UMLS:C0027627 - FACTA Search

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)

The present studies were undertaken to examine the immunotherapeutic properties of recombinant murine interferon-gamma (rM IFN-gamma), recombinant human tumour necrosis factor (rH TNF), and recombinant human interleukin-2 (rH IL-2) in preclinical metastasis models. It was observed that these cytokines have disparate mechanisms of therapeutic activity as well as different optimal therapeutic protocols. Thus, not only is the dose important to the therapeutic activity of each of the agents; so also is the route of administration, schedule of administration, duration of administration, and sequence of administration. The rM IFN-gamma has a narrow window of activity, with a bell-shaped therapeutic response with a dosage optimum at 50,000 U/animal of rM IFN-gamma administered 3 times per week. In contrast, rH IL-2 has optimal therapeutic activity for the treatment of metastatic disease after i.p. as compared to i.v. administration. This appears to be associated with the serum pharmacokinetics, since longer serum concentrations are achieved following i.p. administration although lower serum levels are also achieved. RH IL-2 has a biphasic dose-response curve for therapeutic activity with optima from 100 to 1000 U/animal and at doses greater than 100,000 U/animal. The lower doses appear to be associated with T cell augmentation whereas the higher doses are associated with NK cell or LAK cell augmentation. RH TNF has therapeutic activity for the treatment of metastatic disease after i.v. but not i.p. administration. High levels of rH TNF are readily detected in the serum following i.v. administration, with a serum half-life of approximately 30 min. In contrast, only minimal serum TNF activity is observed after i.p. administration, suggesting that this may be the origin of the increased therapeutic activity following i.v. administration. Furthermore, rH TNF has additive therapeutic activity when administered in conjunction with suboptimal doses of rM IFN-gamma. Unfortunately, the additive therapeutic activity of rM IFN-gamma and rH TNF is also associated with increased toxicity. However, in preliminary experiments it was found that the b.i.d. administration of aspirin at 25 mg/kg resulted in decreased toxicity. In summary, the recombinant cytokines provide a challenge both preclinically and clinically to the development of optimal therapeutic protocols, and suggest that close attention must be paid to the dose, route, schedule, duration, and sequence of their administration.
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PMID:Preclinical approaches to the treatment of metastatic disease: therapeutic properties of rH TNF, rM IFN-gamma, and rH IL-2. 311 44

The impact of interferon-gamma (IFN) treatment of tumor cells on non-adaptive and adaptive immune defense and its reflection by metastatic spread were evaluated using a weakly metastasizing variant of B16 melanoma (B16-FI). Treatment of B16-FI with IFN resulted in a decrease in binding structures for NK cells and concomitantly in augmented metastasizing capacity. In line with this, activation of NK cells and Mo, which led to reduction of metastatic nodes, was less efficient with IFN-treated B16-FI, while after elimination of non-adaptive immune defense, the number of metastases increased significantly, but irrespective of IFN treatment. On the other hand, IFN-treated B16-FI cells become more prone to killing by cytotoxic T-cells (CTL). This was due to increased lysability by CTL and to increased immunogenicity; i.e., a higher frequency of B16-specific CTL was observed after immunization with IFN-treated than with untreated B16-FI. The reverse phenomenon was observed with anomalous and/or lymphokine-activated killer cells (AK/LAK). The common cause of increased antigenicity and immunogenicity may reside in increased expression of class-I and de novo expression of class-II MHC antigens after IFN treatment. Increased antigenicity and immunogenicity of IFN-treated B16-FI was reflected by significant reduction of metastatic nodes, prolonged survival and increased TD100 in animals immunized with IFN-treated vs. untreated melanoma cells. Comparison of the divergent effects of IFN treatment on B16-FI melanoma cells showed that the benefit of increased antigenicity/immunogenicity clearly outweighed the disadvantage of reduced susceptibility to non-adaptive immune defense.
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PMID:Interferon-gamma treatment of B16 melanoma cells: opposing effects for non-adaptive and adaptive immune defense and its reflection by metastatic spread. 312 3

