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

Previously we have demonstrated that the in vitro generation of P815-specific anti-tumor cytotoxic T lymphocytes (CTL) was suppressed by splenic suppressor T cells from late tumor-bearing hosts (TBH). Suppression is not caused by in vitro growth of P815 from splenic metastases, since suppression was also seen with spleen cells from late TBH mice bearing a hypoxanthine/aminopterin/thymidine-sensitive subline (PHS-5) of P815 in the presence of HAT. Cyclophosphamide has been shown to inhibit the induction of suppressor cells selectively in a number of immune responses, but evidence that it can inhibit active tumor-induced suppressor T cells is limited. We have found that suppressor T cells already induced by P815 in syngeneic late TBH are sensitive to low doses of cyclophosphamide (50 mg/kg) given 1 day before spleen harvest, but the in vitro CTL response of late TBH spleen cells could not be restored by pretreating the mice with cyclophosphamide, even when exogenous interleukin-2 was added to the cultures. Although 50 mg/kg cyclophosphamide did not inhibit the CTL response of spleen cells from mice immunized with P815 + Corynebacterium parvum, the same dose of cyclophosphamide eliminated the CTL response of spleen cells from early TBH. Interleukin-2 (IL-2) did not overcome this effect of cyclophosphamide, suggesting a direct effect on CTL. "Ultra-low" -dose cyclophosphamide (10 mg/kg) did not adversely effect early TBH CTL but was still able to eliminate suppressor T cell activity from late TBH. Nevertheless, late TBH CTL remained unresponsive after pretreatment of mice with ultra-low-dose cyclophosphamide, even when exogenous IL-2 was added in vitro. CTL precursor frequency analyses demonstrated that cyclophosphamide pretreatment had little or no effect on the numbers of CTL precursors from early TBH. Late TBH CTL precursor cells were not detectable in these studies, with or without suppressor T cell inhibition by cyclophosphamide pretreatment. Thus, it appears that most CTL precursor cells may be lost or irretrievably inactivated in the spleens of late TBH mice.
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PMID:Cyclophosphamide and abrogation of tumor-induced suppressor T cell activity. 213 31

Bacterial sepsis is a frequent complication in patients with cancer who are receiving high doses of interleukin-2. We evaluated the function of neutrophils from such patients to determine whether there was any abnormality in this form of host defense. Before interleukin-2 therapy, neutrophils from 31 patients with metastatic cancer were normal in assays of random migration and chemotaxis. Superoxide production, phagocytosis, secretion of granule proteins, and bactericidal activity were also normal. Neutrophils from the patients near the end of the first course of interleukin-2 had severely impaired chemotaxis in response to a formylated peptide stimulus (mean [+/- SEM], 49.6 +/- 7.4 percent of base line; P less than 0.001). The detect in chemotaxis improved 5 to 10 days after patients completed the first course of interleukin-2 therapy but recurred toward the end of the second course of such therapy (35.3 +/- 6.9 percent of base line; P less than 0.001). The chemotactic response to a second stimulus (zymosan-activated serum) was also abnormal, but random migration, superoxide production, bactericidal activity, and the secretion of neutrophil granule constituents remained normal or increased throughout treatment with interleukin-2. We conclude that patients who receive interleukin-2 immunotherapy acquire an acute, profound, and reversible defect in neutrophil chemotaxis that may contribute to the high morbidity resulting from bacterial infections in these patients.
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PMID:An acquired chemotactic defect in neutrophils from patients receiving interleukin-2 immunotherapy. 238 74

Anti-tumour effector cells were generated through 4 days culture of normal C57BL/6 splenocytes in a medium containing concanavalin A supernatant and then fractionated with Dolichos biflorus lectin (DBA) into DBA+ (agglutinable with DBA) and DBA- (non-agglutinable with DBA) cells. The DBA- cells, infused intravenously into mice together with B16 melanoma cells, or adoptively transferred into mice 3 days after the injection of B16 cells, caused a marked decrease in the number of lung nodules, while the DBA+ cells exerted no effect. On the other hand, the DBA+ cells exhibited higher cytolytic activity in vitro than the DBA- cells in short-term 51Cr-release assays. Then, we analysed the mechanism of the strong anti-tumour activity of DBA- cells in vivo. We found that DBA- cells showed higher response to recombinant interleukin-2 (rIL-2) than DBA+ cells and proliferated very well with a small amount of IL-2. In addition, DBA- cells adhered more strongly to lung endothelial cells than DBA+ cells in response to rIL-1 or rTNF. Furthermore, DBA- cells produced larger amounts of macrophage activating factor (MAF) including IFN-gamma when cultured with B16 melanoma. Taken together, our results show that DBA- cells are effective in reducing experimental pulmonary metastases not only by the direct lytic activity but also by the indirect killing activity through the activated macrophage.
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PMID:Anti-tumour efficacy of mouse spleen cells separated with Dolichos biflorus lectin (DBA) in experimental pulmonary metastasis of B16 melanoma cells. 217 66

