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)

Tamoxifen, an antiestrogen with efficacy in treatment of both estrogen receptor-positive and negative breast tumors, may be immunomodulatory. We tested tamoxifen's ability to augment the antitumor activity of interleukin-2 (IL-2), a lymphokine capable of expanding and activating lymphocytes, in the treatment of established pulmonary metastases of the weakly immunogenic murine fibrosarcoma MCA-106. Age-matched C57BL/6 female mice bearing pulmonary metastases induced by a tail vein injection of MCA-106 tumor suspension (5 x 10(5) cells/mouse) were treated from days 3 through 12 with intraperitoneal saline solution or IL-2 (50,000 units twice a day). Half of the mice in each group received plain and the remainder received tamoxifen-treated (2 units/ml) drinking water ad libitum for the duration of the experiment. All mice were killed on day 18 for enumeration of pulmonary metastases. Compared with saline-treated control mice, IL-2 and tamoxifen reduced metastases by 66% (p less than 0.0002) and 30% (p less than 0.005), respectively. IL-2 and tamoxifen combined reduced metastases 95% (p less than 0.0002), significantly better than did IL-2 (p less than 0.02) or tamoxifen (p less than 0.0003) alone. In vitro, tamoxifen inhibited proliferation of the weakly estrogen receptor-positive MCA-106 tumor by approximately 30%. Tamoxifen had no effect on the generation of 3-day IL-2-activated lymphocyte cytotoxicity against both natural killer-sensitive (YAC) and natural killer-resistant (MCA-106) target cells. Both YAC and MCA-106 tumor became more resistant to lysis with increased concentration of tamoxifen. This is the first demonstration of in vivo potentiation of IL-2 antitumor activity by tamoxifen and suggests its possible use clinically.
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PMID:Tamoxifen potentiates in vivo antitumor activity of interleukin-2. 238 15

The objective of the present investigation was to evaluate the immunomodulating properties of tetramethylenebisacetamide (N,N' 1-diacetylputrescine, DAP), a known inducer of cellular differentiation. We examined the effect of DAP administration in vivo on splenic and nonadherent peritoneal natural killer (NK) cell activity. A single i.p. injection of DAP (100 mg/kg) enhanced cytolytic activity directed against YAC-1 and MCA-38 tumor target cells 2- to 3-fold. Cytolytic activity peaked 3 days following DAP injection. DAP treatment increased the frequency of asialo-GM1-positive splenocytes to 15% compared with 5% for vehicle treated controls. Furthermore, cytolytic activity could be eliminated by treatment with anti-asialo-GM1 antibodies and complement. Lysis of NK-resistant P815 and EL4 tumor target cells was not observed in leukocytes from DAP-treated mice. DAP treatment of mice given injections i.p. of MCA-38 tumor cells increased survival time of the mice by 37%, curing 10% of the animals of the tumor. DAP treatment of mice given injections intrasplenically of MCA-38 tumor cells reduced both the number and the size of the hepatic metastases. The antitumor effect of DAP in vivo could be eliminated by pretreating mice with anti-asialo-GM1 antibodies or utilizing NK cell deficient beige (bg/bg) mice. These results indicate that the observed anti-tumor activity of DAP is mediated, at least in part, by NK cells.
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PMID:Potentiation of natural killer cell activity and tumor immunity by diacetylputrescine. 238 50

Serum levels of tissue polypeptide antigen (TPA) are related to the proliferative activity and to the mass of the malignancy, differently from any other available tumor marker. We therefore evaluated TPA in comparison with CA15.3 and MCA (mucinous-like carcinoma-associated antigen) in patients with primary breast cancer. TPA was measured in tumor cytosol and in serum. Cytosol and serum TPA levels were not significantly correlated. Serum TPA was higher in patients with locally more advanced disease and in receptor-negative cases. The relation between TPA and disease spread was not directly dependent on tumor bulk, whereas CA15.3 and MCA were highly correlated to the number of positive lymph nodes and tumor size. No correlations were found between TPA and CA15.3 or MCA, and the positivity concordance rate between TPA and CA15.3 or MCA was very low. Patients with higher TPA serum levels showed a worse prognosis in cases with and in those without axillary metastases. From our data we conclude that TPA provides information different from that obtained with breast-specific tumor markers and could therefore be useful in association with CA15.3 and/or MCA in the management of patients with breast cancer.
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PMID:Is tissue polypeptide antigen still a useful tumor marker in breast carcinoma? Comparison with CA15.3 and MCA. 239 65

