Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Lymphokines, the soluble molecules produced by cells of the immune system, regulate cell-cell interactions and, consequently, the functional status of the immune system. Altering immunoregulatory pathways with lymphokines in vivo may provide a mechanism for controlling a variety of immunologic disorders. Although normally produced in vivo in very small quantities, the widespread availability of recombinant lymphokines has made it possible to study the molecular signals involved in production of lymphocyte effectors with activity against tumor. For example, interleukin-2-based cancer immunotherapy programs have, in certain clinical situations, suggested that immunologic intervention can influence the regression of metastatic cancer. Ultimately the successful application of these biologic agents requires an understanding of the interaction between the immune system and tumor on a molecular level. To induce a given biologic effect, it is necessary both to classify the required lymphokines and to identify the relevant effector cell populations. This review will examine the progress made in identifying the requirements for lymphokine-induced cytotoxic T-lymphocyte function.
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PMID:Approaches to immunotherapy of cancer: characterization of lymphokines as second signals for cytotoxic T-cell generation. 188 70

Colonic ischemia (CI) is a rare complication of high-dose interleukin-2 (IL-2) immunotherapy. This complication occurred in three of 141 patients (2.1%) with metastatic cancer treated with high-dose IL-2 therapy; CI only developed in patients receiving interferon-alpha (IFN) with IL-2 (three of 21, 14%) compared with none of 120 in those patients receiving IL-2 alone (P equals 0.0009). Severe diarrhea (greater than or equal to 7 bowel movements/day) also was significantly more common in patients receiving IFN with IL-2 (six of 21, 29%) than in those receiving IL-2 alone (three of 120, 2.5%, P equals 0.001) and preceded the clinical diagnosis of CI in all three patients. Three of nine patients with severe diarrhea had CI. Hematochezia occurred in four patients, all of whom received IFN with IL-2; three had CI, and the other patient had nonspecific colitis. Differences in vasopressor use did not explain the increased risk of CI in patients receiving IFN; those receiving IFN with IL-2 required phenylephrine less often than patients receiving IL-2 alone (P equals 0.01). The administration of lymphokine-activated killer (LAK) cells had no significant effect on the incidence of CI, severe diarrhea, peritonitis, or vasopressor use; two of three patients with CI, however, had their ischemic episode within 24 hours after the last of three LAK cell infusions. In conclusion, CI is an unusual complication of high-dose IL-2 and IFN immunotherapy. In patients receiving such combination therapy, severe diarrhea is a risk factor for the subsequent occurrence of CI.
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PMID:Colonic ischemia complicating immunotherapy with interleukin-2 and interferon-alpha. 189 54

Adoptive transfer of specifically sensitized lymphoid cells constitutes a potential tool for specific cancer immunotherapy, however, the requirement of syngeneic or autologous specifically reactive cells has limited its use in the treatment of human cancer. In several mouse tumor models, large amounts of lymphokine activated killer (LAK) cells associated with high doses of interleukin 2 (IL-2) are able to mediate the regression of established pulmonary and hepatic metastases. Since LAK cells are more easily generated than specifically sensitized lymphocytes and show broad tumor specificity, this approach has been applied in humans to treat cancer, but the acute toxicity associated with the high doses of IL-2 administered represents an important drawback to its clinical use. The observation that lymphocytes can internalize ricin, a toxic plant protein, and then release it in an active form, capable of destroying other cells, led us to investigate the possibility of using antigen-specific cytotoxic T lymphocytes (CTL) or LAK cells as carriers of toxic substances to the tumor site. In our experimental models we observed that tumor-specific CTL or LAK cells can be used to deliver ricin into the tumor mass and cause temporary tumor growth inhibition.
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PMID:Adoptive immunotherapy of experimental tumors using cytotoxic lymphocytes to carry and deliver toxins. 195 33

