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Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The role of cytokines as primary or adjuvant antineoplastic agents has been well established. Interleukin-2 (IL-2) and the interferons have, particularly, proven to be effective antitumor agents when given alone, and seem to act synergistically on the eradication of metastases from immunogenic tumors. Active specific immunotherapy, in the form of viral oncolysates, has also shown effectiveness in cancer therapy. Bearing this in mind, we decided to combine these agents in an adjuvant triple regimen and compare their effectiveness to other treatments in terms of tumor burden and survival in a murine colon cancer hepatic metastases model. BALB/c mice were injected with CC-36, a weakly immunogenic murine colon adenocarcinoma, intrasplenically, to produce artificial liver metastases. The animals were divided into one control group and seven treatment groups receiving either vaccinia colon oncolysate (VCO), IL-2, interferon-alpha (IFN alpha) alone, or combinations of these agents. Half the animals were followed for survival and the other half were sacrificed at the end of the experiment for quantification of tumor burden. The blood of the sacrificed animals was utilized in a series of immunological tests in order to demonstrate the cytolytic potential of the peripheral blood lymphocytes (PBL) in each treatment group, as well as to characterize phenotypically the cells acting as effectors. The triple-adjuvant regimen group was by far the most effective treatment group, demonstrating 100% survival and a significant reduction in tumor burden when compared to other groups. Furthermore, the PBL from the animals in this group showed 69.4% lysis of the CC-36 target cells in vitro. These effector lymphocytes were characterized as ASMG1-/Lyt2.2+ cytolytic lymphocytes. We conclude that these lymphocytes were stimulated by the administration of VCO and further augmented by the immunomodulation of the cytokines given in the triple regimen, and that such a regimen might prove beneficial in the treatment of established hepatic metastases from weakly immunogenic tumors.
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PMID:Active specific immunotherapy with vaccinia colon oncolysate enhances the immunomodulatory and antitumor effects of interleukin-2 and interferon alpha in a murine hepatic metastasis model. 237 48

We have previously shown that interleukin 2 (IL-2) synergizes with interferon alpha (IFN-alpha) in mediating the regression of established pulmonary and hepatic metastases and the reduction of intradermal tumor in various murine tumor models. To understand the mechanism of synergy, we have examined lymphoid cell proliferation in various organs of mice in response to IL-2 and IFN-alpha administration. We have utilized a technique for labeling newly synthesized DNA in vivo with 5-[125I]iodo-2'-deoxyuridine to examine proliferation of endogenous cells in response to IL-2 and IL-2 plus IFN-alpha. A proliferation index was calculated by dividing cpm in the tissues treated with cytokines by cpm obtained in corresponding tissues of control mice. After 4 days of IL-2 administration, a significant uptake of 5-[125I]iodo-2'-deoxyuridine was observed in the lungs, liver, kidneys, and spleen (proliferation index of 13, 10.3, 3.6, and 3.2, respectively). IFN-alpha alone mediated very little incorporation of radiolabel but when administered in combination with IL-2 a reduction of IL-2-induced proliferation was seen on day 4. For example 19,272 +/- 4,556 cpm (mean +/- SE) were obtained in the liver of IL-2-treated mice, compared to 8,103 +/- 2,111 cpm in livers of IL-2 plus IFN-alpha-treated mice (P less than 0.05). Similar inhibition of IL-2-induced proliferation was observed in the lungs, kidneys, and spleen. In contrast, on days 7 or 8, higher uptake of radiolabel was obtained in IFN-alpha plus IL-2-treated lungs, liver, and kidneys, compared to organs of mice treated with IL-2 alone or IFN-alpha alone. A proliferation index of 30.5, 9.8, and 10 was obtained in the lungs, liver, and kidneys of IL-2- plus IFN-alpha-treated animals, compared to 9.6, 3.6, and 5.5 in the corresponding organs of IL-2-treated mice. The effects of IFN-alpha on IL-2-induced proliferation was dose dependent; very low dosages of IFN-alpha (1,000 units/dose) were able to cause the inhibition of proliferation at 3 days of therapy and increase at 7 days of therapy. Continued proliferation of cells was observed in most organs when IL-2 plus IFN-alpha was injected for 9 consecutive days. Pretreatment irradiation of mice at 500 rad largely eliminated the proliferative response to IL-2 as well as to IFN-alpha plus IL-2 at both 3 and 7 days. Histological studies of lungs receiving cytokine therapy for 3 and 7 days corroborated the results of the 5-[125I]iodo-2'-deoxyuridine incorporation assay. At day 3 a significant infiltration of lymphoid cells was seen in IL-2-treated lungs, whereas little or no lymphocytic infiltration was observed in IL-2- plus IFN-alpha-treated lungs.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:In vivo administration of interferon alpha and interleukin 2 induces proliferation of lymphoid cells in the organs of mice. 238 60

