of fresh single-cell suspensions of human malignant melanomas into mice resulted in widely disseminated disease. Metastatic spread of human melanoma in BNX mice mimicked that observed in patients: eg, there were numerous tumor nodules identified in the subcutaneous tissues as well as in a variety of visceral organs, including spleen, kidneys, thyroid, adrenals, lungs, heart, and brain. BNX mouse lymph nodes were replaced consistently by human malignant melanoma cells. The presence of human tumor cells in these mice was confirmed by histologic analysis and microcytofluorometry analyses using human melanoma-specific monoclonal antibodies (MAbs). Moreover, human melanoma cells passaged in BNX mice remained lysable in vitro by specifically cytolytic, autologous human tumor-infiltrating lymphocytes (TILs). The capacity of fresh human malignant melanoma to disseminate widely in BNX mice may prove valuable not only for study of the biology of metastatic spread but also for studies of the immunotherapy of human melanoma using melanoma-specific MAbs and chemotherapeutic agents, as well as human TILs and LAK cells with or without retrovirus-mediated gene transfer modification.
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PMID:Disseminated human malignant melanoma in congenitally immune-deficient (bg/nu/xid) mice. 199 18

A 42-year-old man developed leptomeningeal carcinomatosis 6 years after treatment of a malignant melanoma. He was treated with two courses of recombinant interleukin-2, administered as a continuous intraventricular infusion (6 X 10E5 U/24 h) during 5 days. During the first day of the first course he also received 5 X 10E9 lymphokine-activated killer cells intraventricularly. This gave rise to a severe elevation of intracranial pressure, with headaches and meningismus. During the second course no LAK cells were administered. This course was tolerated much better. The neurological status did not change during the treatment. Recombinant interleukin-2 levels were maintained at about 300 U/mL during both courses.
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PMID:Treatment of leptomeningeal carcinomatosis with continuous intraventricular infusion of recombinant interleukin-2. 199 55

The chemical properties, pharmacology, immunology, pharmacokinetics, clinical trials, adverse effects, and dosage and administration of recombinant interleukin-2 are reviewed. Recombinant interleukin-2 is an immunomodulating agent that stimulates the proliferation, activation, and differentiation of T and B cells, natural killer cells, and thymocytes. Two recombinant interleukin-2 products, aldesleukin and teceleukin, have been extensively studied. Most clinical experience with recombinant interleukin-2 has involved the treatment of renal cell carcinoma, melanoma, and colorectal cancer with a National Cancer Institute protocol. Patients with renal cell cancer and melanoma, who historically respond poorly to conventional therapy, have responded to therapy with recombinant interleukin-2. Recombinant interleukin-2 has been administered alone and in combination with lymphokine-activated killer cells, tumor-infiltrating lymphocytes, and interferons alfa and beta. In addition, the effect of dosage, administration rate, dosage schedule, route of administration, and cyclophosphamide pretreatment have been investigated. The adverse effects of recombinant interleukin-2 are generally reversible but are frequently severe and dose-related. Dose-limiting adverse effects include hypotension, edema, and renal dysfunction. Since hemodynamic monitoring and supportive care are essential, recombinant interleukin-2 should be administered in a critical-care setting by trained personnel. Recombinant interleukin-2 represents an advance in the therapy of renal cell cancer and melanoma and offers a new approach to the treatment of other refractory or recurrent malignancies.
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PMID:Recombinant interleukin-2: a biological response modifier. 200 33

