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)

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

NK cells play an important role in fighting tumor metastases. The incidence of metastasis was found to increase in mice with low cytotoxicity of NK cells. In the mice with high cytotoxicity of NK cells, the incidence of metastasis decreased. LAK cells induced by IL2 mediate the regression of established metastases from a variety of tumors. LAK progenitor cells were predominantly found in CD3-CD16+ Leu19+ fraction, a subset that are known to be the NK cells. Thus, NK cell lineage in LAK cells plays an important role for the inhibition of tumor metastases. Cells having NK cell-like phenotype nature, however, also play a key role in the side effects of adoptive immunotherapy involving IL2. In order to decrease adverse side effects during therapy, we are currently testing combination therapy of LAK cells plus IL2, IL2 alone with IFN, TNF, BRM, indomethacin and so on. Overall, augmentation of NK cells is one of the significant therapeutic methods to prevent metastases.
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PMID:[Role of NK cells in lung metastasis immunosurveillance]. 265 17

A case of renal tumor with secondary erythrocytosis and acute occlusion of the left common iliac artery is reported. The patient was a 73-year-old male who complained of right upper abdominal pain. Laboratory investigation at admission revealed erythrocytosis. Radiological examinations including excretory urography, angiography and computed tomographic (CT) scan showed that the hypervascular tumor was related to the right kidney with pulmonary metastases. Transabdominal echography revealed a tumor thrombus in the inferior vena cava. The tumor was not surgically removed, and IFN-alpha (HLBI) at a dose of 3 x 10(6) units was administered intramuscularly for 6 consecutive days every week and UFT at a dose of 3 capsules was given by oral route daily. About two months later, acute occlusion of the left common iliac artery with necrosis of the left toes occurred, and the left lower extremity was amputated. The high haematocrit resulted in an increase of blood viscosity which caused acute arterial occlusive disease. The association between renal tumor and erythrocytosis is discussed.
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PMID:[A case of renal tumor with erythrocytosis]. 266 May 9

We have administered 1039 courses of high-dose interleukin-2 (IL-2) to 652 cancer patients. Five hundred ninety-six patients had metastatic cancer that either had failed standard effective therapies or had disease for which no standard effective therapy existed, and 56 patients were treated in the absence of evaluable disease in the adjuvant setting. IL-2 was administered either alone (155 patients) or in conjunction with activated immune cells such as lymphokine activated killer (LAK) cells (214 patients) or tumor infiltrating lymphocytes (TIL) (66 patients), with other cytokines such as alpha interferon (a-IFN)(128 patients) or tumor necrosis factor (TNF)(38 patients), with monoclonal antibodies (32 patients), or with the chemotherapeutic agent cyclophosphamide (19 patients). Initial results with the treatment of high-dose IL-2 alone or in conjunction with LAK cells have indicated that objective regressions of cancer can be achieved in 20% to 35% of patients with selected advanced metastatic cancers. Although most responses have been seen in patients with metastatic renal cell cancer, melanoma, colorectal cancer, and non-Hodgkin's lymphoma, many histologic types of cancer have not been treated in significant numbers. These regressions can be durable; of 18 patients achieving a complete response, ten have not experienced recurrence at intervals from 18 to 52 months. Although combinations of IL-2 with TNF do not appear to result in increased responses, there is a suggestion in our initial phase I studies that the combination of a-IFN and IL-2 is more effective than the administration of cytokine alone and this combination deserves further study. Similarly the adoptive transfer of TIL in conjunction with IL-2 also appears to be more effective than the use of IL-2 alone. The toxic side effects in patients treated with high-dose IL-2 are presented and include malaise, nausea and vomiting, hypotension, fluid retention, and organ dysfunction. Treatment-related deaths were seen in 1% of all treatment courses and in 1.5% of patients. These studies demonstrate that a purely immunologic manipulation can mediate the regression of advanced cancers in selected patients and may provide a base for the development of practical, effective biologic treatments for some cancer patients.
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PMID:Experience with the use of high-dose interleukin-2 in the treatment of 652 cancer patients. 267 56