Bryostatins are a novel class of protein kinase C activators which were isolated from the marine bryozoan Bugula neritina and found to possess both antineoplastic and immunoenhancing properties. In this report, we examined the relationship between the in vivo and in vitro antineoplastic effects of bryostatin 1. The in vivo antitumor activity of bryostatin 1 was demonstrated in a B16 melanoma pulmonary metastases model, in which treatment of tumor-bearing C57BL/6 mice with 5 days of bryostatin 1 resulted in a significant reduction in of the number of lung nodules (control, 87; bryostatin, 7). There was a clear dose-response effect, with the optimal antimelanoma dose being 100 micrograms/kg/day, but even low doses of bryostatin 1 of 1 micrograms/kg/day resulted in a 53% reduction in the number of metastases. Although bryostatin 1 shares many biological properties with the phorbol esters, parallel treatment with 12-O-tetradecanoyl 13-phorbol acetate was ineffective against B16 melanoma in vivo. Using a clonogenic assay, bryostatin 1 was found to have a direct antiproliferative effect against B16 melanoma. This inhibition occurred at relatively high bryostatin 1 concentrations (10(-6) M), in comparison with a sensitive cell line REH (10(-10) M). Treatment of mice with bryostatin 1 or preincubation of normal spleen cells with bryostatin 1 failed to enhance nonspecific cell-mediated cytotoxicity against B16 melanoma in vitro. Moreover, bryostatin 1 was found to inhibit both natural killer cell activity and interleukin 2 generation of lymphokine-activated killer cells. Thus, a role for an in vivo immune enhancement mechanism as the basis for the antimelanoma activity observed with bryostatin 1 cannot be invoked from these experiments. These findings indicate that bryostatin 1 may act directly on the B16 melanoma pulmonary metastases. The precise mechanism whereby bryostatin exerts its antimelanoma effects remains unclear.
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PMID:Successful treatment of murine melanoma with bryostatin 1. 198 85

Recently, we reported enhanced tumor reduction using recombinant interferon-alpha A/D (IFN) combined with interleukin-2 (IL-2). Similar synergism affecting survival was assessed in treatment of both early and advanced pulmonary metastases. This combination was compared with the current "standard" IL-2 and lymphokine activated killer (LAK) therapy in the treatment of early and advanced pulmonary metastases. C57BL/6 mice injected via tail vein with the weakly immunogenic methylcholanthrene-induced murine fibrosarcoma MCA-106 were treated intraperitoneally with IL-2 (50,000 units b.i.d.), IFN (50,000 units q.d.), LAK (2.5-10 x 10(7)), or various combinations of above. Treatment of both early Day 3 and advanced Day 10 metastases using IL-2/IFN reduced metastases and prolonged survival over both controls and IL-2 alone. It was superior to IFN, LAK, and IFN/LAK. Addition of LAK to IL-2/IFN demonstrated no added benefit. Although no mortality was observed during treatment of Day 3 metastases, treatment of Day 10 advanced pulmonary metastases for 9 days with IL-2/IFN resulted in early deaths (33%) without visible tumor, indicating possible toxicity of treatment. These results show survival benefit of IL-2/IFN over IL-2, IFN, or LAK treatment in the therapy of early and advanced pulmonary metastases, albeit with added toxicity. Its relative simplicity and comparable efficacy to the more complex and costly IL-2/LAK provide important advantages for potential clinical applications.
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PMID:Enhanced survival of IFN-alpha augmented IL-2 therapy of pulmonary metastases: efficacy comparable to interleukin-2 and lymphokine activated killer cells. 198 29

We investigated the effect of beta-cyclodextrin-benzaldehyde (CDBA) on lymphokine-activated killer (LAK) cell activity of spleen cells from normal or RCT(+)H-2(+)-sarcoma-bearing C3H/He mice. CDBA augmented the induction of LAK cytotoxicity in vitro against RCT(+)H-2+ tumor cells by IL-2, whereas the culture with CDBA alone did not. In a LAK cytotoxicity assay in vitro, the augmentative effect of CDBA was strongly exerted against spleen cells originating from 2-week-tumor-bearing mice, rather than those from normal mice or mice that had born tumors for 5 weeks. Such an augmentative effect was not observed against other tumor cells (YAC-1, D-6, Colon-26 and EL-4 cells) non-specifically. When the intravenous adoptive transfer of LAK cells was carried out in the mice, LAK cells from tumor-bearing mice induced by combined culture with interleukin-2 (IL-2) and CDBA markedly inhibited the pulmonary metastases of RCT(+)H-2+ tumor, while neither LAK cells from the same tumor-bearing mice induced by only IL-2 nor those from normal mice inhibited the pulmonary metastasis. The majority of LAK cells induced either by IL-2 plus CDBA or by IL-2 alone were found to be Thy1.2+ and asialoGM1+ cells by flow-cytometric analysis, but no obvious phenotypical difference was observed between them. However, the most significant effect of CDBA might be the maintenance of the Lyt-2+ cell level in the spleen cells from tumor-bearing mice. These results suggested that the costimulation of spleen cells with IL-2 and CDBA might induce cytotoxic T cells specific for syngeneic tumor cells.
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PMID:Augmentation of murine lymphokine-activated killer cell cytotoxicity by beta-cyclodextrin-benzaldehyde. 200 9

