Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: 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)

Prognostic factors were studied in 91 patients with diagnosed renal adenocarcinoma in stages pT1-4/N0-3/V0-2/M0. All patients had been treated with radical surgery, extended nephrectomy with or without cardiopulmonary by-pass and extracorporeal circulation in those cases with suprahepatic tumoral thrombosis. The tumoral features which have a significant incidence on the patient's survival rate are the degree of cellular anaplasia, GI 72% vs GII 42% vs GIII 22% (p less than 0.0001); pathological stage, pT1-2 86% vs pT3 30% (p = 0.0000), perirenal fat invasion, pT1-2 86% vs pT3a 61% (p = 0.01); renal vein or cava vein invasion, V0 72% vs V1-2 30% (p less than 0.01) and gangliar affection. N0 69% vs N1-3 11% (p = 0.0000). Development of systemic disease is significantly high in pT3 stages (p = 0.0001), mainly in pT3a (p = 0.01), N1-3 (p less than 0.05) and/or V1-2 (p = 0.01). There is premature development of metastasis conditioning death before the second year o study in 90% of patients. In our opinion, patients with renal adenocarcinoma in stages pT3a/N0/M0, pT3b/N0/M0 and pT2-4/N1-3/M0 present a high potential risk of developing metastatic disease following radical surgery. These patients, as well as those with high degree tumours and presumably minimum residual disease, are candidates for supplementary therapy with lymphokine immunotherapy (rIL-2,FNT, alpha or gamma IF, etc) with or without adoptive cellular immunotherapy (LAK or TIL) following radical surgery, and extended nephrectomy plus tumoral thrombectomy, if required, with or without cardiopulmonary bypass.
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PMID:[Neoadjuvant immunotherapy in non-metastatic renal adenocarcinoma]. 208 Jul 25

This article reports the results of adjuvant immunotherapy studies carried out in an experimental tumor model system. A transplantable murine BALB/c colonic adenocarcinoma (C-26) was used to evaluate the therapeutic potential of treatment with recombinant interleukin 2 (rIL-2) at high and low dosage in combination with or without lymphokine activated killer cells (LAK) or tumor-specific immune lymphocytes, either as an adjuvant treatment in mice bearing spontaneous post-surgical metastases or in mice bearing artificial metastases. Moreover the in vivo LAK activation and circulation pattern have been examined during or after treatment. These results show that cytotoxic lymphocytes from tumor-immunized donors are more active than LAKs when given in combination with rIL-2 as an adjuvant treatment, while all treatment modalities exerted a strong but generally transient inhibition on the formation of artificial lung metastases by C-26 cells. Alteration of host lymphocyte responsiveness to rIL-2 was shown to occur in early-tumor-resected and large-tumor-bearing animals in both in vitro and in vivo experiments. Moreover, no evidence of homing or preferential localization of the adoptively transferred LAK cells to the site of tumor growth was observed.
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PMID:Adoptive immunotherapeutic treatments with interleukin 2 and lymphocytes in a mouse colonic adenocarcinoma model. 209 4

The in vivo distribution of intravenously injected lymphokine activated killer (LAK) cells, generated in vitro with rIL-2 from normal murine splenocytes, was studied in BALB/c mice and compared with that of normal splenocytes. Both normal splenocytes and LAK cells were labeled with 51Cr, and the results were analyzed at 6, 24, and 48 hours after injection by localization index as the parameter. After injection through tail veins of mice, LAK cells were found to migrate to the spleen, lungs, liver, lymph nodes, bones and the kidneys. The apparent increased distribution pattern of LAK cells to the lung at 6 and 24 hours after injection was not detected when normal splenocytes were injected. Since almost one third of the injected LAK cells were found to localize in the spleen, it was postulated that splenectomy would affect the in vivo organ distribution of LAK cells. Accordingly, the in vivo distribution of LAK cells in splenectomized mice was further investigated. Results indicated that splenectomy enhanced the convergence of LAK cells to the lungs, liver, lymph nodes and bones. Therefore, splenectomy may augment the therapeutic effect of the adoptive transfer of LAK cells in pulmonary, hepatic, lymph node and bony metastases.
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PMID:The in vivo distribution of murine lymphokine activated killer cells in splenectomized host. 210 49

