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)

Our earlier work revealed that PGE-mediated inactivation of NK cells in tumor-bearing mice by host macrophages promoted spontaneous lung metastasis that could be prevented or ameliorated by chronic indomethacin therapy. Since PGE was found to suppress the in vitro development and/or activation of a family of tumoricidal lymphocytes such as CTL, NK, and LAK cells by one or both of two mechanisms, that is to say, a down regulation of IL-2-R and an inhibition of IL-2 production, the present study tested whether a combined therapy with indomethacin and IL-2 was more effective than one with indomethacin or IL-2 alone in ameliorating established experimental lung metastasis. B6 mice injected intravenously with 10(6) highly metastatic B16F10 melanoma cells showed profuse micrometastases in the lungs by day 5, and macrometastases by day 10 which were confluent on day 21. Chronic indomethacin therapy by the oral route (14 micrograms/ml in drinking water) starting on day 0 or day 5, or a single round of IL-2 therapy (25,000 U rIL-2, every 8 h for 5 d on days 10-14) reduced the number of metastatic nodules by two-thirds (from a median of 473 in control mice receiving vehicles alone) by day 21. A single round of IL-2 as above, combined with either protocol of indomethacin therapy, completely or nearly completely irradicated the lung metastases, corroborated by a histological examination. An evaluation of splenic killer cell activity measured with a 4-h 51Cr-release assay against NK-sensitive YAC-1 lymphoma and B16F10 melanoma or NK-resistant thymic lymphoma 9705 targets revealed negligible activity in control tumor-bearing mice, and a good restoration of activity against NK-sensitive targets with either protocols of indomethacin therapy. IL-2 alone or a combination of IL-2 and indomethacin given by either protocol generated strong killer activity against all these targets, most marked with the combination therapy. Splenic killer cell phenotype in normal as well as all treated animals was ASGM1+, Thy-1-, and Lyt-2-. The combination therapy resulted in the strongest mononuclear cell infiltration in the lungs, with areas of young granulation tissue suggestive of repair sites of original metastases.
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PMID:Amelioration of B16F10 melanoma lung metastasis in mice by a combination therapy with indomethacin and interleukin 2. 349 67

Peripheral blood lymphocytes obtained from patients by leukapheresis were cultured in RPMI 1640 containing human plasma and interleukin 2. The morphology, phenotypes and cytotoxicity of induced LAK cells were studied. Lymphoblastoid cells mainly proliferated were OKIa1+ cells and were thought to be LAK cells. Maximal cytotoxicity was obtained after two weeks of incubation. IL-2 enhanced the cytotoxicity of LAK cells. Autologous LAK cells induced by two weeks of incubation were injected into patients. One case of pulmonary metastases of breast cancer showed reduction and two lesions showed partial regression. Also, no new lesions appeared in the lungs of a patient with alveolar soft-part sarcoma.
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PMID:[Adoptive immunotherapy of malignant diseases with LAK cells]. 349 32

Effectiveness of IL-2 and LAK cells induced by IL-2 on malignant diseases was discussed. IL-2 alone administered systemically showed a poor effect, and combination of IL-2 are necessary for LAK cells to kill the target malignant cells. Adoptive immunotherapy using IL-2 and LAK cells should be applied for pulmonary and hepatic metastases. Postoperative adjuvant therapy and combination with chemotherapy will become important in the future.
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PMID:[Interleukin 2]. 349 39

