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)

A retrospective analysis of 35 stage IV HCC (26 IV-A case and 9 IV-B cases) which underwent reduction surgery from 1983 suggested a possibility to extend their survival period by decrease in their tumor-mass and subsequent immunochemotherapy for improvement of their depressed immunity. Their operability depended on the clinical stage of accompanying liver cirrhosis and extent of distant organ metastasis. It is of first importance for reduction surgery to select intrahepatic multiple tumors, slow-growing and not rapidly to induce distant organ metastases, among them. Intrahepatic tumors arising from multicentric origins were found in 42% in IV-A cases but 0% in IV-B. DNA ploidy analysis of the multicentric tumors in 8 cases did not show any clear indication of resectable tumors according to DNA index. The present immunochemotherapy is composed of a continuous infusion of IL2 and intermittent one-shot injections of 10mg ADR to the remnant liver by using subcutaneously implanted pump. In patients who could enhance peripheral NK and LAK activities by the immunotherapy, decreases in intra- and extra- hepatic tumors were observed. The 2 year-survival rate was 49% in IV-A, but only one case who is receiving the immunotherapy is surviving over 2 years in IV-B.
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PMID:[Significance of reduction surgery for stage IV hepatocellular carcinoma (HCC) and postoperative immunochemotherapy for extension of survival period]. 165 92

Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2(IL2), 18 x 10(6) IU/m2/d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC), 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2, 18 x 10(6) IU/m2/d for 5 days alternating with DTIC, 850 mg/m2 IV every 3 weeks, for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventricular tachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with IL2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone.
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PMID:Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study. 187 25

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

Passive, active and adoptive immunotherapy of human cancers and leukemias raise a renewed interest strengthened by the availability of purified biological substances such as IL2, interferon, thymic hormones and by some recent favourable therapeutic results which have demonstrated the possibility of obtaining objective tumor regressions by immunotherapy. Analysis of results of chemotherapy shows that only 8 human cancers and malignant hemopathies are curable at an advanced diffuse stage of disease. These cancers are characterized by the rarity or absence of late metastases (more than 3-4 years after initial diagnosis). Cure may be considered as complete with a high probability if disease free status is maintained for 3 years. This finding suggests the absence of tumor stem cells capable to produce late metastases. Other cancers are not chemocurable at an advanced systemic stage. In most of them late metastases (greater than 4 years after diagnosis) are observed. A model of organization of malignant tumors based on the distinction between primitive tumor stem cells which are rarely or exceptionally in cycle and protected by a specific microenvironment and committed tumor stem cells is proposed. According to this model, only cancers and/or metastases and malignant hemopathies containing but committed tumor stem cells would be chemocurable. Analysis of a trial of adjuvant therapy of breast cancer with poly A: poly U shows the possibility of immunotherapy to prevent the development of late metastases, independently of hormonal status in contrast with standard adjuvant chemotherapy which is only active on early micrometastases in premenopausal women.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:[Tumor stem cells and implications for the immunotherapy of cancer]. 353

This study was performed with the aim of discovering the characteristics and survival of patients with metastatic renal carcinoma who undergo immunotherapy with an Interleukin 2 based regimen. One hundred and eighty-one patients with metastatic renal carcinoma were referred to our institute from October 1987 until August 1991; 129 were treated with Interleukin 2 with or without Interferon alpha in three successive protocols. Fifty-two patients were not treated with immunotherapy due to the exclusion criteria of the protocols. Sixty-four patients with the same disease who had been referred to our institute before the initiation of this programme (1982, 1987) were also analysed as a control group. The main characteristics of the three different cohorts of patients were analysed and compared with univariate statistical tests; the median survival of the patients was calculated and compared. The referral rate increased from 13 a year to 45 a year while the IL2 trials were being conducted. Patients treated with cytokines have a median survival of 18 months after occurrence of metastases, compared to 6 and 8 months, respectively, in excluded patients and the control group. This parameter is of 15 months when the 181 patients, treated with cytokines or not, are considered. The survival of treated vs excluded patients is significantly different (P < 10(-6); so is the survival of the 181 patients recently included when compared to the historical group (P:10(-5). When the 181 recent patients are compared to the historical control group, a number of differences appear in their characteristics, which prevent us from drawing any conclusion about the role of immunotherapy in the improvement of survival observed. This study clearly evidences the selection of the patients receiving immunotherapy and the modification in referrals of a disease induced by a new available therapy. This emphasises the need for prospective studies in this setting.
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PMID:Patients with metastatic renal carcinoma candidate for immunotherapy with cytokines. Analysis of a single institution study on 181 patients. 821 94