We have previously established an in vitro sensitization (IVS) procedure with which lymphocytes from tumor-bearing mice could be expanded and sensitized to acquire antitumor reactivity capable of mediating the regression of established pulmonary metastases from the weakly immunogenic MCA 105 murine sarcoma. Culture conditions required for the optimal generation of therapeutic effector cells were evaluated in the current study. Generation of effector cells by IVS required stimulation by intact tumor cells. Tumor cells killed by heat or disrupted by sonication were ineffective, but the antigenicity of tumor cells was not affected by gamma-irradiation. Long term established tumor cell lines could also serve as antigenic stimulator cells albeit with lower efficiency than fresh tumor cells. IL-2 was essential for cellular proliferation during IVS. The concentration of 1000 U/ml of IL-2 also induced nonspecific lymphokine-activated killer (LAK) activity. However, cytotoxic cells were generated during IVS in response to a broad range of IL-2 concentrations. At low IL-2 concentrations (2 to 10 U/ml), IVS cells were generated which displayed little or no LAK activity, had a greater therapeutic efficacy than those generated with high concentrations of IL-2 (100 to 1000 U/ml). Despite having high LAK activity, IVS cells, from cultures where IL-2 was added 3 or more days after initiation, had no therapeutic effect. Thus, the generation of therapeutic cells occurred independently of LAK cell production. Adoptive immunotherapy with IVS cells from MCA 105 tumor-bearing mice demonstrated cross-reactivity with the immunologically distinct MCA 106 but not the nonimmunogenic MCA 102 tumor. In contrast, IVS cells from MCA 106 tumor-bearing mice exhibited specific in vivo reactivity. In vitro cytotoxicity analyses revealed that IVS cells from MCA 105 and MCA 106 tumor-bearing mice were able to lyse both MCA 105 and MCA 106 target cells, but the reactivity toward inoculating tumors was highest. Considering previous findings that the MCA 105 and MCA 106 sarcomas possessed distinct tumor-specific transplantation Ag, the cross-reactivity observed in this study suggests that the immune response during progressive tumor growth may be different from that elicited in response to active immunization.
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PMID:Generation of therapeutic T lymphocytes from tumor-bearing mice by in vitro sensitization. Culture requirements and characterization of immunologic specificity. 245 Sep 25

Interleukin-2 (IL-2) can mediate in vivo tumor regression at high doses. To enhance this efficacy, we studied the effect of adding a human hybrid recombinant interferon alpha A/D (rHuIFN-alpha-A/D) because of its known in vitro augmentation of immune-mediated tumoricidal activity. C56BL/6 mice bearing established pulmonary metastases induced by the iv injection of the methylcholanthrene-induced fibrosarcoma MCA 106 were treated for 12 days with intraperitoneal injections of (1) Hanks' balanced salt solution, (2) recombinant IL-2, (3) rHuIFN-alpha-A/D, and (4) a combination of IL-2 and HuIFN-alpha-A/D. IL-2 and interferon each had some antitumor activity. However, maximal reduction of pulmonary metastases consistently resulted from combining IL-2 with interferon. In two of four experiments, this combination was significantly better compared to either IL-2 or interferon treatment alone. The most potent regimen was 12 days of IL-2 (50,000 units bid) together with rHuIFN-alpha-A/D (50,000 units ip qd). No consistent pattern of proliferative or cytotoxic activity was found against a panel of stimulator and target cells. These results demonstrate enhanced antitumor efficacy of combining recombinant interferon alpha and IL-2 against established pulmonary metastases. Potential clinical applications are suggested by these data.
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PMID:Enhanced in vivo therapy of pulmonary metastases with interferon and interleukin-2. 245 34