The in vivo anti-tumor activity of 2 recombinant cytokines, interleukin-2 (rIL-2) and human hybrid interferon alpha (rHuIFN-alpha A/D), were tested using the murine reticulum cell sarcoma M5076. Experimental hepatic metastases, following i.v. injection of tumor cells, and tumor growth and spontaneous metastases, following s.c. injection of tumor cells, were inhibited to a greater extent in mice treated with a combination of these cytokines than in animals treated with either one alone. When used in conjunction with surgical removal of the s.c. tumor, treatment of mice with both cytokines significantly prolonged survival of tumor-bearing animals. Injection of normal mice with a combination of cytokines, but not with either cytokine alone, resulted in a marked increase in cytotoxic activity of hepatic effector cells. The effector cells in these mice appeared to be NK cells since this enhanced cytotoxicity was markedly reduced in animals treated in vivo with anti-asialo GM1 or in NK-deficient beige mice. Furthermore, no in vivo efficacy was observed in M5076-bearing beige mice treated with these cytokines. Thus, injection of mice with rIL-2 and rHuIFN-alpha A/D results in the induction of an NK-cell-like population in the liver with enhanced cytotoxic activity that correlates with the observed anti-tumor activity in vivo in this murine model. These results suggest that combinations of cytokines, in particular IFN-alpha and IL-2, can be effectively used in combination for the treatment of tumors and/or metastases.
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PMID:In vivo anti-tumor activity of combinations of interferon alpha and interleukin-2 in a murine model. Correlation of efficacy with the induction of cytotoxic cells resembling natural killer cells. 349 83

Cytotoxic activity of lymphocytes cultured in IL-2 against autologous primary lung cancer cells was studied in relation to curativity, prognosis and relapse rate. A total of 51 patients, 44 males and 7 females, consisting of those with adenocarcinoma (n = 27), squamous cell carcinoma (n = 19), large cell carcinoma (n = 2), small cell carcinoma (n = 1), lung sarcoma (n = 1), and carcinoid (n = 1), were evaluated. Pathological stages of the patients were stage I (n = 16), stage II (n = 1), stage III (n = 28), and stage IV (n = 6). Thirteen patients (25.5%) underwent curative surgery, 23 patients (45.1%) received relative curative surgery and 15 patients (29.4%) received non-curative surgery. The mean value of cytotoxic activity in the patients who received curative surgery was 34.7 +/- 15.3%, relative curative surgery 26.5 +/- 18.9%, and non-curative surgery 42.8 +/- 22.3%. Among the patients who underwent curative and relative curative surgery, 23 patients survived more than 2 years and 13 patients died of cancer recurrence. Mean value of cytotoxic activity in the former (36.7 +/- 15.9%) was significantly (p less than 0.01) higher than that in the latter (17.1 +/- 14.7%). Positive rate (percentage of patients whose CA exceeded 15%) of the former (86.9%) was also higher than that of the latter (46.1%). Comparison between the survival curves of the positive cases (CA 15.0%) and negative cases (CA less than 15.0%) revealed a significantly better prognosis for the former (generalized Wilcoxon test: W/square root VarW = 2.198). The mean cytotoxic activity in the cases of local recurrence (25.7 +/- 16.6%, n = 7) was higher (p less than 0.10) than that in the cases with distant metastases (9.3 +/- 6.3%).
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PMID:[Cytotoxic activity of autologous lymphocytes against lung cancer cells; correlation of prognosis and recurrence pattern]. 349 20

The capacity of inbred W/Fu rats bearing syngeneic colon carcinomas to generate interleukin(s) (IL) was studied during primary tumor growth, after tumor resection, and during postresection immunotherapy. During local tumor growth, there was a significant decrease in the capacity of the host's adherent mononuclear cells to generate IL-1 and of peripheral blood mononuclear cells to generate IL-2 (16.6 and 23%, respectively, when compared to control animals; P less than .01). The presence of regional metastases or large primary tumor burden resulted in a further sharp fall in IL generation (0.9 and 10% for IL-1 and IL-2, respectively, when compared to control animals; P less than .01). With the use of three different doses of tumor inoculum, inhibition of IL generation was shown to occur when tumors were barely palpable. Decrease in IL correlated with tumor growth and not with the initial number of tumor cells injected. Tumor resection resulted in a rise in IL-2 generation from 36 to 64% of control animals' levels. Postresection immunotherapy with the use of an active specific immunization protocol successfully modulated IL-2 production to normal in animals protected from tumor recurrence. Animals that developed recurrent tumors despite immunization exhibited a continued inability to generate IL (mean values of IL-2 production compared to controls: 184% in animals free of recurrence after immunotherapy, 1% in animals developing recurrent tumors after immunotherapy; P less than .01). These results suggested that alterations in IL generation may lead to immune unresponsiveness during tumor growth. Active specific immunotherapy protecting animals from recurrence after primary tumor resection may be predicated on the successful modulation of IL level generation by host immunocytes.
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PMID:Interleukin generation in experimental colon cancer of rats: effects of tumor growth and tumor therapy. 387 59