Treatment of tumor cells with interferon-gamma (IFN) frequently reduces their susceptibility towards NK cells and results in augmented expression of MHC antigens, which may increase immunogenicity of tumor cells. Depending on the relative strength of these opposing effects, i.e. escape from non-adaptive immune defense versus facilitated activation of T-cell-mediated defense, IFN-treatment may be beneficial or disadvantageous for the tumor-bearing host. This is demonstrated for the variants F1 and F10 of the B16 melanoma, which differ in metastasizing capacity. IFN-treatment of B16-F1 melanoma cells significantly reduced susceptibility towards non-adaptive immune defense, and increased metastasizing potential. On the other hand, H2K antigen expression was augmented by a factor of 50; concomitantly, lysability by CTL was increased, together with the number and expansion rate of cytotoxic T-cell precursors (CTLp) recruited after immunization with IFN-treated B16-F1. The benefit of increased antigenicity and immunogenicity outweighed the disadvantage or reduced susceptibility towards non-adaptive immune defense. B16-F10 cells were less susceptible to NK cells, expression of MHC antigens was found to be stronger and they were more immunogenic than B16-F1 cells. After IFN-treatment, susceptibility to non-adaptive immune defense was further reduced. Expression of MHC antigens as well as antigenicity and immunogenicity were only moderately augmented. As a consequence, the decreased susceptibility to non-adaptive immune defense was dominating in the tumor bearing host and could not be counterbalanced by immunization with IFN-treated B16-F10 cells. We interpret these data to show that a precise knowledge of the relative decrease in susceptibility to non-adaptive immune defense, the relative increase in MHC antigen expression, antigenicity and immunogenicity may allow a more precise prognosis of the influence of IFN on metastatic capacity in the B16 system, and eventually also in a clinical therapeutic regimen.
Clin Exp Metastasis
PMID:IFN-treatment of B16-F1 versus B16-F10: relative impact on non-adaptive and T-cell-mediated immune defense in metastatic spread. 313 43

The mechanism of therapeutic activity of recombinant murine interferon-gamma (rMu IFN-gamma) and the IFN inducer polyinosinic-polycytidylic acid solubilized with poly-L-lysine in carboxy methyl cellulose (pICLC) in treating metastatic disease was investigated by comparing effector cell augmentation with therapeutic activity in mice bearing experimental lung metastases (B16-BL6 melanoma). Effector cell functions in spleen, peripheral blood, and lung (the organ with tumor) were tested after 1 and 3 weeks of rMu IFN-gamma or pICLC administration (intravenous, three times a week). In these studies, natural killer (NK), lymphokine-activated killer (LAK), cytolytic T lymphocytes (CTL) (against specific and nonspecific targets), and macrophage tumoricidal and tumoristatic activities were measured. rM IFN-gamma and pICLC had therapeutic activity and immunomodulatory activity in most assays of immune function examined. Specific CTL activity of pulmonary parenchymal mononuclear cells (PPMC), but not in splenocytes or peripheral blood lymphocytes (PBL), during week 3 and not during week 1, correlated with the therapeutic activity of rMu IFN-gamma and of pICLC. Macrophage tumoricidal activity in PPMC, but not in alveolar macrophages, also correlated with the therapeutic activity of rMu IFN-gamma, but the opposite was true for the therapeutic activity of pICLC. NK activity of PPMC, but not of splenocytes or PBL, during week 1 correlated with the therapeutic activity of pICLC; in contrast, NK activity at any site did not correlate with the therapeutic activity of rMu IFN-gamma. LAK activity at any site did not correlate with the therapeutic activity of either agent.
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PMID:Correlation of immunomodulatory and therapeutic activities of interferon and interferon inducers in metastatic disease. 313 67

The combination of the immunomodulator interferon-gamma (IFN-gamma) with the chemotherapeutic drug adriamycin (ADM) was assessed in vitro and in vivo in murine tumor models. When tested in vivo against the murine Lewis lung carcinoma, significantly greater reduction of spontaneous pulmonary metastases was obtained by combination treatment with IFN-gamma, followed 1 day later by ADM. Intraperitoneal ADM treatment also resulted in an increased recruitment of peritoneal mononuclear cells. It is noteworthy that, although the antitumor efficacy was significantly increased by the IFN-gamma/ADM combination treatment, gross toxicity of ADM was not increased. Thus, a net increase in the therapeutic index of ADM was achieved. In vitro, the effects of ADM on the ability of murine peritoneal macrophages, with or without the addition of immunological macrophage activators, to kill tumor cells was studied. Resident macrophages were able to sequester ADM (when present at 10 micrograms/ml) from the medium, and could subsequently mediate killing of target tumor cells. However, incubation of macrophages with low (ineffective by themselves) doses of ADM (1 microgram/ml) prevented their simultaneous or subsequent activation to the tumoricidal state after incubation with the normal macrophage-activating mixture of IFN-gamma plus a muramyl dipeptide (MDP) analog. When the order of addition of reagents was reversed such that the macrophages were preincubated for 24 hr with IFN-gamma (100 U/ml) plus the MDP analog (0.1-10 micrograms/ml), no antagonism of tumoricidal activity was obtained upon subsequent incubation with ADM. There were no interactions between IFN-gamma and ADM on the direct proliferation of tumor cells. Taken together, these results suggest that the enhanced antitumor efficacy of IFN-gamma/ADM combinations in vivo was not due to direct antiproliferative effects on the tumor cells, but rather may be mediated by direct cytotoxicity of ADM on tumor cells enhanced by phagocytic mononuclear cells.
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PMID:Enhanced antitumor efficacy of adriamycin in combination with interferon-gamma: effects on macrophages. 313 73