IL-2 gene was introduced through retroviral vectors into the highly malignant and poorly immunogenic 3LL-D122 clone. Both high and low D122-IL-2 secretors showed elimination of tumorigenicity in syngeneic immune-competent mice; however, in nude mice only the high IL-2 secretor showed reduced tumorigenicity as compared with parental D122 cells. Also, following intravenous inoculation, only the high IL-2 secretor showed reduced generation of metastases, whereas the low IL-2 secretors were as highly metastatic as parental cells. These results seem to indicate that low levels of IL-2 secreted by tumor cells are sufficient to activate T cells, while higher levels are needed in order to activate non-T-cell effectors. D122-IL-2 secretors induced high levels of anti-tumor CTL, while their sensitivity to the lytic activity of these CTL was similar to the sensitivity of D122 cells, thus indicating that the elevation of immunogenicity of IL-2 secretors was essentially due to the secreted IL-2. In accordance with CTL induction, pre-immunization with IL-2 secretors protected mice against subsequent challenge of parental cells. Moreover, immunization in an "immunotherapy protocol" i.e., vaccination of mice carrying an established tumor of parental D122 cells with inactivated D122-IL2 infectants, almost completely eliminated the generation of lung metastases by D122 cells, thus providing a rationale for the use of IL-2 gene transferred tumor cells as a modality for treatment of metastasis.
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PMID:Anti-metastatic vaccination of tumor-bearing mice with IL-2-gene-inserted tumor cells. 842

Antibody-cytokine fusion proteins combine the unique targeting ability of antibodies with the multifunctional activity of cytokines. Here, we demonstrate the therapeutic efficacy of such constructs for the treatment of hepatic and pulmonary metastases of different melanoma cell lines. Two antibody-interleukin 2 (IL-2) fusion proteins, ch225-IL2 and ch14.18-IL2, constructed by fusion of a synthetic sequence coding for human IL-2 to the carboxyl end of the Cgamma1 gene of the corresponding antibodies, were tested for their therapeutic efficacy against xenografted human melanoma in vivo. Tumor-specific fusion proteins completely inhibited the growth of hepatic and pulmonary metastases in C.B-17 scid/scid mice previously reconstituted with human lymphokine-activated killer cells, whereas treatment with combinations of the corresponding antibodies plus recombinant IL-2 only reduced the tumor load. Even when treatment with fusion proteins was delayed up to 8 days after inoculation of tumor cells, it still resulted in complete eradication of micrometastases that were established at that time point. Selection of tumor cell lines expressing or lacking the targeted antigen of the administered fusion protein proved the specificity of the observed antitumor effect. Biodistribution analysis demonstrated that the tumor-specific fusion protein accumulated not only in subcutaneous tumors but also in lungs and livers affected with micrometastases. Survival times of animals treated with the fusion protein were more than doubled as compared to those treated with the combination of the corresponding antibody plus IL-2. Our data demonstrate that an immunotherapeutic approach using cytokines targeted by antibodies to tumor sites has potent effects against disseminated human melanoma.
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PMID:Eradication of human hepatic and pulmonary melanoma metastases in SCID mice by antibody-interleukin 2 fusion proteins. 861 Jan 4

