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)

The observation that malignant cells express antigens that may be recognized by immunocytes and that immune effector mechanisms have the capability of destroying tumor cells has increased our appreciation of the biology of cancer and its relationship to immune function as well as offered new options for therapeutic intervention. Clinical trials are in progress to evaluate several different approaches to modifying the host's immune response against tumor. One approach is to administer agents that have direct activity against the malignancy. For example, antibody conjugates bring cytotoxic molecules of chemotherapy, radioisotopes, or toxins directly to the tumor. A second approach is to administer agents that modulate the host's own antitumor response such as IFN-alpha and IFN-gamma. Adoptive cellular immunotherapy aimed at isolating and expanding the host's own tumor-specific lymphocytes and inducing activation and proliferation with lymphokines such as IL-2 has shown encouraging results. Even though clinical data are still quite premature, it is reasonable to assume that in the future immunomodulation including the stimulation of immune effector mechanisms to eradicate tumor, the reconstitution of immune deficiency in diseases such as AIDS, the suppression of immune function to avoid graft rejection and GVHD, and the isolation and insertion of genes encoding tumor antigens into recombinant vectors to immunize the host to the tumor antigen will be commonly and successfully employed.
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PMID:The role of the immune system in the pathogenesis of cancer. 154 19

Polyethylene glycolated (pegylated) interleukin-2 (PEG IL-2) was administered as a weekly i.v. bolus to patients with metastatic cancer in a phase-I trial. Efficacy, toxicity and pharmacokinetics have been described previously. To explore mechanism of IL-2 action and discover predictors of efficacy, the levels of several lymphokines were measured in pharmacokinetic serum samples. IL-1 beta and IL-6 were elevated in many patients before PEG IL-2 administration, forming a continuous, log-normal distribution among patients. The levels of the two lymphokines were strongly correlated. However, no significant correlation could be found between these levels, clinical chemistry, or tumor regression seen after PEG IL-2 administration. Three hours after PEG IL-2 administration, IL-1 beta and IL-6 levels, if elevated, fell to normal. In all patients, independent of initial levels, IL-6 and IFN-gamma, but not IL-1 beta, increased 4 to 6 h after the injection and then fell rapidly, even though PEG IL-2 levels were high and often changed only slightly during this period. This suggests an active shut down of lymphokine synthesis, or an increase in elimination rate. After the fourth administration of PEG IL-2, the peak level of IFN-gamma was 2 to 20 times higher than after the first, while the peak level of IL-6 did not change in a consistent direction. Responding patients had typical peak levels of IL-6 and IFN-gamma. Low levels of TNF and IL-4 were occasionally seen before and after PEG IL-2 administration, but no consistent pattern was evident.
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PMID:Suppression and transient induction of lymphokines in cancer patients after administration of polyethylene glycolated interleukin-2. 154 19

Quantitative evaluation of the levels of endogenous gamma-interferon (IFN-gamma) and tumor necrosis factor-alpha (TNF-alpha) in the extracts of tumor, peritumoral and normal colorectal tissues resected surgically from 43 patients with colorectal adenocarcinoma was carried out using solid-phase, sandwich radioimmunoassay (RIA). The levels of both IFN-gamma and TNF-alpha detected in the tumor tissues were higher than those in the peritumoral and normal tissues obtained from each patient. A significant negative correlation was observed between the levels of IFN-gamma and TNF-alpha in each tumor tissue. The decrease of endogenous IFN-gamma in the tumors correlated with the advance of histopathological stages. Thirty seven patients were classified into three types according to the endogenous IFN-gamma distribution (intratumoral dominant type, peritumoral dominant type and nonreactive type). There was no significant difference concerning to the tumor diameters among them. However, the mean stage of the intratumoral dominant type was significantly earlier than that of the nonreactive types. On the other hand, the increase of endogenous TNF-alpha correlated with the maximum diameter of primary tumors. The production of endogenous TNF-alpha was localized in the tumor tissues, and the significant elevation of endogenous TNF-alpha was not observed in the peritumoral tissues. The immunohistochemical staining of IFN-gamma- and TNF-alpha-producing cells in tumor tissues represented that IFN-gamma was mainly produced by CD4+CD8-CD11c- lymphocytes and that TNF-alpha was mainly produced by CD4-CD8-CD11c+ cells with macrophage-like morphology. These results suggest that CD4+ lymphocytes producing IFN-gamma might play an important role in the anti-tumor response against cancer progression in human colorectal adenocarcinoma.
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PMID:[Detection of endogenous IFN-gamma and TNF-alpha in tumor-infiltrating mononuclear cells of human colorectal cancer]. 155 60