DBA/2 mice were injected i.v. with IFN alpha/beta-resistant 3CI8 Friend erythroleukemia cells (FLC) which metastasize to the liver and spleen. IFN alpha/beta treatment of FLC-injected mice increased their survival time and these mice developed a resistance to a second challenge with FLC. The efficacy of IFN alpha/beta in increasing the survival time was compared between normal immunocompetent and immunodeficient mice. The anti-tumor action of IFN was markedly reduced or abolished in newborn DBA/2 mice, in adult athymic nu/nu and beige DBA/2 mice, and in BALB/c scid/scid mice. To determine the phenotype of the effector cells involved, FLC-injected DBA/2 mice were treated with antibodies to asialo-GMI, CD4, or CD8 antigens, or with cyclosporin A or silica. IFN alpha/beta treatment proved much less effective in these mice, indicating that a variety of effector cell types participated in the IFN-induced suppression of visceral metastases. Thus, an intact immune system appears to be essential to obtain optimal therapeutic effects of IFN alpha/beta in this experimental model.
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PMID:Anti-tumor effects of interferon in mice injected with interferon-sensitive and interferon-resistant Friend erythroleukemia cells. VIII. Role of the immune system in the inhibition of visceral metastases. 239 14

The effects of treatment of human lung carcinoma cell line A 549 with recombinant DNA-derived human leukocyte interferons A (rIFN-alpha A) or D (rIFN-alpha D), and human lymphoblastoid interferon (Wellferon) on in vitro cell invasion were investigated in a quantitative invasion assay using human amnion. The A 549 cells treated with IFN for one day were incubated on the denuded basement membrane of the amnion in the absence of IFN, and cells which penetrated the full thickness of the connective tissue barrier were measured after 4 days. A dose-dependent inhibition of cell invasion was produced by the recombinant IFNs. The one day treatment of cells with 2.4 X 10(3) to 1.8 X 10(4) units/ml of rIFN-alpha A resulted in a 60-80 per cent inhibition of invasiveness compared to untreated cells. After a one day exposure of cells to 2.2 X 10(4) units/ml of rIFN-alpha D, cell invasion was reduced by approximately 70 per cent; a concentration of 4.4 X 10(3) units/ml had no apparent effect. Similar treatment with lymphoblastoid IFN (6 X 10(4) units/ml) had no significant effect on cell invasion. Accompanying the one day exposure to rIFN-alpha A (1.8 X 10(4) units/ml) or rIFN-alpha D (2.2 X 10(4) units/ml), (2',5') oligo (A) synthetase activity was induced approximately 20-fold; a 4-fold induction of enzyme activity was found in cells exposed to lymphoblastoid IFN (6 X 10(4) units/ml). After exposure of A 549 cells to the three IFNs at these concentrations, no significant alteration of the ability of the cells to attach to the basement membrane was found. Moreover, none of the one day IFN treatment regimens were cytocidal, and cell proliferation ability was not affected. This model system may be useful for investigating anti-invasive activity of other IFN types and subtypes.
Clin Exp Metastasis
PMID:Treatment with human recombinant leukocyte interferons inhibits in vitro invasive ability of human lung carcinoma cells. 242 70