We performed an escalating dose study of the combined administration of interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) in 94 patients with metastatic cancer. Patients received alpha-IFN at a dose of 3 x 10(6) U/m2 in conjunction with IL-2 at doses of either 1 x 10(6) U/m2 (six patients), 3 x 10(6) U/m2 (32 patients), or 4.5 x 10(6) U/m2 (26 patients). Thirty patients received alpha-IFN at 6 x 10(6) U/m2 plus IL-2 at 4.5 x 10(6) U/m2. Patients each received cytokine as an intravenous bolus infusion every 8 hours for up to 5 consecutive days and after a 10-day rest received a second cycle of combination cytokines. Of the 91 patients evaluable for response, seven patients had a complete regression of cancer, and 18 had a partial regression. At the four increasing dose levels used in patients with renal cell cancer (35 patients) or melanoma (39 patients), objective responses were seen in 17% (of six patients), 24% (of 25 patients), 38% (of 16 patients), and 41% (of 27 patients), respectively. Of the 25 total responding patients, 16 are still responding 5 to 14 months after treatment. The toxicities associated with the combined administration of IL-2 and alpha-IFN were similar to those expected from each agent alone. There was one treatment-related death in the 94 patients treated in this study. Thus, using increasing doses of the combination of IL-2 and alpha-IFN, it appears that response rates may be related to the doses of the cytokines used, and that at the highest doses of these combination cytokines, response rates may be higher than those for either cytokine alone. A prospective randomized trial comparing the cytokine combinations with each cytokine administered alone is necessary as is the extension of this combination cytokine treatment to patients with other types of solid cancer.
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PMID:Combination therapy with interleukin-2 and alpha-interferon for the treatment of patients with advanced cancer. 268 81

The prognosis of malignant melanoma (MM) depends on the level of invasion, vertical tumour size, location of the primary, clinical stage, and sex. Whereas MMs are potentially curable in the early stage of disease, the therapeutic possibilities are very limited in advanced and disseminated MM. Most chemotherapeutic agents lack sufficient activity in MM especially with regard to survival. Dacarbazine (DTIC) is the most effective drug in MM with response rates of 20-25% followed by other drugs such as melphalan with 15-20%, hydroxyurea and platin derivates. Multidrug regimens were not shown to be more effective than DTIC alone. Radiotherapy may be relevant in local treatment of metastases. With regard to the poor prognosis and limited therapeutic approaches in advanced and disseminated MM, new strategies are required. In this context immunotherapeutic strategies with biological response modifiers are of interest for adjuvant or palliative approaches. Earlier trials with Bacillus Calmette-Guerin (BCG) +/- DTIC as adjuvant or palliative treatment revealed no effect of BCG on the prognosis. Alpha-interferon (alpha-IFN) was shown to induce remissions in about 15% and gamma-IFN in about 10% of patients. A very interesting new approach is the induction and/or activation of autologous cytotoxic cells by systemic administration of recombinant interleukin-2 (rIL-2) with response rates of 20-25% and the in vivo propagation and transfer of so-called tumour infiltrating lymphocytes. Further trials combining rIL-2 with other cytokines, chemotherapy, tumour vaccination or monoclonals against melanoma cells are required.
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PMID:Malignant melanoma--prognosis and actual treatment strategies with chemotherapy and biological response modifiers. 269 76

Recombinant alpha-2a interferon (IFN alpha-2a; Roferon-A) was administered as adjuvant therapy in 21 patients with malignant melanoma stage IIa or IIb after surgical removal of all detectable metastases. Patients received 9 x 10(6) units of IFN alpha-2a s.c. 3 times weekly over 6 months. One patient was treated over 12 months. Relapses occurred in 5 of the 21 patients during therapy, and 10 patients developed new metastases a few weeks or months after the end of therapy. Of the 15 patients with recurrent disease, 9 have since died. One patient without any relapse died of a myocardial infarction 5 months after the start of therapy. Comparison of the 21 treated patients with an untreated historical matched control group did not show any prolongation of the recurrence-free period in the interferon-treated group.
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PMID:[Adjuvant therapy with recombinant interferon alfa-2a in metastasized malignant melanoma]. 273 1