A major problem in the treatment of solid tumors is the eradication of established, disseminated metastases. Here we describe an effective treatment for established experimental hepatic metastases of human neuroblastoma in C. B.-17 scid/scid mice. This was accomplished with an antibody-cytokine fusion protein, combining the unique targeting ability of antibodies with the multifunctional activity of cytokines. An anti-(ganglioside GD2) antibody (ch14.18) fusion protein with interleukin-2 (ch14.18-IL2), constructed by fusion of a synthetic sequence coding for human interleukin-2 (IL-2) to the carboxyl end of the C-gamma1 gene of chl4.18, was tested for its therapeutic efficacy against xenografted human neuroblastoma in vivo. The ch14.18-IL2 fusion protein markedly inhibited growth of established hepatic metastases in SCID (severe combined immunodeficiency) mice previously reconstituted with human lymphokine-activated killer cells. Animals treated with ch14.18-IL2 showed an absence of macroscopic liver metastasis. In contrast, treatment with combinations of ch14.18 and recombinant IL2 at dose levels equivalent to the fusion protein only reduced the tumour load. Survival times of SCID mice treated with the fusion protein were more than double that of control animals. These results demonstrate that an immunotherapeutic approach using a cytokine targeted by an antibody to tumor sites is highly effective in eradicating the growth of established tumor metastases.
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PMID:Eradication of established hepatic human neuroblastoma metastases in mice with severe combined immunodeficiency by antibody-targeted interleukin-2. 862 May 25

Induction of a T-cell mediated antitumor response is the ultimate goal for tumor immunotherapy. We demonstrate here that antibody-targeted IL2 therapy is effective against established pulmonary and hepatic melanoma metastases in a syngeneic murine tumor model. The effector mechanisms involved in this tumor eradication are not dependent on NK cells, since the therapeutic effect of antibody-IL2 fusion protein was not altered in NK cell-deficient mice. In contrast, T cells are essential for the observed antitumor effect, since therapy with antibody IL2 fusion proteins is unable to induce tumor eradication in T cell-deficient SCID mice. In vivo depletion studies characterized the essential effector cell population further as CD8 + T cells. Such CD8 + T cells, isolated from tumor bearing mice after antibody-directed IL2 therapy, exerted a MHC class I-restricted cytotoxicity against the same tumor in vitro. These data demonstrate the ability of antibody-targeted IL2 delivery to induce a T cell-dependent host immune response that is capable of eradicating established melanoma metastases in clinically relevant organs.
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PMID:T cell-mediated eradication of murine metastatic melanoma induced by targeted interleukin 2 therapy. 864 46

Localized cytokine therapies with recombinant monoclonal antibody-cytokine fusion proteins, designated immunocytokines, have become of increasing interest for tumor immunotherapy, since they direct immunomodulatory cytokines into the tumor microenvironment. To investigate their mechanisms of action in a variety of syngeneic tumor models, recombinant mouse cytokines IL2 and GM-CSF were engineered as fusion proteins to the carboxyl terminus of a chimeric rat/mouse antitransferrin receptor antibody, ch17217 and expressed in stable-transfected Chinese hamster ovary cells. The recombinant immunocytokines were readily purified by affinity chromatography and their binding characteristics were identical to those shown for the ch17217 antibody. The IL2 immunocytokine had an activity similar to recombinant mouse IL2, whereas the GM-CSF immunocytokine had enhanced cytokine activity relative to recombinant mouse GM-CSF. The clearance rates of ch17217 and the GM-CSF and IL2 immunocytokines were relatively similar with elimination phases (t1/2alpha) of 1.8 h and distribution phases (t1/2beta) of 83, 88, and 91 h, respectively. Both immunocytokines demonstrated effective antitumor activity by suppressing the growth of hepatic metastases of mouse neuroblastoma and pulmonary metastases of mouse colon carcinoma in syngeneic A/J and BALB/c mice, respectively. These results indicate that biologically effective IL2 and GM-CSF immunocytokines combine the targeting ability of an antitransferrin receptor monoclonal antibody with the immunomodulatory functions of each cytokine. Because of the universal expression of the transferrin receptor on mouse tumor cell lines, these constructs should prove useful to determine their efficacy in a wide variety of syngeneic mouse tumor models and to perform detailed studies of their modes of action.
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PMID:Recombinant immunocytokines targeting the mouse transferrin receptor: construction and biological activities. 966 50


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