A functional analysis of tumor-infiltrating lymphocytes (TILs) from renal cell carcinoma (RCC) and malignant melanoma was performed. TILs were expanded in recombinant interleukin-2 (50 U/ml) in Iscoves medium. Phenotypic and functional (cytolytic vs regulatory) analyses were carried out with the fresh and expanded TIL populations after 4 weeks in culture. Only one TIL population from an RCC case (out of six cases studied) was CD8+ and demonstrated MHC class I-restricted tumor-specific cytotoxicity against the autologous RCC target. TIL populations from the other five cases became predominantly CD4+ and they neither killed the respective autologous tumor cells nor killed the NK-sensitive target K-562 cells. When studied for other functions, two CD4+ TIL populations were found to suppress the lymphokine-activated killer cell response by peripheral blood lymphocytes (PBL) in coculture. Of these two, a TIL population from an RCC case (MJ TIL) was used to study the cellular and molecular mechanisms of suppression. The MJ TIL synthesized a supernatant factor that blocked activation of resting PBL as measured by the induction of high-affinity IL-2 receptor (IL-2R) when stimulated by phytohemagglutinin but did not down-regulate the fully expressed IL-2R on activated T cells. The suppression of high-affinity IL-2R induction on T cells did not result from tumor necrosis factor-alpha and beta or from transforming growth factor-beta as these cytokines were not detected in the cell-free supernatant from the MJ TIL culture. The supernatant factor also suppressed IL-2-mediated enhancement of cytotoxicity by natural killer (NK) cells without demonstrating direct toxic effect on the NK cells. Thus, when TIL are used for adoptive immunocytotherapy, it may be useful to fully characterize them functionally, in vitro.
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PMID:Suppression of lymphokine-activated killer cell generation by tumor-infiltrating lymphocytes. 202 93

In patients with metastatic malignant melanoma the distribution patterns of radiolabelled lymphokine-activated killer (LAK) cells were investigated. Peripheral mononuclear cells (PMC) were isolated from six patients. LAK cells were generated by culturing PMC in complete medium containing 1000 U interleukin (IL)-2/ml and labelled with indium 111 before retransfer. We obtained scans at 2.5, 24, 48 or 96 h after injection with a high resolution gamma-camera. Intravenously injected LAK cells distributed to the lungs, liver, spleen and bone marrow. External tumour detection of known lymph node and bone metastases was successful in four. It failed in one patient with a solitary lung metastasis and in another patient with subcutaneous metastases. Our results suggest that LAK cells show tumour homing, providing a direct interaction between tumour and cytotoxic cells. We conclude that PMC seem to retain their ability to migrate after IL-2 stimulation and 111In-labeling. This technique may be helpful for kinetics studies or external detection of metastases in patients with malignant melanoma.
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PMID:Imaging pattern of radiolabelled lymphokine-activated killer cells in patients with metastatic malignant melanoma. 204 69

We conducted a multicenter, phase II trial of continuous-infusion recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells. Patients had advanced cancer, measurable disease, and a good performance level. Treatment included a 5-day continuous infusion of 18 x 10(6) IU/m2/d of rIL-2 followed by 1 day of rest, 4 days of leukapheresis to collect cells for in vitro augmentation of cellular cytotoxicity, and 5 more days of rIL-2 infusion with reinfusion of LAK cells for 3 successive days. Therapy was repeated after 2 weeks. There were 117 patients enrolled: 63% were males, with a median age of 51 years. Eighty-two percent were managed in oncology units, and 18% were in intensive care units. Six patients died within 1 month of initiating therapy. In renal cell carcinoma, the response rate was one of 31 patients (3%), with a median survival of 10.7 months. In melanoma, the response rate was four of 33 patients (12%), with a median survival of 6.1 months. For all other histologies, response rate was three of 53 patients (5%), with a median survival of 7.4 months. All responders were asymptomatic when therapy was initiated. This trial confirms the feasibility of administering continuous rIL-2 and LAK cells outside the intensive care unit environment. Antitumor activity in melanoma was similar to that seen in multicenter trials of bolus rIL-2 and LAK cells. Activity in renal cell cancer was disappointing.
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PMID:Continuous interleukin-2 and lymphokine-activated killer cells for advanced cancer: a National Biotherapy Study Group trial. 204 64

Serum-free supernatants from the human melanoma cell line G361 contain a factor that can potently suppress the generation of tumouricidal lymphokine-activated killer (LAK) cells in response to interleukin-2. To characterise the suppressive factor of tumour origin we performed a number of physicochemical and functional comparisons with another immunosuppressive protein, transforming growth factor beta (TGF beta). The bioactivity of tumour-derived suppressor factor (TDSF), assayed by suppression of LAK cell generation, was unaffected by a reducing agent but lost when denatured with a chaotropic agent. In contrast, TGF beta was inactivated by reduction but not denaturation. TDSF lost bioactivity in conditions of pH less than 4, whereas TGF beta showed no loss of activity. The TDSF moiety has an estimated pI of 4.3 and a molecular mass of 69-87 kDa. This differs from published values of pI 9.5, and 25 kDa molecular mass for TGF beta. Anti-TGF beta antiserum reversed the effects of TGF beta but did not affect the suppression of LAK cell generation caused by TDSF. These findings provide compelling evidence that the TDSF moiety is not TGF beta, and may be a novel immunoregulatory cytokine.
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PMID:Comparison of transforming growth factor beta and a human tumour-derived suppressor factor. 205 65