Eight patients with epithelial ovarian carcinoma persisting after chemotherapy, selected for having a residual tumor no larger than 1 cm in diameter, were treated intra-peritoneally (i.p.) with recombinant interferon-gamma twice weekly for 3 months. Toxicity consisted of fever and malaise in all patients and a transient rise in hepatic enzyme levels in 3 patients. The cytotoxic function of peripheral blood and peritoneal tumor-associated lymphocytes (TAL) and macrophages (TAM), was studied using cell lines as targets. I.p. IFN-gamma augmented the cytotoxic activity of lymphocytes and mononuclear phagocytes: stimulation was more marked and more frequently observed with TAL and occasionally TAM than with blood effectors, suggesting preferential modulation at the site of tumor growth and IFN administration. Surgical laparotomy revealed that 1 patient had a complete response, 2 a partial response and 2 had stable disease, while 3 patients had progressive disease. In this small series of patients there was no obvious, strict correlation between immunomodulation by IFN-gamma and clinical response. These results indicate that, in contrast to its lack of activity in advanced ovarian carcinoma, IFN-gamma has definite immunomodulatory and antitumor activity in the presence of limited tumor burden.
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PMID:Anti-tumor and immunomodulatory activity of intraperitoneal IFN-gamma in ovarian carcinoma patients with minimal residual tumor after chemotherapy. 156 43

Both bacterial and mammalian heat shock proteins (HSP) are recognized by some T cells, and hsp60 recognition has been implicated in rheumatoid arthritis. We have developed a model to study the induction of hsp60 in human monocytic cell lines. An anti-mycobacterial hsp65 mAb (ML30), cross-reacting with human hsp60 was used to screen 21 human tumor cell lines in Western blot analysis. All T cell and B cell lymphomas constitutively expressed hsp60 protein at moderate to high levels, while little or no hsp60 protein was detected in two monocytic leukemia lines. Moderate to high levels of hsp60 mRNA and protein could be induced in the THP-I monocytic leukemia cell line by heat shock, retinoic acid, interferon (IFN)-gamma or tumor necrosis factor (TNF)-alpha treatment, the highest levels obtained with a combination of IFN-gamma/TNF-alpha. This was also seen using two rabbit anti-hsp60 antisera directed against the N-terminal or C-terminal part of the human hsp60 protein. The determinants detected by the ML30 mAb or the two rabbit anti-hsp60 antisera were not cell surface expressed, as measured with immunofluorescence (FACS) analysis on control cultured or cytokine treated cell lines. This could be a useful model for studies related to the induction of hsp60 in human cells.
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PMID:Induction of human hsp60 expression in monocytic cell lines. 156 88

We have analyzed mechanisms controlling infiltration of T lymphocytes into tumor tissues. A lymphocyte chemotactic factor-b (LMF-b) produced by tumor infiltrating CD4+ T lymphocytes was purified. LMB-b was specifically chemotactic for CD8+ T lymphocyte. Furthermore, LMF-b augmented lymphocyte adhesion to high endothelial venule (HEV) cells. The binding of CD8+ T cells to HEV cells was specifically augmented by LMF-b. The LMF-b primarily acted on T lymphocytes, whereas tumor necrosis factor as well as IFN-gamma acted on HEV cells or fibroblast cells. The binding of lymphocytes to fibroblast cell line was not augmented by LMF-b. The augmentation of lymphocyte adhesion to endothelial cells by LMF-b was mediated by the lymphocyte function associated antigen-1/intercellular adhesion molecule (LFA-1/ICAM) pathway, the CD2/LFA-3 pathway, and the very late antigen-4/culture supernatant-1 (VLA-4/CS-1) pathway.
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PMID:Functional analysis of mononuclear cells infiltrating into tumors. VI. The effect of lymphocyte chemotactic factors on lymphocyte adhesion to endothelial cells. 156 94