We have evaluated the effects of combinations of various cytokines on the reconstitution of natural killer (NK) cell activity and resistance to metastases from B16 melanoma, in lethally irradiated mice transplanted with syngeneic bone marrow. Treatment with some combinations of interleukin-2 (IL-2) and other cytokines (IL-2 + IL-1 + TNF alpha or IL-2 + IL-1 + LT) induced appreciably greater and more rapid augmentation of NK cell regeneration than IL-2 alone, as measured in vitro in the 4-h 51Cr release assay against YAC-1 or in vivo in an assay of lung clearance of 125IUdR-labeled tumor cells. The same treatments also induced significant augmentation of in vivo resistance against pulmonary metastases in C57BL/6 mice injected with B16 melanoma cells. These data indicate that stimulation of NK activity in tumor-bearing bone marrow transplanted recipients may be of value in the control of metastatic disease.
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PMID:In vivo effects of cytokines on development of natural killer cells and antitumor activity in lethally irradiated bone marrow transplanted recipients. 218 Oct 70

Tumor-infiltrating lymphocytes (TILs) comprise a subpopulation of lymphoid cells that infiltrate into growing tumors. These cells can be activated in vitro with recombinant interleukin-2 (rIL-2) to become highly cytotoxic against fresh tumor targets in vitro and against a variety of systemic metastases in vivo. OK-432 is a well-known inducer of NK cells and immune effector T cells. This study was designed to evaluate the effects of OK-432 on (a) the generation and (b) the cytotoxic potential of rIL-2-induced TILs. When TILs obtained from a murine colon adenocarcinoma (the MC-38 tumor) were cultured in complete media supplemented with 100 U of rIL-2/ml and 1.0 microgram of OK-432/ml, the number of TILs generated was greater than that seen with rIL-2 or OK-432 alone (number of TILs on day 15 of culture: 100 U of rIL-2/ml: 268 x 10(5) TILs; 1.0 microgram of OK-432/ml: 30 x 10(5) TILs; 100 U of rIL-2/ml + 1.0 microgram of OK-432/ml: 528 x 10(5) TILs). Higher concentrations of OK-432 had deleterious effects on TIL growth characteristics. TILs generated in 100 U of rIL-2 and 1.0 microgram of OK-432/ml of complete media demonstrated greater tumor lysis compared to rIL-2 alone (% lysis against MCA-102 target; 100 U of rIL-2/ml: 12%; 100 U of rIL-2/ml and 1.0 microgram of OK-432/ml: 50%; effector target ratio 20:1; p less than 0.001). Similar results were seen against the NK-sensitive YAC-1 lymphoma target.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Synergistic actions of picibanil (OK-432) on recombinant interleukin-2 induction of tumor-infiltrating lymphocyte expansion, cytotoxicity, and phenotypic differentiation. 218 Oct 72

It appears that lymph node metastases are more frequent in lung cancer than in other cancers because of impaired defensive mechanisms in the regional lymph nodes. However, little is known about the immunologic function of regional lymph node lymphocytes (RLNL) in patients with lung cancer. We have studied the immunologic properties of RLNL in comparison with peripheral blood lymphocytes (PBL). We measured the natural killer (NK) cell activity of RLNL and PBL in patients with lung cancer and found that the NK activity was significantly more depressed in the RLNL than in the PBL. In contrast, interleukin-2 (IL-2) production was markedly higher in the RLNL than in the PBL. The cytotoxic effect of RLNL in nonmetastatic lymph nodes on target cells (such as K562 cells) or PC-3 and PC-10 cells (NK-resistant, human lung cancer of adenocarcinoma and epidermoid carcinoma, respectively) was significantly enhanced by in vitro incubation with recombinant IL-2 (rIL-2). Furthermore, we clarified that both rIL-2 and OK-432, which is a biologic response modifier and IL-2 inducer as well, augmented the cytotoxicity of RLNL and that these effector cells were lymphokine-activated killer (LAK) cells. The depletion of lymphocyte subsets by pretreatment with specific monoclonal antibody showed that the LAK activity in RLNL was mediated by CD3+ and CD8+ cells, whereas the lymphocyte subsets contributing the LAK activity in PBL were CD3+ and CD16+ cells. It was concluded that a majority of the effector cells in RLNL were LAK cells of the cytotoxic T cell population.
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PMID:Functional character and augmentation of lymphocytes in regional lymph nodes of patients with lung cancer. 222 81