We administered 10 (E5) units per kg. interleukin-2, 3 times daily, with or without lymphokine-activated killer cells, to 10 patients with metastatic renal cell carcinoma. All patients had metastases to the lung, and 3 of 5 patients who had previously undergone nephrectomy had metastases to the renal fossa. Of the 9 patients who completed at least 1 course of therapy 3 had complete regression of disease outside the abdomen, including 2 who were rendered disease-free after subsequent cytoreductive surgery (nephrectomy in 1 and resection of the renal fossa recurrence in 1). Viable tumor comprised less than 1% of each surgical specimen. Our results support the view that initial treatment with interleukin-2 immunotherapy, followed by abdominal cytoreductive surgery if the peripheral metastases have regressed, may be preferable to the practice of performing abdominal cytoreductive surgery before administering interleukin-2 immunotherapy for patients with widely metastatic renal cell carcinoma.
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PMID:Interleukin-2 immunotherapy followed by resection of residual renal cell carcinoma. 201 5

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

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

Fourteen patients with metastatic renal cell carcinoma (RCC) were treated by systemic administration of autologous lymphokine-activated killer (LAK) cells and interleukin-2 (IL-2). Pulmonary metastases alone were found in 9 cases, pulmonary and mediastinal nodal metastases in 3, and pulmonary and bone metastases in 2. LAK cells, generated by incubation in 2 units/ml of IL 2 for 3-4 days, were intravenously administered once or twice a week. In addition, beginning on the day of the first LAK cell infusion, 1000 units of IL 2 diluted in normal saline were intravenously infused once or twice a day with occasional supplementation of 1000 units of IL-2 on each day of LAK cell infusion. The total number of LAK cells and total amount of IL-2 administered per patient in this study ranged from 0.8 x 10(10) to 6.9 x 10(10) cells and from 3.3 x 10(4) to 21.4 x 10(4) units, respectively. As toxic effects caused by the infusion of LAK cells, headache, shaking chills, fever and leukocytosis were found in all 14 cases. Side effects possibly induced by IL-2 infusion were tolerable fever, fluid retention (body weight gain of 2-3 kg) and eosinophilia. No objective regression of mediastinal nodal or bone metastases was observed. In regard to lung metastases, however, partial and minor responses were observed in 3 and 2 cases, respectively. One of the 3 patients with a partial response was clinically free of disease after undergoing a thoracotomy for resection of residual lesions, but a brain metastasis was detected 10 months after the thoracotomy. The remaining 2 patients are being closely followed up at present. In 3 of 11 patients who showed a minor response, no change or progressive disease, brain metastases were observed during or after the immunotherapy. Furthermore, we examined the possibility of selection of suitable candidates for this therapy on the basis of the degree of in vitro LAK activity against autologous cultured tumor cells in 6 patients, but there was no significant correlation between in vitro autologous tumor cell lysis by LAK cells and the clinical response to immunotherapy. In conclusion, although a complete response could not be obtained, it can be said that this immunotherapy may be effective against RCC, in particular lung metastases, since a partial response was achieved in 3 of 14 patients. However, it should be taken into consideration that this immunotherapeutic approach may have a risk of increasing the frequency of brain metastases.
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PMID:[Usefulness and limitation of immunotherapy of metastatic renal cell carcinoma with autologous lymphokine-activated killer cells and interleukin 2]. 207 2


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