Thirty-three patients with metastatic melanoma were treated in a phase II study with an intravenous continuous infusion (IVCI) of interleukin-2 (IL2) given with lymphokine-activated killer (LAK) cells. The dose of IL2 was the optimal priming dose for LAK-cell induction, followed by the maximally tolerated LAK-cell dose that could be given by an IVCI schedule as determined by a previous phase I trial. The CI schedule was chosen for evaluation because of a postulated reduction in toxicity with the possibility of administering a more prolonged IL2 infusion and because greater rebound lymphocytosis and LAK-cell generation had been reported using this dose and schedule. The 33 patients were similar in age, performance status, and sites of disease to those treated in previous IL2 trials. All patients were assessable for response and toxicity. One patient (3%) achieved a partial response of 10 months duration. There were no other clinically significant responses. Significant toxicity included hypotension requiring pressors (45%), dyspnea (36%), renal insufficiency (24%), hepatic dysfunction (66%), and cardiac arrhythmias (18%). These toxicities reversed with cessation of the infusion. There were four deaths during the first 30 days of treatment, three from infection (one related to central line, one related to LAK cells, one related to tumor), and one from tumor-related hemorrhage. Toxicity was unexpectedly high and at least comparable to that seen in previous studies using a high-dose IV bolus schedule of IL2. When comparing the IVCI schedule with high-dose bolus IL2 to LAK cells in nonrandomized but sequential studies in patients with advanced melanoma, it appears that CI IL2 is less efficacious.
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PMID:A phase II study of high-dose continuous infusion interleukin-2 with lymphokine-activated killer cells in patients with metastatic melanoma. 206 60

Tumor-infiltrating lymphocytes (TILs) can be grown in vitro in medium containing interleukin-2 (IL-2). In clinical trials at the Surgery Branch of the National Cancer Institute, patients with metastatic malignant melanomas were treated with IL-2 plus the adoptive transfer of autologous TILs. At the time of treatment, TILs were assayed for in vitro lysis of fresh autologous and allogeneic melanoma cells and Daudi cells. Patients were evaluated for clinical response 4-8 weeks later. Lysis of autologous tumor cells by TILs was significantly higher for responding than for nonresponding patients. Tumor cells from responding and nonresponding patients were equally sensitive to lysis by allogeneic lymphokine-activated killer (LAK) cells. There was no difference between TILs from responding and nonresponding patients for lysis of LAK-sensitive Daudi cells, which was low in most cases and demonstrated that TIL lysis of autologous tumor cells was not due to LAK cells. The observed association of autologous tumor cell lysis by TILs with clinical response suggests that the development of culture methods to optimize lysis of autologous tumors may lead to increased response rates using this TIL treatment regimen.
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PMID:Lysis of autologous melanoma cells by tumor-infiltrating lymphocytes: association with clinical response. 206 36

A murine model of pulmonary B16 melanoma was used to study the infiltration into metastases of lymphokine-activated killer (LAK) cells and adherent lymphokine-activated killer (A-LAK) cells and, specifically, to study whether A-LAK cells are able to leave the tumor microcirculation and establish cell-to-cell contact with malignant cells. Fluorescence microscopy demonstrated that A-LAK cells accumulated in metastases twice as efficiently as LAK cells during interleukin-2 stimulation. Electron microscopy of pulmonary metastases 16 hours after administration of 2.5 x 10(7) A-LAK cells revealed A-LAK cells, identified by the presence of typical two-compartment granules, in direct contact with melanoma cells. This finding was confirmed by using A-LAK cells prelabeled with polycationized ferritin. In conclusion, our observations demonstrate unambiguously the ability of adoptively transferred A-LAK cells to establish contact with extravascular metastatic melanoma cells.
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PMID:Establishment of cell-to-cell contact by adoptively transferred adherent lymphokine-activated killer cells with metastatic murine melanoma cells. 206 37


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