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

In a murine pulmonary metastases model, interleukin-2 (IL-2), a lymphokine capable of expanding all classes of T lymphocytes, synergizes with interferon-alpha (IFN-alpha) to reduce established metastases and prolong survival. We tested whether indomethacin (INDO), which inhibits synthesis of prostaglandin E2 (a potent immunosuppressor), could further augment the antitumor efficacy of these lymphokines. Age-matched C57BL/6 mice bearing pulmonary micrometastases of a weakly immunogenic fibrosarcoma MCA-106 were treated intraperitoneally for 6 consecutive days, starting on day 3 with (1) saline solution, (2) IL-2 (50,000 units twice a day), (3) IFN-alpha A/D (50,000 units per day), and (4) IL-2 and IFN-alpha A/D. Half of each treatment group was given plain water and the rest INDO-treated (14 micrograms/cc) drinking water throughout the duration of the experiment. Pulmonary metastases were enumerated on day 21. IFN or INDO alone had little effect, whereas IL-2 reduced metastases and prolonged survival. All combination treatments, including INDO/IFN, decreased metastases and prolonged survival except INDO/IL-2/IFN in which several early deaths negated any significant survival prolongation. Early mortality (less than 21 days) was seen with IFN/INDO (8.3%), IL-2/IFN (7.7%), and IL-2/IFN/INDO (8.3%) indicating toxicity of these treatments. Spontaneous proliferation of splenocytes from non-tumor-bearing mice treated for 5 days showed that INDO combined with IL-2 or IFN enhanced proliferation measured 3 days after cessation or treatments. A striking reduction in T-cell marker (Thy 1.2+) in groups treated with IL-2/IFN, INDO/IL-2, INDO/IFN, and INDO/IL-2/IFN 3 days after cessation of IL-2 and IFN suggests that a non-T-cell is amplified when INDO is combined with IL-2 or IFN. These results show that INDO can enhance efficacy of IL-2 or IL-2/IFN. Furthermore, INDO/IFN offers an equi-efficacious, albeit similarly toxic, alternative to IL-2 treatment of tumors and may be useful clinically.
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PMID:Indomethacin-enhanced immunotherapy of pulmonary metastases using IL-2 and IFN-alpha. 278 16

The therapeutic potential of rHuIFN-alpha A/D, a hybrid human IFN molecule with equal activity on murine cells, was studied in experimental and spontaneous metastatic models of a murine colon carcinoma COLON 26. rHuIFN-alpha A/D inhibited experimental pulmonary metastases of COLON 26 and prolonged the survival of BALB/c mice. Dose scheduling, survival and tumour-cell clearance studies showed that the first 5 days were critical in the inhibition of pulmonary metastases. However, it is unlikely that lung NK cells were involved in the anti-metastatic effect of rHuIFN-alpha A/D because inhibition of pulmonary metastases and a decrease in radio-labelled tumour-cell survival was seen in BALB/c mice depleted selectively of their NK cells by prior treatment with rabbit antiasialoGMI serum. Although rHuIFN-alpha A/D stimulated NK-cell activity in BALB/c mice, it was ineffective in abrogating the NK suppressant action of rabbit anti-asialoGMI serum on murine lung NK cells. Thus, IFN may mediate its early antimetastatic effect via a mechanism independent of NK-cell stimulation. IFN also inhibited the development of lung metastases from s.c. COLON 26 tumors in normal, NK-depleted and T-cell-deficient mice.
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PMID:Action of recombinant alpha interferon against experimental and spontaneous metastases in a murine model. 291 Aug 26


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