Twenty patients with advanced malignant melanoma received daily intramuscular recombinant leukocyte A interferon (rIFN-alpha A, Roferon-A, Hoffmann-Laroche, Nutley, NJ) concomitant with recombinant human interferon-gamma (rIFN-gamma Genentech, South San Francisco, CA). During the first week alpha dose was 2 X 10(6) U/m2 and the gamma dose was 0.01 mg/m2 with escalations, if clinically tolerable, during the second week to 5 X 10(6) U/m2 and 0.025 mg/m2, respectively. Twelve patients received the escalated doses; subsequent granulocytopenia and a flu-type illness were severe in four of the 12. We observed one partial response of MRI-documented and biopsy-confirmed osseous metastases for 7+ months. For all study participants, the median time to progression was 1 month with a median survival of 6 months. From the dose and schedule which we utilized, concurrent rIFN-alpha A and rIFN-gamma provided little impact on advanced malignant melanoma.
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PMID:A phase I-II trial of the combination of recombinant leukocyte A interferon and recombinant human interferon-gamma in patients with metastatic malignant melanoma. 314 75

Based upon the in vitro synergistic activity of interferon-beta (IFN-beta) and interferon-gamma (IFN-gamma) observed in melanoma cells, we initiated a Phase II trial using the combination to determine the clinical antitumor efficacy in patients with advanced disease. Fifteen patients with metastatic malignant melanoma were given 2,000 micrograms of recombinant IFN-gamma (rIFN-gamma) (Biogen) intravenously (i.v.) over 10 min, followed by a 10 min i.v. injection of 30 million units of recombinant IFN-beta (rIFN-beta ser) (Triton) 3 x/week. Six patients had skin, soft tissue, nodal, or subcutaneous metastases, 6 had visceral disease only, and 3 had both. Seven patients had received prior treatment, including chemotherapy (6), radiotherapy (3), and/or immunotherapy (3). Side effects included typical IFN constitutional symptoms such as anorexia, fatigue, nausea, and myalgias, but were not dose limiting. The mean drop in the white blood cell count (WBC) following 1 month of therapy, compared to baseline, was 3.3 x 10(3)/mm2 (p = 0.002); the mean increase in SGOT was 24.1 U/l (p less than 0.001). One patient had a dose reduction for Grade III anorexia and fatigue which did not resolve with repeated treatment. One patient with liver metastases had radiographical and clinical stabilization of his disease for 1 year. No responses were seen. The median time to progression was 6 weeks. Two patients' tumors were evaluable in the human tumor colony forming assay (HTCFA) and were markedly sensitive to the antiproliferative effects of IFN combinations. Both patients, however, failed to respond clinically.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phase II trial of a combination of interferon-beta ser and interferon-gamma in patients with advanced malignant melanoma. 314 69

We investigated the antitumor effects of combined immunotherapy with recombinant human interleukin-2 (rhIL-2) and the recombinant human interferon-alpha (rhIFN-alpha) A/D hybrid in the treatment of established single or multiple murine hepatic metastases. Mice bearing either weakly immunogenic MCA-106 or nonimmunogenic MCA-102 were treated with rhIL-2 alone, rhIFN-alpha alone, or the combination of lymphokines. Therapy was initiated on Day 3 or 10 and continued for 3-4 consecutive days. In the treatment of 3- and 10-day multiple MCA-106 liver metastases, significant reductions in the number of metastases, often more than 90%, were observed with the combination of rhIL-2 and rhIFN-alpha at doses of each lymphokine which had no effect when given alone. This decrease in the number of metastases resulted in a survival benefit that was seen in the combination therapy groups in a dose-dependent manner. Similarly, substantial reductions in tumor weight were seen when the combination of rhIL-2 and rhIFN-alpha was administered to mice with single large hepatic metastases. The decreases in both single and multiple metastatic tumor deposits by the combination of lymphokines were more than that predicted by the additive effect of each treatment alone. With the nonimmunogenic tumor, MCA-102, however, no benefit was derived from the addition of rhIFN-alpha to rhIL-2 therapy. Immunotherapy with recombinant murine interferon-gamma and rhIL-2 was directly compared to therapy with rhIL-2 and rhIFN-alpha. The combination of rhIL-2 and rhIFN-alpha again was found to be effective while recombinant murine interferon-gamma added toxicity but no therapeutic benefit to immunotherapy with rhIL-2 alone. The synergy between rhIL-2 and rhIFN-alpha was shown to be dependent on the host's intact immune system since mice immunosuppressed by sublethal irradiation prior to inoculation of tumor did not respond to the combined treatment. Possible mechanisms of the in vivo synergy between rhIL-2 and rhIFN-alpha are discussed.
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PMID:Synergistic antitumor effects of combination immunotherapy with recombinant interleukin-2 and a recombinant hybrid alpha-interferon in the treatment of established murine hepatic metastases. 326 13