The functional properties of the melanoma-associated antigens detected by monoclonal antibodies (MAbs) AMF-6 and AMF-7 were investigated. These MAbs were selected previously because of their capacity to block the anti-melanoma reactivity of cytotoxic T-lymphocyte clones AMF-6 and AMF-7 detect a melanoma-associated proteoglycan (MW greater than 450-250 kDa) and a molecular complex, which under reducing conditions consists of 4 compounds of 120, 95, 29 and 25 kDa respectively. AMF-6 reacted strongly with all 30 cultured melanomas and all 41 melanomas in frozen tissue sections. Significant cross-reactivity was only observed with nevi and perineurium, whereas normal skin melanocytes were negative. AMF-7 reacted with all 25 cultured melanomas and all 34 melanomas in frozen sections. AMF-7 cross-reacted with a proportion of nevi and endothelial cells from small vessels. The antigen detected by AMF-6 and AMF-7 could not be modulated by retinoic acid or recombinant gamma-IFN, which induced or enhanced the expression of HLA-DR, HLA-DQ and Class-I MHC antigens. In addition, the antigens were not readily modulated when cells were incubated in excess amounts of AMF-6 and AMF-7. Interestingly, the antigen detected by AMF-7 was strongly associated with the adhesion and cytoplasmic spreading of melanoma cells to plastic surfaces and monolayers of vascular endothelial cells. AMF-6 did not block the adhesion of melanoma cells but delayed cytoplasmic spreading. Both AMF-6 and AMF-7 blocked fibronectin-induced chemotaxic motility and chemokinesis of melanoma cells. In addition to their membrane localization, the antigens detected by AMF-6 and AMF-7 were also abundant in extracellular adhesion plaques deposited by cultured melanoma cells. Our results indicate that the high-MW melanoma-associated proteoglycan and the antigen detected by AMF-7 are associated with adhesion and/or cytoplasmic spreading and motility of human melanoma cells, suggesting that these antigens are associated with the (hematogenic) dissemination of human melanoma. This is supported by the finding that AMF-7 stained primary tumors heterogeneously, whereas metastases were homogeneously stained.
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PMID:Characterization of melanoma-associated surface antigens involved in the adhesion and motility of human melanoma cells. 242 58

Therapy with human lymphoblastoid interferon HuIFN-alpha(N1), or recombinant human interferon gamma, rHuIFN-gamma, inhibited experimental pulmonary metastases of the human melanoma cell line, DX3-azac, in BALB/c nude mice and significantly prolonged survival. The human IFNs had no effect on nude mouse lung and spleen NK cell activity, lung macrophage activity, haemoglobin or white cell counts. HuIFN-alpha(N1) had no effect on the levels of the IFN induced enzyme 2-5A synthetase in nude mouse lungs although the rHuIFN-gamma caused some elevation. In addition, clearance of radiolabelled DX3-azac cells was identical in control or human IFN treated mice, and there was no histological evidence of an increase in immune effector cells associated with the metastatic lesions in treated mice. Human IFN therapy did not affect the state of differentiation of the melanoma cells in vivo as measured by melanin content, but both IFNs inhibited the development of colonies of DX3-azac cells in vitro. We conclude that in this model system IFNs have direct anti-proliferative effects on metastatic cells.
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PMID:Human interferons inhibit experimental metastases of a human melanoma cell line in nude mice. 246 Jan 19

