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 single dose of inactivated streptococci (OK-432) was injected into the popliteal lymph nodes of male CDF1 mice and its effects on popliteal, inguinal, and para-aortic lymph node cells and spleen cells were investigated and compared with the effects of subcutaneous injections of the same dosage of OK-432. Regional lymph node cells and spleen cells obtained from intralymphnodally injected mice lysed not only natural killer (NK)-sensitive YAC-1 cells, but also NK-resistant P-815 and meth-A cells. Lysis of target cells was inhibited when effector cells were treated with anti-Thy-1.2 or anti-Lyt-2.2 monoclonal antibody and complement, but no inhibition was apparent after treatment with anti-asialo-GM1 or anti-Lyt-1.2 antibody and complement. These results suggest that the effector cells are lymphocyte-activated killer (LAK) cells. An enhanced capacity of lymph node cells to produce cytokines, tumor necrosis factor and interleukin 1 upon restimulation with lipopolysaccharide was found only in intralymphnodally injected mice. Thus, the induction of LAK-like cells and cytokine production in regional lymph nodes and spleen cells by the intralymphnodal administration of OK-432 should be effective for the inhibition or treatment of lymph node metastases.
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PMID:Enhancement of LAK-like activity and cytokine induction in regional lymph nodes and spleen cells of mice after intralymphnodal injection of OK-432, a killed streptococcal preparation. 835 67

IL-2 induces tumour regression in some patients with metastatic disease, but the dose of IL-2 is limited by severe toxicity. Agents that increase the expression of IL-2 receptors in the effector cells could be used to improve the effectiveness of IL-2 in mediating its anti-tumour effect. We have reported that haemin increased the expression of IL-2 receptors in human peripheral blood mononuclear cells (PBMC) and synergized with IL-2 in the induction of mitogenicity, cytotoxicity and cytokine production. We now report on haemin-induced immune stimulation and tumour regression in mice. Haemin-induced mitogenicity in mouse splenocytes was potentiated up to two-fold by IL-2. The combination of haemin and IL-2 was also effective in inducing cytotoxicity for natural killer (NK)-resistant target cells. Maximal induction of cytotoxicity was attained at an optimal concentration of haemin of 10 microM. Higher concentrations were less effective. Splenocytes isolated from mice that had been treated in vivo with haemin and IL-2 incorporated twice the amount of 3H-thymidine compared with splenocytes from mice treated with either haemin or IL-2 alone. Cytotoxicity of splenocytes for NK-resistant target cells was not increased following in vivo administration of haemin and IL-2 when fresh splenocytes were tested. Cytotoxicity was enhanced, however, up to five-fold following 48 h in vitro incubation with IL-2. Administration of haemin and IL-2 resulted in a significant decrease (40%) of established hepatic metastases in mice. Either IL-2 or haemin alone at the dose used were ineffective. The anti-tumour effect of haemin and IL-2 was enhanced (63% decrease in metastases) by administration of the thiol compound, N-acetylcysteine. Since haemin can safely be administered to patients, it may represent a new class of biologic response modifiers that could enhance IL-2-mediated anti-tumour effects.
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PMID:Immune stimulatory and anti-tumour properties of haemin. 837 Jan 58

In order to evaluate the biological response after intraperitoneal administration of OK-432, we studied the changes of cytokine levels in ascitic fluid. In 6 advanced gastric cancer patients with peritoneal dissemination or extensive lymph node metastases, OK-432 20 KE was administered intraperitoneally during operation and the IL-6, IL-8 and IFN-gamma levels in ascitic fluid were measured from 0 to 5 postoperative days. These results were compared with those obtained from non-OK-432 administered control groups (17 cases). The ascitic level of IL-8 increased immediately after operation and gradually decreased. In the OK-432 treated group, the elevation of IL-8 on 0 and 1 postoperative days was remarkable, and there were statistically significant differences with the control group. Similarly, the ascitic level of IL-6 elevated soon after operation and then decreased gradually. In the OK-432 treated group, the ascitic level of IL-6 was significantly higher than in the control group after 3 postoperative days. There were no differences in changes of ascitic IFN-gamma levels between the groups. From these results, IL-6 and IL-8 appeared to be induced in ascitic fluid by intraperitoneal administration of OK-432.
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PMID:[Changes in cytokine levels in ascitic fluid after intraperitoneal administration of OK-432]. 837 2