Lyt-1+, L3T4a+ autoreactive cloned T cells, producing lymphotoxin (LT) and interferon-gamma (IFN-gamma) in response to self-class II major histocompatibility complex antigen in vitro were examined for their anti-tumor effect in vivo against B16 melanomas. Without the aid of exogenous interleukin 2, the autoreactive T cells, when injected immediately and at an equal cell number into the site of s.c. inoculated B16 melanoma cells inhibited tumor growth in sublethally irradiated and nonirradiated syngeneic mice. The autoreactive T cells also induced regression of tumors established 3 days earlier. Normal spleen cells or class II-restricted cloned T cells specific for chicken gamma-globulin (CGG) had no inhibitory effect on tumor growth. A single injection of autoreactive T cells delayed tumor growth and prolonged the survival of mice that had received a lethal dose of B16 melanoma cells. The autoreactive T cells caused extensive necrosis at the injection site. A treatment regime consisting of two successive injections of anti-I-Ab monoclonal antibody 3JP prevented the inhibition of tumor growth, supporting the hypothesis that the autoreactive T cells inhibited the growth of melanomas by releasing LT and IFN-gamma upon recognition of I-A antigen-bearing cells at the injection site. The CGG-specific control T cells did not cause necrosis and survived within the nests of uninhibited tumor cells. Autoreactive T cells administered i.v. immediately after i.v. injection of B16 melanoma cells markedly reduced pulmonary metastases, whereas CGG-specific T cells did not. These results indicate that autoreactive T cells can function in vivo as inhibitors of tumor growth.
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PMID:Anti-tumor activity of class II MHC antigen-restricted cloned autoreactive T cells. II. Novel immunotherapy of B16 melanomas by local and systemic adoptive transfer. 349 92

Adequate wide excision of a primary cutaneous melanoma is associated with a 10-year cure rate of 85% when the tumor's depth is less than 1.5 mm (American Joint Committee on Cancer [AJCC] Stage I). However, 50% of patients with deep (> 4 mm) primary melanomas, 60-85% of those with regional lymph node metastases (AJCC Stage III), and 95% of those with metastases to distant sites (AJCC Stage IV) will experience recurrence, which is associated with a dismal prognosis. Adjuvant therapy of melanoma assumes that treatment will be more effective when the tumor burden is small. In the 1970s and 1980s, randomized trials tested the efficacy of chemotherapy, nonspecific immunotherapy, levamisole, and regional perfusion therapy in patients with AJCC Stage II and III melanoma. Dacarbazine (DTIC) alone or in combination with other chemotherapeutic drugs or with nonspecific immunotherapy did not significantly improve disease free or overall survival. Of the four levamisole trials, only the study conducted by the National Cancer Institute of Canada revealed a reduction in recurrence and mortality; however, this reduction was not significant by multivariate analysis. The value of regional perfusion therapy following resection of high risk extremity melanomas is currently being determined by multiinstitutional studies conducted by the World Health Organization and the North American Perfusion Group. Multi-institutional trials also are examining the adjuvant role of interferon-alpha in patients with deep (> 3 mm) primary melanomas or positive regional lymph nodes; results should reveal its optimum dose and duration of treatment (3 x 10(6) U for > or = 2 years versus 10 x 10(6) U/m2 for 1 year, subcutaneously 3 times a week) and its impact on survival. A randomized trial of interferon-gamma undertaken by the Southwest Oncology Group was discontinued after interim analysis indicated an adverse effect. Phase II trials indicate that active specific immunotherapy can alter the natural course of AJCC Stage III and IV melanoma following surgical resection of nodal or distant metastases. Upcoming results of Phase III trials will establish the role of active specific immunotherapy for adjuvant treatment of patients with resected AJCC Stage III and IV melanoma.
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PMID:The role of adjuvant therapy in melanoma management. 780 1

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