Twenty-six patients with metastatic cancer were entered into a phase I trial of concurrent recombinant interleukin-2 (IL-2) and recombinant interferon-gamma (IFN-gamma). IL-2 was administered as a continuous intravenous infusion for 5 days. IFN-gamma was administered by a daily intramuscular (IM) injection during the 5 days of IL-2 administration. Treatment was repeated twice after 9-day rest periods. After a 2-week rest, patients without evidence of tumor progression were retreated. Natural killer (NK)- and lymphokine-activated killer (LAK)-cell activity were assayed in each patient before treatment, on day 1, and on day 5 of each cycle. Constitutional symptoms occurred in most patients but were not dose-limiting. Other toxicities included hypotension responsive to fluids, transient elevations in liver function tests, erythema/pruritus, eosinophilia, and transient leukopenia/thrombocytopenia. The maximum-tolerated dose (MTD) of the combination was 1 x 10(6) U/m2/d of IL-2 combined with 0.50 mg/m2/d of IFN-gamma. The dose-limiting toxicity was pulmonary manifesting as rales and shortness of breath. The dose of the combination that resulted in the optimal generation of in vivo LAK-cell activity was a dose of at least 0.25 mg/m2/d of IFN-gamma combined with 1 x 10(6) U/m2/d of IL-2. Objective clinical responses were seen in five of 26 patients. These included a partial response of 2 months duration in a patient with non-Hodgkin's lymphoma (NHL), mixed responses in a patient with NHL and two patients with renal cell carcinoma (RCC), and an ongoing assessable response in a patient with bone metastases from RCC. The recommended dose for phase II trials of this combination is 0.50 mg/m2 of IFN-gamma and 1 x 10(6) U of IL-2.
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PMID:A phase I trial of recombinant interleukin-2 combined with recombinant interferon-gamma in patients with cancer. 211 71

The purpose of this study was to generate lymphokine-activated killer cells via alternative pathways using combinations of biologic agents. Immunotherapy with the mouse anti-CD3 analogue combined with low-dose interleukin 2 (IL-2) and tumor necrosis factor alpha (TNF-alpha) was tested for in vivo antitumor efficacy against established pulmonary metastases from a variety of mouse tumor-cell lines. Administration of a single dose of anti-CD3 followed by low-dose IL-2 and TNF-alpha potentiated reduction of metastases compared with higher doses of IL-2 alone or IL-2 plus TNF-alpha. Treatment with anti-CD3 plus IL-2 plus TNF-alpha significantly prolonged survival and resulted in 60% of the mice achieving long-term survival compared with no survival using single agents or other combinations. The lymphokine-activated killer and natural killer activities of mouse splenocytes increased following treatment with anti-CD3 plus IL-2 plus TNF-alpha. These results indicate that the sequential use of anti-CD3, IL-2, and TNF-alpha for the induction and maintenance of lymphokine-activated killer activity potentiates antitumor activity and provides novel strategies for combination immunotherapy.
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PMID:Successful combination immunotherapy for the generation in vivo of antitumor activity with anti-CD3, interleukin 2, and tumor necrosis factor alpha. 213 27

An experimental model of hepatic metastases in C57BL/6 mice was used to compare the antitumor effects of lymphokine-activated killer (LAK) cells, anti-CD3-activated T-cells (ATC), and anti-CD3 alone. Liver metastases were produced by in vivo passage of MCA-38-LD adenocarcinoma via the ileocolic vein. LAK cells and ATC were generated by 3-day in vitro incubation of spleen cells in interleukin 2 and anti-CD3, respectively. Percentage of tumor volume in livers was determined with a morphometric technique. With less than therapeutic LAK cell doses (0.5-1.0 x 10(7) cells), no effect was seen in mean (+SE, -SE) percentage of tumor volume of control [23.3 (29.3, 18.5)] compared to LAK cell-treated [21.6 (29.3, 15.9)] animals. The same number of ATC significantly reduced the mean percentage of tumor volume [2.7 (4.7, 1.4)] (P less than 0.005). High dose interleukin 2 also significantly decreased tumor volume. More strikingly, a single dose of anti-CD3 alone had a beneficial effect on mean percentage of tumor volume when given i.p. [1.0 (1.9, 0.4)] or i.v. [1.2 (1.7, 0.7)] (P less than 0.0003). A total of 33% of anti-CD3-treated mice had no detectable liver metastases. In 51Cr release assays, the cytotoxicity of ATC was shown to be partially mediated by nylon wool-adherent accessory cells. The effectiveness of anti-CD3 in this immunotherapy model suggests that a similar approach may be taken to immunotherapy of human malignancies, without the requirements for in vitro-generated killer cells or exogenously administered interleukin 2.
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PMID:Comparison of cellular immunotherapies and anti-CD3 in the treatment of MCA-38-LD experimental hepatic metastases in C57BL/6 mice. 213 7

We evaluated the antitumor effect of an interleukin 2 (IL-2) slow delivery system, the IL-2 minipellet, using a murine hepatic metastasis model. The IL-2 minipellet consists of atelocollagen derived from natural bovine skin together with 1 x 10(6) units of recombinant IL-2. Administration of the IL-2 minipellet was performed into the spleens of BALB/c mice after translocation of the spleens to the s.c. position. Administration produced detectable serum IL-2 levels for 72 h. The IL-2 minipellet was evaluated for its efficacy against hepatic metastases from colon 26 adenocarcinoma in the BALB/c mice. Both the administration of the IL-2 minipellet alone and its combination with the injection of 5 x 10(7) lymphokine-activated killer cells resulted in significant reductions of the number of metastatic nodules. Moreover, increased survival of mice bearing colon 26 adenocarcinoma was noted in these two treatment groups. To investigate the mechanism of the IL-2 minipellet activity, we tested the lytic potential of splenocytes obtained after administration of the IL-2 minipellet in a 51Cr release assay. Cytotoxicity against YAC-1 cells and colon 26 cells was significantly augmented on Day 2 after minipellet administration. These results demonstrated that local administration of the IL-2 minipellet into the hepatic circulation was extremely effective against metastatic liver cancer.
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PMID:Application of an interleukin 2 slow delivery system to the immunotherapy of established murine colon 26 adenocarcinoma liver metastases. 220 66