The investigational drug flavone acetic acid (FAA) has been previously shown to systemically augment NK activity in vivo in normal mice within 24 h of i.p. or i.v. administration. The current study investigates the ability of FAA, and/or rIL-2, to augment NK activity and antitumor responses in mice bearing murine renal cancer (Renca). The results demonstrate that FAA potently augments NK activity in the blood, spleen, and liver of Renca-bearing mice and that the administration of rIL-2 in addition to FAA results in a further augmentation of NK activity over that observed with FAA alone. Renca-bearing mice treated with FAA (200 to 250 mg/kg) plus rIL-2 exhibited a significantly increased incidence of long term survivors (59%) over that observed following treatment with FAA (0%) or rIL-2 (5%) alone. Therapeutic synergy between FAA and rIL-2 was observed against primary tumors, minimal residual disease, and experimental-induced pulmonary metastases. Mice cured of Renca by FAA plus rIL-2 treatment were largely resistant to rechallenge with Renca suggesting a role for T lymphocytes. The augmentation of NK activity and the therapeutic effects of FAA coincided with the rapid induction of high titers of serum IFN of the alpha/beta type within 4 h of FAA administration. Subsequent studies demonstrated that the contribution of FAA could be partially replaced by the administration of several doses of human rIFN-alpha A/D Bg1 before the initiation of rIL-2 administration. The observed synergistic antitumor effects of FAA plus rIL-2 coincided with the augmentation of NK activity, induction of IFN-alpha/beta, and induction of long lasting tumor immunity. Overall, these results suggest that this approach may obviate the need for adoptive immunotherapy in association with rIL-2 administration for at least some tumor types.
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PMID:Augmentation of natural killer activity, induction of IFN and development tumor immunity during the successful treatment of established murine renal cancer using flavone acetic acid and IL-2. 246 May 46

IFN proteins are a family of lymphokines with anti-viral effects. Several other effects of IFNs have also been described, including enhancement of natural killer (NK) cell activity, enhancement of cytotoxic T-lymphocyte activity, and enhancement of the expression of major histocompatibility complex (MHC) antigens. The latter effects have been characterized as immunomodulatory, whereas the well-known inhibition of growth of malignant cells has been termed anti-proliferative. This review summarizes the current knowledge of the enhancement of MHC products by IFNs. Whereas the basic methodologies for demonstrating the enhancement are simple and reliable, especially when using flow cytometry (FCM), the biological relevance of this reaction is largely unknown. Based on recent findings, however, we have hypothesized that the above-mentioned diverse effects of IFNs are all - in some way or other - related to the classical anti-viral mechanism. This concept proposes that the MHC-enhancing effect of IFNs is a vital part of the immunological defense against virus infections and an integral part of the anti-viral effects of IFN proteins.
Cancer Metastasis Rev 1988 Nov
PMID:IFN-induced modulation of histocompatibility antigens on human cells. Background, mechanisms and perspectives. 246 42

The toxicity and therapeutic efficacy of the combination of recombinant interferon gamma (rIFN-gamma) and alpha (rIFN-alpha) was investigated in 15 patients with metastatic melanoma. Patients were treated with an escalating dose of rIFN-gamma and a fixed dose of rIFN-alpha administered s.c. 3 times a week. The maximum dose was well tolerated. The median survival time of the patients was 7 months; no clinical remissions were observed. In the majority of cases, expression of HLA class-I and -II antigens on the patients' peripheral blood lymphocytes and monocytes increased markedly during treatment. An increase in HLA-DR expression of peripheral blood T lymphocytes was correlated with a longer survival time. This suggests that activation of T lymphocytes may have a favourable influence on the course of metastatic disease. The in vitro anti-proliferative activity of IFNs on melanoma cell lines isolated from melanoma metastases during treatment of 3 patients was determined. In contrast to the lack of in vivo anti-tumour effect in patients, both rIFN-gamma and rIFN-alpha inhibited DNA synthesis of these melanoma cell lines in vitro, combined IFNs acting synergistically. Anti-proliferative activity observed in vitro occurred at IFN concentrations below the peak serum levels achieved in vivo.
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PMID:In vivo effects of combination treatment with recombinant interferon-gamma and -alpha in metastatic melanoma. 249 52

An integrated therapeutic approach was adopted to treat metastatic renal carcinoma, the reason being: 1) to effect a regression of metastasis that could not be attacked surgically either because of its location or extent; 2) to limit micrometastatic diffusion in patients with N+.0.05 mg/kg Vinblastine was used every three weeks in association with alfa-2A-IFN in a dose of 18 X 10(6) U 3 times a week. Included in this study were twelve patients with renal carcinoma subjected to nephrectomy with lymph nodal metastases and with or without remote M+. Without drawing hasty conclusions, this therapy can be said to have a useful role after correct surgical approach.
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PMID:[Adjuvant therapy with vinblastine and interferon in metastatic renal carcinoma]. 261 74


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