Despite adequate locoregional control, colorectal metastasis to the liver remains a significant cause of death. Resection of hepatic metastasis improves five-year survival 18% to 34%. A study of the impact of 40% partial hepatectomy on cytokine production in the liver was undertaken. Nonparenchymal liver cells (NPCs) were prepared by collagenase perfusion and metrizamide gradient from partially hepatectomized and laparotomized control C57BL/6Ros mice. Nonparenchymal cell from partially hepatectomized mice compared with laparotomized mice showed a twofold to threefold increase in interferon (IFN) activity. Both interferon alpha/beta and supernatants from cultured NPCs of partially hepatectomized mice suppressed the proliferation of liver-derived MCA-38 colon adenocarcinoma cells in vitro. This tumor has been shown to metastasize to the liver of C57BL/6Ros mice. The production of various cytokines by NPCs induced by partial hepatectomy may provide a possible antimetastatic mechanism.
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PMID:Partial hepatectomy augments the liver's antitumor response. 246 82

The growth, phenotype, in vitro cytolytic characteristics, and in vivo antitumor activity of murine splenocytes stimulated with anti-murine CD3 mAb in combination with IL-2 as compared with IL-2 alone was investigated. When cultured for 12 days with anti-CD3 mAb + IL-2, murine splenocytes increased 100- to 4000-fold in number compared with only 6- to 20-fold for cultures stimulated with IL-2 alone. Anti-CD3 mAb + IL-2 activated cultures developed high lymphokine-activated killer activity against NK-resistant targets including the P815 mastocytoma cell line and fresh MCA 106 sarcoma. Peak cytotoxicity on a per cell basis developed by day 8 after anti-CD3 mAb + IL-2 activation. A large proportion of the total cytolytic activity of long term anti-CD3 mAb + IL-2-stimulated cultures was related to the presence of anti-CD3 in the assay, indicating enhancement of cytotoxicity by activated CD3+ T cells. Phenotypic analysis indicated that anti-CD3 mAb + IL-2-stimulated cultures contained heterogeneous populations of T cells with increased percentages of both CD4+ and CD8+ phenotypes compared with cultures stimulated with IL-2 alone. Anti-CD3 mAb + IL-2-stimulated cells were tested for their in vivo antitumor activity by using C57BL/6 mice bearing MCA 106 sarcoma pulmonary metastases. IL-2-activated murine killer cells were given in combination with in vivo IL-2 and indomethacin, the latter of which was shown to potentiate the antitumor effect of IL-2. When given on day 5 after tumor inoculation, cell doses as low as 5 x 10(6) anti-CD3 mAb + IL-2-stimulated cells per mouse significantly reduced the number of pulmonary metastases (p less than 0.005). Thus, activation with the combination of anti-CD3 mAb + IL-2 produces rapidly expanding cultures of cytolytic cells with demonstrated in vivo antitumor efficacy.
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PMID:Anti-CD3 + IL-2-stimulated murine killer cells. In vitro generation and in vivo antitumor activity. 252 62

Pulmonary metastases of a weakly immunogenic methylcholanthrene-induced murine fibrosarcoma MCA-106 were treated on day 10 for 10 days with saline, interleukin-2 (IL-2), hybrid recombinant interferon A/D (rIFN A/D) or the combination. IL-2/IFN effected greater than 99% reduction in tumor compared to saline, IL-2 or IFN alone. However, IL-2/IFN also resulted in early (less than 25 days) mortality of 33% in two consecutive experiments. Excluding these early deaths, a significant prolongation of survival resulted in 1 long-term survivor (greater than 150 days). Interruption of the 10-day treatment with a 2-day rest at 5 days abrogated early mortality, but despite significant prolongation of survival, no long-term survivors were seen. These data suggest possible clinical application of IL-2/IFN in the treatment of advanced tumor metastases but cautions of increased treatment toxicity associated with this regimen.
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PMID:Interleukin-2 and alpha interferon therapy of advanced pulmonary metastases. 262 80