It appears that lymph node metastases are more frequent in lung cancer than in other cancers because of impaired defensive mechanisms in the regional lymph nodes. However, little is known about the immunologic function of regional lymph node lymphocytes (RLNL) in patients with lung cancer. We have studied the immunologic properties of RLNL in comparison with peripheral blood lymphocytes (PBL). We measured the natural killer (NK) cell activity of RLNL and PBL in patients with lung cancer and found that the NK activity was significantly more depressed in the RLNL than in the PBL. In contrast, interleukin-2 (IL-2) production was markedly higher in the RLNL than in the PBL. The cytotoxic effect of RLNL in nonmetastatic lymph nodes on target cells (such as K562 cells) or PC-3 and PC-10 cells (NK-resistant, human lung cancer of adenocarcinoma and epidermoid carcinoma, respectively) was significantly enhanced by in vitro incubation with recombinant IL-2 (rIL-2). Furthermore, we clarified that both rIL-2 and OK-432, which is a biologic response modifier and IL-2 inducer as well, augmented the cytotoxicity of RLNL and that these effector cells were lymphokine-activated killer (LAK) cells. The depletion of lymphocyte subsets by pretreatment with specific monoclonal antibody showed that the LAK activity in RLNL was mediated by CD3+ and CD8+ cells, whereas the lymphocyte subsets contributing the LAK activity in PBL were CD3+ and CD16+ cells. It was concluded that a majority of the effector cells in RLNL were LAK cells of the cytotoxic T cell population.
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PMID:Functional character and augmentation of lymphocytes in regional lymph nodes of patients with lung cancer. 222 81

Given the association of deficient natural immunity with the risk of metastatic disease, the ability to activate natural killer cell function may have a therapeutic significance. The effect of continuous infusion of interleukin 2 plus intramuscular interferon alfa on natural immune status was, therefore, analyzed in eight patients with head and neck cancer. Also evaluated was the effect of interleukin 2-interferon alfa therapy on lymphokine-activated killer cell activity as well as total lymphocyte count, percent of lymphocyte subsets, and levels of both circulating immune complexes and antibody classes. Both the percent and absolute number of natural killer cells (ie, CD56+ CD3- lymphocytes) within peripheral blood as well as natural killer cell activity against K562 targets increased significantly with treatment. The remaining immune parameters were not significantly altered. The demonstrated capacity to modulate natural immune function supports the potential use of interleukin 2-containing regimens as a preventive measure against metastatic disease in patients with head and neck cancer.
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PMID:The in vivo biologic effect of interleukin 2 and interferon alfa on natural immunity in patients with head and neck cancer. 224 61

The efficacy in cancer treatment of novel therapeutic agents such as monoclonal antibodies, cytokines and effector cells has been limited by their inability to reach their target in vivo in adequate quantities. Molecular and cellular biology of neoplastic cells alone has failed to explain the nonuniform uptake of these agents. This is not surprising since a solid tumor in vivo is not just a collection of cancer cells. In fact, it consists of two extracellular compartments: vascular and interstitial. Since no blood-borne molecule or cell can reach cancer cells without passing through these compartments, the vascular and interstitial physiology of tumors has received considerable attention in recent years. Three physiological factors responsible for the poor localization of macromolecules in tumors have been identified: (i) heterogeneous blood supply, (ii) elevated interstitial pressure, and (iii) large transport distances in the interstitium. The first factor limits the delivery of blood-borne agents to well-perfused regions of a tumor; the second factor reduces extravasation of fluid and macromolecules in the high interstitial pressure regions and also leads to an experimentally verifiable, radially outward convection in the tumor periphery which opposes the inward diffusion; and the third factor increases the time required for slowly moving macromolecules to reach distal regions of a tumor. Binding of the molecule to an antigen further lowers the effective diffusion rate by reducing the amount of mobile molecule. Although the effector cells are capable of active migration, peculiarities of the tumor vasculature and interstitium may be also responsible for poor delivery of lymphokine activated killer cells and tumor infiltrating lymphocytes in solid tumors. Due to micro- and macroscopic heterogeneities in tumors, the relative magnitude of each of these physiological barriers would vary from one location to another and from one day to the next in the same tumor, and from one tumor to another. If the genetically engineered macromolecules and effector cells, as well as low molecular weight cytotoxic agents, are to fulfill their clinical promise, strategies must be developed to overcome or exploit these barriers. Some of these strategies are discussed, and situations wherein these barriers may not be a problem are outlined. Finally, some therapies where the tumor vasculature or the interstitium may be a target are pointed out.
Cancer Metastasis Rev 1990 Nov
PMID:Vascular and interstitial barriers to delivery of therapeutic agents in tumors. 229 38


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