Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cytokines are soluble mediators involved in cell-cell regulations in the immunological and the hematopoietic systems-genetic engineering now allows the characterization and the availability of recombinant molecules, some of them being recently introduced in clinical trials. Interleukin-2 (IL-2) is the first factor having demonstrated a reproducible therapeutic effect on human metastatic solid tumors, mainly chemo-resistant. High-dose IL-2 alone could achieve about 25% objective responses in metastatic renal cancers, with a low but significant number of complete, relatively long-lasting complete responses. Similar data are obtained in metastatic melanoma. IL-2 is probably acting through the activation of cytotoxic lymphocytes (LAK: lymphokine activated killers). The interest for simultaneous administration of autologous LAK cells generated through in vitro culture with IL-2 is discussed. Cytokine therapy is currently limited by important systemic toxicities, including mainly general symptoms with fever, and a capillary leak syndrome with weight gain, edema and functional renal failure-cardiac are respiratory troubles can be life-threatening. Future trends for cytokine therapy will be: The discovery of new cytokines, and a better knowledge of their synergies, allowing the design of rational associations. A letter understanding of the mechanisms of toxicities, allowing specific prevention of adverse effects not needed for efficient anti-tumor action. Gene therapy, which will lead to important and prolonged release of cytokines by the tumor cells themselves, or by infiltrating peri-tumoral cells, in order to achieve local efficacy and to circumvent systemic toxicities.
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PMID:[Immunotherapy: current problems and outlook]. 146 35

Quantitative and qualitative tumor-associated changes in T cell phenotype and function were identified in CD8+ T cells. Tumor growth changed splenic CD4+/CD8+ T cell ratios and induced the appearance of more cells with the CD8+ phenotype. In comparison to equal concentrations of normal host (NH) counterparts, tumor-bearing host (TBH) CD8+ T cells were highly suppressive to allorecognition and autorecognition. Suppression was not due to quantitative reductions in CD4+ T cells, although minor qualitative differences were observed. Suppression appeared to be mediated partly by prostaglandin E2 (PGE2). Interferon-gamma (IFN-gamma) and interleukin-4 (IL-4) contributed to TBH CD8+ T cell-mediated suppression. Blocking studies using monoclonal antibodies (mAb) in conjunction with indomethacin suggested that cytokine networks involving IFN-gamma, IL-4, and PGE2 were disrupted during tumor growth and promoted TBH CD8+ T cell suppression. Alloresponses and autoresponses were significantly suppressed when TBH CD8+ T cells mediated these reactions simultaneously with TBH Ia- macrophages. Inhibition of PGE2 production was unable to reverse the additive suppression caused by these two cell types. These results collectively suggest that tumor-induced changes in CD8+ T cells lead to suppressed allo-recognition and autorecognition through both soluble mediator molecules and cellular interactions.
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PMID:Cytokines and suppressor macrophages cause tumor-bearing host CD8+ T cells to suppress recognition of allogeneic and syngeneic MHC class II molecules. 146 37

Renal cell carcinoma (RCC) is one of the few cancers partially sensitive to biotherapy. However, involvement of T cell immunity in host-defense against autologous tumor cells remains unclear. This manuscript investigated T cell functions of interleukin-2 (IL-2)-activated tumor-infiltrating lymphocytes (TILs) from human RCCs by studying their oligoclonality, cytotoxicity, and cytokine production. IL-2-activated RCC-TILs from 17 of 33 cases (52%) (p < 0.01 vs. IL-2-activated patients' peripheral blood mononuclear cells, PBMC) displayed oligoclonal expansion as determined by seven different monoclonal antibodies (mAbs) to T cell receptor (TCR) V alpha or beta regions after 2 to 5 weeks in culture. By comparison, IL-2-activated PBMC from only 1 of 15 healthy donors (7%), 3 of 23 patients (13%), and IL-2-activated lymphocytes from nontumorous kidney from 1 of 8 (12.5%) cases (V beta 5.1) did. Specifically, IL-2-activated RCC-TILs showed oligoclonal expansion of V alpha 2+ cells (8/33 cases, p < 0.05 vs. IL-2-activated patient's PBMC), V beta 5.1+ cells (6/33), V beta 8+ cells (4/33), V beta 12+ cells (4/33), and V beta 6.7+ cells (2/33). Oligoclonal expansion of plural TCR V regions was observed in 6 of 33 cases. IL-2-activated RCC-TILs from 4 of 16 cases produced higher levels of interferon-gamma (IFN-gamma) in culture with autologous tumor cells than with allogeneic tumor cells. Those from 11 of 16 cases did not produce IFN-gamma in response to autologous tumor cells, and the remaining case produced it in a major histocompatibility complex (MHC)-nonrestricted manner. IL-2-activated RCC-TILs with oligoclonal expansion in 4 of 5 cases showed IFN-gamma production in response to the corresponding anti-TCR V region mAb as well as anti-CD3 mAb. IL-2 and IL-4 were not detected in any cases tested. IL-2-activated RCC-TILs displayed cytotoxicity relatively restricted to autologous tumor cells in only 1 of the 16 cases evaluated, MHC-nonrestricted cytotoxicity in 12 cases, NK activity in one case and no cytotoxicity in two cases. In summary, IL-2-activated RCC-TILs demonstrated the oligoclonality in approximately half of the cases (17 of 33, 52%), but rarely displayed either autologous tumor-specific-IFN-gamma production (4 of 16 cases) or -cytotoxicity (1 of 16 cases).
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PMID:T cell functions of IL-2-activated tumor-infiltrating lymphocytes from renal cell carcinoma. 147 75