To determine if mononuclear cells (MNC) infiltrating various types of human solid tumours express genes for cytokines, in situ hybridisation with 35S-labelled cDNA antisense probes for interleukin 2 (IL2), interferon gamma (IFN-gamma), tumour necrosis factor alpha (TNF-alpha), interleukin 1-beta (IL1-beta), transforming growth factor beta (TGF-beta) and interleukin 2-receptors (IL2R) was performed. Fresh-frozen tissue samples of ovarian carcinomas (n = 13), breast carcinomas (n = 12), and squamous cell carcinomas of the head and neck (SCCHN, n = 7) were evaluated for the presence and localization in the tumour of MNC positive for cytokine genes. In ovarian tumours and those breast carcinomas producing little or no mucin, only rare positive MNC were observed. In contrast, breast carcinomas producing mucin and all SCCHN contained numerous MNC expressing gene transcripts for IL2, IFN-gamma, TNF-alpha, IL2R as well as TGF-beta. In tumour-involved lymph nodes of patients with SCCHN, MNC expressing genes for cytokines were found around tumour metastases but not in non-involved areas. These data suggest that tumours expressing immunogenic antigens (e.g. mucin) contain many activated MNC, while other tumours either fail to activate or suppress functions of infiltrating MNC. In SCCHN or tumour-draining lymph nodes, local down-regulation of antitumour responses might be mediated by TGF-beta produced by activated tumour-infiltrating MNC.
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PMID:In situ hybridisation for cytokine gene transcripts in the solid tumour microenvironment. 839 38

A 47 year old woman underwent excision of a malignant melanoma on the right shoulder. Nine years later she was attacked by intense pain in the back. Computed tomography, bone scans and immunohistochemical study of a liver biopsy specimen revealed metastases from the malignant melanoma in the liver, spleen and skeleton. Her Karnovsky score was 50%. Chemoimmunotherapy given for five cycles consisting of dacarbazine (800 mg/m2 body surface area every 4 weeks) together with ambulatory cytokine therapy (interferon alpha-2b subcutaneously, 5 million I.U. on days 1 and 3 to 7 in the first week, days 1, 3 and 5 in the second and third weeks and interleukin 2.9 million I.U. on days 1 to 5 in the second and third weeks; no treatment was given in the fourth week) raised the Karnovsky score to 90% and abolished the pain. Lactate dehydrogenase activity, originally 3372 U/l, dropped to normal. Computed tomography demonstrated definite shrinkage of the liver metastases and some regression of the splenic and bony deposits. This improvement has now been maintained for a total of eight cycles of therapy.
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PMID:[Dramatic remission of a multiple metastasized melanoma caused by chemo-immunotherapy]. 845 2

Previous results on the peripheral blood immune status of renal cell carcinoma had indicated immunosuppression in metastatic disease, possibly mediated by prostaglandin E2 (PGE2). In the present study the immunologic effects of inhibition of PG synthesis by piroxicam in combination with interleukin 2 (IL 2) + lymphokine-activated killer (LAK) cell therapy were tested by immunomonitoring. In addition to peripheral blood parameters (lymphocyte subpopulations, neopterin, beta 2-microglobulin, TNF, IL 1, IFN gamma) we recorded in vitro cellular activity by incubating the patients' peripheral blood mononuclear cells (PBMC) in media containing fetal calf serum (FCS) or autologous serum, and either IL 2 or buffer. After 24 h of incubation we measured PGE2 and cytokine levels in supernatants. Systemic application of IL 2 induced in vivo lymphocyte proliferation and clearly influenced the serum levels of neopterin, beta 2-microglobulin and TNF. There was minor affection of IFN gamma and none of IL 1. PBMC in vitro produced high amounts of PGE2, IL 1 and TNF pretherapeutically, during therapy in vitro synthesis of these parameters decreased. Consistent production of IFN gamma was detected in supernatants only when FCS and IL 2 were added to the medium. Lack of affection of IFN gamma production in the autologous system during therapy indicated impaired cellular activity, which could neither be improved by therapy of the patient using IL 2 nor by adding IL 2 to the culture medium. Immunosuppression seems to interfere in a complex way with immunotherapy. Therapeutical influence of immunosuppression based on the results of immunomonitoring, however, seems to be a promising strategy for improving the still limited clinical results of immunotherapy.
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PMID:Influence of immunotherapy (IL2 + LAK + inhibition of prostaglandin synthesis) on peripheral blood immune parameters and in vitro cytokine production in metastatic renal cell carcinoma. 846 78