Evidence for heterogeneity of several biological features of human malignant melanoma (Me) like morphology, cytogenetics, oncogenes activation, antigenic expression, metastatizing capacity and procoagulant activity are briefly reviewed in an attempt to distinguish findings related to primary vs. metastatic lesions. In our own studies monoclonal antibodies were used to study expression of MHC class I, class II products and of Me-associated antigens (MAA) on primary and metastatic Me cells. High expression of class I antigens was found in a high percentage of both primary and metastatic tumors, whereas DR and MAA showed a significant variation (from 3 to 90% of cells) in expression both in primary and in metastatic Me. When autologous cell-mediated immune responses were evaluated, it was found that Me cells from primary tumors but not those from lymph node metastases were able to stimulate autologous lymphocytes to proliferate and become cytotoxic for autologous Me. Clonal analysis of cytotoxic lymphocytes was then carried out in order to see whether the lack of lymphocytes reactivity to metastatic cells was due to the absence or to a low frequency of cytotoxic cells in the unstimulated PBL. CTL clones cytotoxic for autologous Me (Auto-Me) cells were indeed isolated. Three classes of CTL clones were identified: 1) one which is cytotoxic for Auto-Me; 2) a second one which lyse Auto-Me and allogeneic Me; and 3) a third one which is cytotoxic for Auto-Me and allogeneic normal and neoplastic cells. Metastatic Me cells, however, had the ability to suppress the stimulation of autologous PBL by alloantigens or IL-2. This effect was dose-dependent and was not due to absorption of IL-2 by Me cells. Since it has been reported that Me cells express class II MHC antigens, we investigated whether there was any correlation between autologous immune responses and DR expression on Me cells. Autologous lymphocytes stimulation was found to occur only with DR+ Me cells from primary lesions, whereas metastatic cells, either DR+ or DR-, did not stimulate autologous PBL. Moreover, the suppressive effect of metastatic Me cells was associated with their expression of DR antigens. The modulation of DR antigens on Me cells by Interferon-gamma correlated positively with their suppressive capacity. Thus, it appears that primary Me can behave differently from the metastatic one in their interactions with the immune system of autologous host. These findings suggest that DR antigens on Me cells may have an important role in the regulation of autologous immune responses.
Cancer Metastasis Rev 1985
PMID:Autologous cellular immune response to primary and metastatic human melanomas and its regulation by DR antigens expressed on tumor cells. 388 84

Intravenous inoculation of the AKR mouse-strain-derived BW lymphoma into CBA recipients resulted in a case of liver metastasis; cells derived from this metastatic nodule were termed BW-Li cells. BW-Li cells, upon reinoculation, generated metastases in the spleen, liver, kidney and ovaries in 100% of CBA recipients. Furthermore, BW-Li cells, in contrast to BW cells, were found to infiltrate in vitro monolayers of hepatocytes, thus confirming their inherent invasive potential. Analysis of the alloantigenic phenotype of BW-Li cells revealed that such cells were Thy 1.1+, Thy 1.2+, Lyt 1.2+, Lyt 1.1-, Lyt 2- and H-2Dk+, as compared to BW cells which exhibited the membrane phenotype Thy 1.1+, Thy 1.2-, Lyt 1.2-, Lyt 1.1-, Lyt 2-, H-2Dk-. BW-Li cells also differed functionally from BW cells since these cells secreted IL-2 upon stimulation with Concanavalin A. BW tumor transplantation experiments were repeated in a semi-allogeneic F1 strain combination, i.e. (AKR X CBA)F1, and again a case of massive liver metastasis was observed. Cells derived from these liver metastases (termed BW-O-Li) manifested an invasive and metastatic potential similar to that of BW-Li cells. Furthermore, BW-O-Li cells secreted IL-2 upon stimulation with Con A and manifested the following alloantigenic phenotype: Thy 1.1+, Thy 1.2+, Lyt 1.2+, Lyt 1.1-, Lyt 2-, H-2Dk+ and H-2Kk+. These results indicate that BW-Li and BW-O-Li cells are functional T-cell hybrids which express T-cell markers derived from BW cells and Thy 1.2+ CBA host cells. The acquisition of host-derived T-cell properties may have led to the expression of metastatic and invasive capabilities. From these results we conclude that the acquisition of metastatic properties following somatic cell fusion with normal lymphoreticular cells may represent a mechanism for tumor progression in vivo.
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PMID:Generation of invasive and metastatic variants of a non-metastatic T-cell lymphoma by in vivo fusion with normal host cells. 633 39