Previous results from this laboratory have shown the preservation of non-MHC-restricted, constitutive oncolytic activity of human peripheral blood NK cells in the elderly as assessed by the chromium release assay which quantitates the lytic endpoint at the cell population level. We have now addressed this senescence-related change at single-cell level using 101 blood samples. Both the efficiency of the initial tumor target binding step i.e., recognition of K562, the NK-sensitive erythroleukemia cell line, as well as the ability of NK cells to deliver lethal hit are highly conserved during healthy aging. In fact, the elderly exhibit a statistically significant, moderately higher frequency of active killers among circulating lymphocytes. Analyzed in another way, a majority of "high NK responders" were found to be older donors, while none in the "low NK responders" group were > 70 years old. Gamma interferon, a gene product as well as an autocrine activator of NK cells, is effective in converting non-lytic "pre-NK" cells to active killers at single-cell level. This in vitro cytokine sensitivity of NK cells is unaltered during immune senescence. The intactness of the NK cell's capacity to be modulated may be vital in both tumor resistance and host viral defenses of aged humans.
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PMID:Immunosenescence of human NK cells: effects on tumor target recognition, lethal hit and interferon sensitivity. 147 9

For the past several years immunologists have been fascinated by a series of experiments showing that transforming growth factor beta (TGF beta) suppresses T- and B-lymphocyte growth as well as IgM and IgG production by B cells. Moreover, while exerting chemotactic activity on monocytes and inducing expression of interleukin-1 and interleukin-6 by these cells, TGF beta interferes with bacterially induced tumor necrosis factor alpha production, oxygen radical formation and the adhesiveness of granulocytes to endothelial cells. These mechanisms may provide the basis for the effect of TGF beta to prevent the microvascular changes associated with brain edema formation in bacterial meningitis. Given the potential of lymphocytes as well as macrophages to produce TGF beta 1, this cytokine may exert negative feedback signals on the immune response, provided the cytokine is processed from its latent form to the bioactive homodimer. Potent effects of TGF beta have been observed in experimental animals including the inhibition of the generation of virus-specific cytotoxic T cells and antiviral antibodies as well as the diminution of cellular infiltrates with decreased major histocompatibility complex class-II expression and CD8+ T cells in the tissue of virally infected animals. TGF beta may also be of importance in tumor immunology. By the production of bioactive TGF beta as detected in glioblastoma and acute T-cell leukemia, tumor cells may induce an immunodeficiency state and escape immune surveillance. In inflammation, monitoring of TGF beta in the tissue will bring light on the immune regulation in acute and chronic inflammatory diseases.
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PMID:Modulation of the immune response by transforming growth factor beta. 148 57

The cytokine levels of soluble interleukin-2 receptor (sIL-2R), interleukin-6 (IL-6) and tumor-necrosis-factor alpha (TNF-alpha) were studied in 12 healthy volunteers at 11 different times of day. TNF-alpha levels were below the detection limit, and IL-6 levels were at baseline values of the respective assay used. Interindividual variations were found for the plasma levels of sIL-2R (179-524 U/ml). Shedded IL-2 receptors displayed a pronounced circadian phase-dependency (p less than 0.0001) with a peak value at 12:29 h and a trough at 4:14 h when a complex cosine function (period lengths: 24 h plus 12 h) was fitted to the data. These findings may be of importance when using sIL-2R as a diagnostic tool as well as in controlling efficacy of drug treatment.
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PMID:Circadian rhythm of soluble interleukin-2 receptor in healthy individuals. 149 63