The influence of endogenous and exogenous tumor necrosis factor (TNF) on metastasis was investigated in an experimental fibrosarcoma metastasis model. A single intraperitoneal injection of recombinant human (rh) TNF or recombinant mouse (rm) TNF into mice 5 h before intravenous inoculation of methylcholanthrene-induced fibrosarcoma cells (CFS1) induced a significant enhancement of the number of metastases in the lung. Dose responses of rmTNF and rhTNF demonstrated a stronger metastasis-augmenting effect by rmTNF compared with rhTNF. This effect was time dependent, as administration of rmTNF 5 h before or 1 h but not 24 h after tumor cell inoculation caused an increase of tumor cell colony formation on the lung surface, suggesting an influence of TNF on the vascular adhesion and diapedesis of tumor cells. Since tumor-bearing mice showed an enhanced ability to produce TNF after endotoxin injection compared to control mice, tumor-bearing mice were treated with anti-mTNF antibodies. Neutralization of endogenous tumor-induced TNF led to a significant decrease of the number of pulmonary metastases. Histological analysis of micrometastases in the lung on day 5 by silver staining of proteins associated with nucleolar organizer regions revealed more metastatic foci and augmented proliferative activity of the tumor cells after rmTNF pretreatment of mice. However, no direct effect of rmTNF on the proliferation rate of tumor cells was seen in vitro. These findings suggest that low doses of endogenous TNF or administered TNF during cytokine therapy might enhance the metastatic potential of circulating tumor cells.
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PMID:Enhancement of experimental metastasis by tumor necrosis factor. 847 14

Human melanomas can become progressively resistant to the growth-inhibitory effects of a broad family of structurally diverse cytokines which includes interleukin 6 (IL-6). Uncovering this multicytokine resistance was made possible by the availability of cell lines established from early-stage radial growth phase or vertical growth phase primary melanomas as well as more advanced primary lesions and distant metastases. Because Oncostatin M (OSM) is also a member of the IL-6 family we evaluated the effects of this cytokine on the growth of human melanoma cell lines obtained from different stages of disease progression. The results showed that three different cell lines derived from early-stage melanomas were strongly growth inhibited by OSM, as they are by IL-6. Three cell lines, established from advanced-stage melanomas, were growth inhibited by OSM, but much higher concentrations (in the range of 10-fold) were required to obtain 50% growth inhibition; these cell lines were not inhibited by IL-6. Three other cell lines that were IL-6 resistant (two of which were advanced stage) were also found to be OSM resistant. Only one advanced-stage IL-6-resistant cell line was found to be highly sensitive to OSM-mediated growth inhibition. In addition, we found that variants isolated from early-stage WM35 melanoma cells that possess a much more aggressive tumorigenic phenotype in nude mice were significantly more resistant to both OSM- and IL-6-mediated growth inhibition. The results demonstrate that OSM can function as a growth inhibitor of human melanoma cells but that its ability to do so is progressively diminished or lost with disease progression. This finding is consistent with the concept of acquired "multicytokine resistance" during melanoma progression.
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PMID:Increased resistance to oncostatin M-induced growth inhibition of human melanoma cell lines derived from advanced-stage lesions. 850 8