This study delineates the temporal relationship between immune complex formation and tumor growth, and provides one possible explanation for host immunosuppression during tumor growth. The authors have studied serial circulating immune complex (CIC) levels and interleukin (IL) elaboration by peripheral blood cells (IL-1 production by adherent mononuclear cells [AMC]; and IL-2 generation by peripheral blood mononuclear cells [PBMC]) during the growth of syngeneic tumor isografts in an inbred rat model. Male Wistar/Furth (W/Fu) rats were injected, subcutaneously (SC) with 2 X 10(6) W163 ( a dimethylhydrazine [DMH]-induced colon adenocarcinoma) cells into their hind limbs. Serial CIC levels, (measured by the antigen nonspecific polyethylene glycol turbidity assay) and IL-1 and IL-2 production were measured before isografting and weekly thereafter. Progressive local tumor growth occurred for 3 weeks followed by regional lymph node metastases during the fourth week. During local tumor growth, there was a progressive rise in CIC levels (123% rise compared with baseline value; P less than 0.05) which correlated with a fall in both IL-1 and IL-2 generation (r = -0.768). At the time of regional metastasis, the mean CIC levels declined, and there was a further significant decrease in IL production (IL-1 = 0.9% and IL-2 = 10% of controls in tumor bearers). These results show that progressive tumor growth results in decreased IL production by host PBC, and suggest that CIC may be involved in regulating IL generation.
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PMID:Effects of tumor growth on interleukins and circulating immune complexes. Mechanisms of immune unresponsiveness. 660

Immunoregulatory factor (IRF) is a 70,000 molecular weight glycoprotein produced by human tumors that suppresses lymphocyte function including mitogen-stimulated tritiated leucine (3H-leu) and tritiated thymidine (3H-Tdr) uptake, in vitro immunoglobulin synthesis, induction of allospecific cell-mediated cytotoxicity, and proliferation of T-cell growth factor-dependent lymphocyte cultures. Antisera to IRF were produced by immunization of goats and rabbits with IRF purified by diethylaminoethyl (DEAE)-anion exchange and affinity chromatography. Antisera specificity was demonstrated by binding to IRF but not control muscle extract in an ELISA test and by specific removal of IRF activity by antibody coupled to acrylamide beads. Using these antisera, a double antibody-binding assay was developed to measure circulating levels of IRF and to determine its relationship to tumor growth and relevance for monitoring the clinical course of cancer patients. Quantitative autologous as well as allogeneic binding of sarcoma patients' sera to anti-IRF antibody was demonstrated. Of five tumor extracts tested, two had immunosuppressive activity, and IRF was detected in the preoperative sera of both patients. These extracts were not suppressive and IRF was not detected in the preoperative sera of these patients. In a double-blind study, analysis of serial serum samples from 26 sarcoma patients, 11 normal volunteers, and eight noncancer patients, demonstrated four patterns of circulating IRF: sustained high levels, increasing levels, decreasing levels, and no detectable IRF. Seven of 14 patients who eventually developed metastatic disease demonstrated sustained high or increasing levels of IRF. Eleven of 12 patients clinically free of tumor for five years or more, ten of 11 normal volunteers, and eight of eight noncancer patients had either a pattern of decreasing levels or no detectable IRF. Circulating IRF levels are correlated with the presence of tumor and may be useful in monitoring the clinical course of cancer patients.
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PMID:Detection of a suppressive immunoregulatory factor (IRF) in the sera of sarcoma patients by enzyme-linked immunoassay (ELISA) and correlation with clinical course. 687 4


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