The adoptive transfer of sensitized lymphocytes is an effective means to mediate the regression of established tumors. However, successful therapy can only be demonstrated in animal models where tumors are intrinsically immunogenic, capable of eliciting systemic immunity. To explore the potential of this therapeutic approach to tumors of less immunogenicity, we have selected and used a murine tumor, MCA 102, for the current study because all attempts to immunize syngeneic mice failed. We report here that inoculation of mice with a mixture of tumor cells and a bacterial adjuvant, Corynebacterium parvum led to the production of sensitized, but not fully functional, lymphocytes in the draining lymph nodes (LN). These cells, termed pre-effector cells, could nevertheless further differentiate to acquire full immunologic function by an established in vitro sensitization culture method. In adoptive immunotherapy experiments, transfer of as few as 1.5 X 10(7) in vitro sensitized cells not only reduced established pulmonary MCA 102 metastases but also prolonged survival and cured tumors in a majority of the treated animals. In order to elicit pre-effector cells in vivo, inoculation with both tumor cells and C. parvum was essential. Although a broad range of numbers of MCA 102 tumor cells appeared to be effective, generation of pre-effector cells was dependent on the dose of C. parvum. We have found that a C. parvum dose of 25 micrograms was optimal, whereas higher doses of the adjuvant had suppressive effects. Analysis of the kinetics of their appearance revealed that the generation of pre-effector cells was transient. They were detectable 7 days after in vivo priming followed by a rapid decline. Furthermore, pre-effector cells were detected only in the regional draining LN. No reactivity was demonstrable in the spleen, mesenteric LN, PBL, or bone marrow. Taken together, these results expand the scope of immunotherapy by demonstrating the feasibility of manipulating a limited and obscure immune response to the MCA 102 tumor for therapeutic efficacy.
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PMID:Lymphocytes generated by in vivo priming and in vitro sensitization demonstrate therapeutic efficacy against a murine tumor that lacks apparent immunogenicity. 273 8

The administration of interleukin 2 (IL-2) to mice and humans is limited by the induction of a dose-dependent increase in vascular permeability causing a vascular leak syndrome (VLS). We have investigated the impact of the injection of recombinant interleukin 1 alpha (IL-1 alpha) on the VLS induced by IL-2 by measuring the extravasation of 125I-albumin into tissues and by assessing wet and dry lung weights. IL-1 alpha alone did not induce any significant extravasation of radiolabeled albumin. IL-2 alone, however, caused a significant increase in the extravasation compared to control lungs. IL-1 alpha injection along with IL-2 significantly reduced the IL-2-induced extravasation of radiolabeled albumin [9,886 +/- 533 (SEM) cpm were observed in IL-2 and IL-1 alpha-treated lungs compared to 14,172 +/- 2,628 cpm in lungs treated with IL-2 alone (P less than 0.02)]. IFN-alpha in combination with IL-2 produced more severe vascular leakage than caused by IL-2 alone. IL-1 alpha also significantly decreased (P less than 0.05) the vascular permeability induced by the combination of IFN-alpha and IL-2. We observed 44,811 +/- 13,131 cpm in IFN-alpha- and IL-2-treated lungs compared to 18,350 +/- 2,622 cpm in IFN-alpha-, IL-2-, and IL-1 alpha-treated lungs. The IL-2- and IFN-alpha-induced increase in lung water weight was also reduced significantly by the addition of IL-1 alpha. The decrease in vascular leakage was dependent on the dose and timing of IL-1 alpha administered. When recombinant IL-1 alpha was given as a single i.p. injection, 24 h before the injection of IL-2 (or Hanks' balanced salt solution) or IL-2 and IFN-alpha no abrogation of the VLS was observed. Although IL-1 alpha decreased VLS significantly in mice treated with IFN-alpha and IL-2 the survival of mice was not improved by the simultaneous administration of IL-1 alpha. Histologically, treatment with IFN-alpha and IL-2 produced marked perivascular and intraalveolar edema which was completely eliminated by the addition of IL-1 alpha. However, some perivascular edema in IL-1 alpha-treated mice remained which was equivalent to that caused by IL-2 alone. Treatment of MCA-106 induced pulmonary metastases was enhanced by the administration of IFN-alpha and IL-2 together.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Decrease in interleukin 2-induced vascular leakage in the lungs of mice by administration of recombinant interleukin 1 alpha in vivo. 278 61


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