Interleukin 12 (IL-12) enhances lysis mediated by NK- and lymphokine activated killer (LAK) cells. It also causes proliferation of IL-2 stimulated T and NK cells in vitro. For these IL-2 complementing properties murine pulmonary metastases of a coloncarcinoma line were treated with IL-12 and IL-2 or with the individual agents. Results were compared to sham treated controls. IL-2 alone mediated significant tumor reduction but provoked pulmonary edema and concomittand toxicity, graded in three steps. IL-12 combined with an IL-2 dose reduced by 81% still resulted in significant antitumoral activity. Toxicity, however, was not discernable from sham treated controls. IL-12 thus appears as an attractive cytokine for combination with IL-2 in antitumor therapy. Particularly treatment of tumors, like gastrointestinal tract cancers, so far mainly resistant to cell mediated antitumor therapy, might profit from this approach.
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PMID:Addition of interleukin 12 to low dose interleukin 2 treatment improves antitumor efficacy in vivo. 852 51

In adoptive immunotherapy (AIT) of cancer, lymphocytes are isolated from the patient's blood and activated in vitro by the cytokine interleukin-2 (IL-2). In response to the IL-2 the lymphocytes proliferate vigorously and their cytotoxic potential increases several fold. After 5-10 days in culture, the cells-now called lymphokine-activated killer (LAK) cells-are injected back into the patient together with IL-2. The many positive results from preclinical animal models justified the rapid transit of AIT into the clinic, but the clinical results have far from fulfilled expectations. Many cancer centers have concluded that AIT in its present configuration is not cost-effective given that the average response rate is as low as 20-30%. Since a significant group of patients has shown complete responses after AIT, the challenge is to elucidate the conditions leading to optimal efficacy of AIT. It is generally accepted that the antineoplastic effect of LAK cells requires a close contact between the LAK cells and tumor cells. A central question in analyses of the mechanisms behind AIT is the ability of the LAK cells to localize to the malignant tissues. The earliest studies of the tissue distribution of 51Cr- and 111In-labeled LAK cells indicated that LAK cells, upon intravenous (i.v.) injection, are initially retained in the lungs, but redistribute to liver and spleen during the following 16-24 hours. However, our studies of the traffic and fate of i.v. injected tumor cells have shown that the use of 51Cr and 111In as cell labels often results in an over-estimation of the traffic of cells to liver and spleen and leads to falsely high predictions as to the survival of the injected cells, due to non-specific accumulation of 51Cr and 111In in liver and spleen after their release from dead cells. Use of 125IUdR, which does not accumulate in liver and spleen following release from dead cells, shows that the traffic of LAK cells into these organs was much lower than previously thought. These experiments have now been repeated using other cell labels (such as fluorescence dyes and immunohistochemistry) and they confirm that only few LAK cells redistribute from the lungs to the liver and spleen and that most die within the first 24 hours following injection. Thus, the circulatory potential of LAK cells is very low and chances that i.v. injected LAK cells will be able to localize into tumors and metastases located in other organs than the lungs, seems small. Indeed, while fluorescence-labeled LAK cells selectively localize into pulmonary metastases following intravenous injection, no infiltration of extrapulmonary metastases is seen. Furthermore, quantitative analyses have shown that even though the localization of LAK cells into pulmonary metastases is highly specific (5-10 fold higher numbers of LAK cells are often found in the metastases compared to the surrounding normal lung tissue), only 5% of the injected cells reach the malignant tissues. It is therefore reasonable to assume that the efficacy of AIT can be improved if the in vivo survival of the LAK cells can be prolonged and if their ability to infiltrate tumors regardless of their location, can be augmented. Previous studies in murine models have shown that i.v. injected tumor cells are sequestrated in the lungs and that only few of them reach other organs. However, when the tumor cells were injected into the left ventricle of the heart (bypassing the lung capillaries), significant numbers of tumor cells were found in the liver. It therefore seemed reasonable to speculate that LAK cells injected into the left ventricle of the heart or directly into the arteries supplying the tumor-bearing organ would have better chances of localizing to the malignant tissue. This seemed to be correct in that 10 fold higher numbers of LAK cells were found in the liver following intraportal injection compared to intravenous injection.
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PMID:Tissue distribution and tumor localization of effector cells in adoptive immunotherapy of cancer. 853 22


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