A 68-year-old man with multiple pulmonary metastases from a right renal cell carcinoma was treated with alpha interferon, but there was no improvement. For this reason, alpha interferon was ceased, and daily monotherapy with recombinant interleukin-2 (1,000,000 units/day) was commenced. After 4 months, plain chest x-ray and chest CT revealed complete clearance of the pulmonary metastases. There were no side effects except general fatigue and slight fever. Immunological studies revealed elevation of the leukocyte count (lymphocytes, eosinophils) and enhancement natural killer activity. At 10 months after discontinuation of the drug, recurrence has not been observed. Our case indicates the potential value of interleukin-2 following treatment with alpha interferon.
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PMID:Complete resolution of multiple pulmonary metastases of renal cell carcinoma following intravenous drip infusion of r-interleukin 2: a case report. 223 95

Lymphokine activated killer (LAK) cells were first described by Rosenberg, et al in the early 1980s. In attempting to grow lymphoid cells infiltrating solid tumors, they discovered that such cells, when incubated with the cytokine Interleukin-2 (IL-2), gained the ability to lyse a wide range of auto and allogeneic tumors while sparing normal non-malignant cells. A number of preliminary clinical trials have shown that when LAK cells and IL-2 are infused into patients with end-stage metastatic cancer, impressive tumor regression, and in some cases tumor eradication, can occur, albeit in the face of significant toxicity. Little is understood about how a potential target cell "signals" its malignant character to a LAK cell. Our approach to this problem has been to investigate the role of the absence or modification of certain self antigens which seem to provide LAK cells with a lysis trigger. By manipulating the culture conditions in which the killer cells are grown, we provide evidence that different subsets of LAK cells may lyse different types of tumor targets. These differences may be important in fine-tuning LAK treatment that is more active at the tumor site in vivo and less toxic to patients.
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PMID:Cell surface recognition determinants involved in triggering the lymphokine activated killer cell phenomenon: enhanced killing of modified "anti-self" targets by varying LAK culture conditions. 226 45

Lymphokine-activated killer (LAK) cells are a heterogeneous population of immune effector cells that nonspecifically destroy neoplastic cells but not normal cells. Although parenteral treatment with interleukin-2 (IL-2) alone or a combination of IL-2 and LAK cells reduces tumor load and prolongs survival in mice with pulmonary, peritoneal, or hepatic metastases, the effect of these treatments on brain metastases has not been studied. To determine in an animal model if intracerebral metastases would be protected by the immunologically privileged status of the brain, intracardiac and intravenous injections of 10(5) KHT sarcoma cells were performed in C3H mice to create brain and lung metastases, respectively. The mice were treated with adoptive immunotherapy to determine if efficacy seen in an extracerebral site could be reproduced in the brain, and if histological examination of these brains would reveal a significant degree of lymphocyte infiltration and cytolytic activity. Animals were treated with either parenteral IL-2 (7500 U three times daily on Days 3 to 7 after tumor injection), or IL-2 plus LAK cells (7500 U IL-2 times daily on Days 3 to 7, and 10(8) LAK cells intravenously on Days 3 and 6 after tumor injection), or IL-2 excipient (three times daily on Days 3 to 7 after tumor injection). As compared to control animals, pulmonary metastases on Day 14 after tumor injection were reduced or eliminated in animals treated with either IL-2 or IL-2 plus LAK cells (p less than 0.01). In these same animals, there was no reduction in the number of intracerebral metastases and no evidence of lymphocytic infiltration or cytolytic activity in the brain. This is the first study that reveals an organ-specific resistance to the treatment of metastases with adoptive immunotherapy, and affirms the concern that due to inadequate trafficking of endogenous or exogenous-activated lymphocytes or due to inadequate activation of in situ brain lymphoid precursors, there is no rejection of tumors in the brain. This information suggests that brain metastases in patients with systemic malignancies will not respond to intravenous treatment with LAK cells and IL-2, and that alternative forms of treatment are needed. Furthermore, this modification of a previously existing model of murine brain metastasis provides a method for concurrently evaluating the effectiveness of treatments for intra- and extracranial cancers.
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PMID:Adoptive immunotherapy of intracerebral metastases in mice. 229 69

A 53-year old male with multiple pulmonary metastases from a renal cell carcinoma was treated with high dose recombinant interleukin-2 (rIL-2). rIL-2 was administered intravenously, and the dose was gradually increased to a subsequent daily dosage of 3 x 10(6) units for a total amount of 470 x 10(6) units. After 3 months, plain chest film and chest computerized tomography revealed a remarkable reduction in pulmonary metastases. There were no side effects except general fatigue and fever. Immunological studies revealed an increase in lymphocytes and enhancement of natural killer activity. These results suggested that rIL-2 is effective for pulmonary metastases from renal cell carcinoma.
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PMID:Multiple pulmonary metastases from renal cell carcinoma treated effectively by recombinant interleukin-2. 230 97


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