The variable clinical response seen with most cancer immunotherapy suggests that there is a large interindividual variation in immunologic response to tumors. One of the key functional parameters of an immune response is the local production of cytokines. As a method to survey the immune status of tumor-infiltrating cells, we have investigated the constitutive expression of cytokine mRNA in biopsies from epithelial ovarian carcinomas by using a PCR-assisted mRNA amplification assay. Using a set of cytokine-specific primers for 10 different cytokines, we have found selective expression of interleukin 10 (IL-10), granulocyte-macrophage colony-stimulating factor, and interferon gamma mRNA in ovarian tumor tissue as compared to normal ovaries and ovarian tumor cell lines. Such differences could not be explained by the extent of T-cell infiltration, since comparing samples with the same intensity of T-cell receptor (TCR) constant region alpha-chain product from the tumor and normal biopsies demonstrated different cytokine patterns. No IL-2 gene expression was detected in the tumor biopsies. IL-2 mRNA, however, became expressed after stimulation of the tumor-derived cells via the CD3 molecule but not after growth in recombinant IL-2 alone. Using the same methodology, we also analyzed the TCR variable region beta-chain gene repertoire. No restriction or biased expression of these genes was observed.
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PMID:Selective expression of interleukin 10, interferon gamma, and granulocyte-macrophage colony-stimulating factor in ovarian cancer biopsies. 150 88

In a serum-free culture system, the release of TNF, lI-1, lI-6, IFN-alpha, and IFN-beta during interaction of elutriated human monocytes (MO) with human tumor cells (TC) was studied by ELISA-technique. Contributions of these cytokines to inhibition of TC-growth and to induction of TC-death by supernatants (SU) gained from such MO/TC-interaction cultures were investigated using affinity chromatography for removal of individual cytokines. Although the TC used are relatively insensitive to recombinant human TNF, withdrawal of TNF causes 50% to 75% reduction of SU-induced TC-death rates, suggesting that susceptibility to TNF is raised during MO/TC-interaction by the other cytokines. Individual removal of other cytokines does not cause reduction of SU-mediated TC-death. However, combined withdrawal of lI-1 and IFN-alpha/beta causes in 2 of 4 TC-lines significant reduction of TC-death. Combined removal of TNF, IFN-alpha/beta, lI-1, and lI-6 leads to complete prevention of SU-mediated growth inhibitory and lytic effects, suggesting that besides these cytokines other signals are not involved significantly. SU-effects can be mimicked by appropriate combinations of authentic cytokines. The response of TC to SU- or cytokine-exposure is strikingly dependent on TC-density, leading at subconfluent TC-density exclusively to inhibition of growth and at postconfluent TC-density to induction of cell death. The principal effect of SU or cytokine combinations in this context seems to be the activation of growth inhibitory signal transduction pathways leading to TC-death in postconfluent TC-populations exclusively if growth stimulatory pathways are activated at the same time. Mouse L cells do not follow this reaction pattern: Their death is exclusively dependent on the presence of TNF in SU and they die upon SU-exposure at postconfluent as well as at subconfluent cell density.
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PMID:Cytokines involved in monocyte mediated tumor cell death and growth inhibition in serum-free medium. 150 17

Antiproliferative cytokine secretion by lymphokine-activated killer (LAK) cells during coculture with glioblastoma cell lines, autologous glioma cells, and nongliomatous tumor cell lines (Daudi and K562 cells) was assessed, as was the antiproliferative activity of the culture supernatants against the T98G (glioblastoma) cell line. A neutralization test using agents against interferon-gamma (IFN-gamma), tumor necrosis factor (TNF), and lymphotoxin (LT) showed that antiproliferative activity was due to IFN-gamma, but not to TNF or LT. Nongliomatous tumor cells stimulated LAK cells to secrete cytokines, but gliomatous tumor cells did not. It was found that there is a discrepancy between the LAK cell capability to lyse malignant glioma cells and the ability to secrete cytokines. This may be due to the factors secreted by glioblastoma cells.
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PMID:Antiproliferative cytokines secreted by lymphokine-activated killer cells stimulated with tumor cells. 150 88

Interleukin-1 alpha (IL-1 alpha) is a low-molecular-weight cytokine that regulates proliferation and differentiation of lymphatic and myeloid cells. It also has pleiotropic activity on a variety of other target cells and acts as an important mediator of inflammation and septic shock. Recombinant human IL-1 alpha (rhIL-1 alpha) is undergoing clinical evaluation of its potential as an anticancer agent. We have studied the growth modulating effects of rhIL-1 alpha on a variety of freshly explanted human tumor specimens using an in vitro soft agar cloning system. Final concentrations of 0.01-100 ng/ml were used in continuous incubation experiments. Of 139 specimens tested, 56 (40%) were evaluable for determination of tumor growth modulating activity. The most common tumor types examined included breast, nonsmall cell lung, ovarian, colorectal cancer, and melanoma. Stimulation of tumor colony-forming units (colony formation greater than or equal to 1.5 x controls) was observed in only 1/56 (2%) tumors. No evidence was found for increased size of individual colonies after incubation with rhIL-1 alpha. At a concentration of 100 ng/ml, colony formation of 9/56 (16%) tumor specimens was significantly inhibited (colony formation less than or equal to 0.5 x controls). We conclude that rhIL-1 alpha is not a major modulator of tumor colony formation in vitro. However, some antitumor effects may be observed at high concentrations.
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PMID:Effects of recombinant human interleukin-1 alpha on clonogenic growth of primary human tumors in vitro. 151 20


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