Extracorporeal photopheresis (ExP) has been shown to be an efficacious and well-tolerated therapy in the treatment of cutaneous T-cell lymphoma (CTCL) and systemic sclerosis. However, the precise mechanisms of its action have not been defined. Because of a correlation between the development of fever in the early phase of treatment of CTCL and subsequent anti-tumor responses, we examined the production of the proinflammatory, pyrogenic cytokines tumor necrosis factor-alpha (TNF), IL-6, IL-1 alpha, and IL-1 beta before and after ExP. Monocytes were purified from peripheral blood specimens of normal volunteers (n = 4) or from peripheral blood specimens of CTCL (n = 6) or systemic sclerosis (n = 3) patients that were obtained immediately prior to ExP and also directly from the photopheresis unit after ExP, just prior to reinfusion into the patient. Monocytes were then cultured under various conditions for 16 h, after which the culture supernatants were collected and assayed for specific cytokine production. ExP induced a significant increase in the production of TNF (p less than 0.008) and IL-6 (p less than 0.05) as compared to non-ExP-treated cells, whereas no significant differences were observed in IL-1 alpha (p less than 0.5) and IL-1 beta (p less than 0.2) production following ExP. Exposure of monocyte cultures to IFN-gamma (100 U/mL) either before or after ExP further enhanced TNF production by 4 to 28 times. In contrast, incubation with IFN-alpha (100 U/mL) had no significant effect on TNF production. Addition of TNF (500 U/ml) to monocyte cultures obtained prior to ExP resulted in a slight but insignificant increase in TNF production in 2 of 10 cases. However, when monocytes obtained prior to ExP were incubated with 8-methoxypsoralen (8-MOP, 100 ng/ml), exposed to ultraviolet light A (UVA, 2J/cm2), washed, and then incubated with TNF, a significant increase (p less than 0.01) in TNF production was observed in 8 of 10 cases, suggesting that the combination of 8-MOP and UVA may sensitize cells to TNF. Based on studies of endotoxin (LPS)-stimulated production of TNF by monocytes, levels of endotoxin in culture reagents or photopheresis equipment could not account for the increased production of TNF following treatment by ExP. Increased TNF production as a result of ExP may have important implications for treating both CTCL and systemic sclerosis because, in the case of CTCL, it could mediate numerous anti-tumor effects, whereas, in the case of systemic sclerosis, it could suppress collagen synthesis and induce collagenase production.
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PMID:Extracorporeal photochemotherapy induces the production of tumor necrosis factor-alpha by monocytes: implications for the treatment of cutaneous T-cell lymphoma and systemic sclerosis. 156 19

Macrophage inflammatory protein 1 (MIP 1), initially purified from the conditioned medium of endotoxin-stimulated macrophages, is a low m.w. heparin-binding protein doublet comprising two peptides, MIP 1 alpha and MIP 1 beta. Although native doublet MIP 1 has previously been shown to exert pyrogenic, mitogenic, and proinflammatory effects on other cell types, its actions on its cell of origin, the macrophage, have not been well catalogued. Our study reports several aspects of macrophage function that are modulated by MIP 1. MIP 1 was not directly cytotoxic for WEHI tumor cells, but MIP 1-treated macrophage exhibited enhanced antibody-independent macrophage cytotoxicity for tumor targets. MIP 1 treatment stimulated proliferation of mature tissue macrophages, and this effect was enhanced upon costimulations with either CSF-1 or granulocyte-macrophage-CSF. Thioglycollate-elicited peritoneal exudate macrophages incubated with native doublet MIP 1-secreted bioactive TNF and IL-6, as well as immunoreactive IL-1 alpha, and these effects were enhanced significantly when the cells were costimulated with IFN-gamma. Purified preparations of the recombinantly derived MIP 1 alpha peptide alone stimulated the secretion of TNF, IL-1 alpha, and IL-6 by peritoneal macrophages, but MIP 1 beta did not. In fact, as little as eightfold excess MIP 1 beta blocked TNF-induction by MIP 1 alpha to a significant degree. By contrast to these apparent "macrophage activating" properties of MIP 1, the cytokine failed to trigger the macrophage oxidative burst, or to up-regulate the expression of Ia on the macrophage surface. Taken together, these data reveal that MIP 1 peptides act as autocrine modulators of their cells of origin, and raise the possibility that MIP 1 peptides may play a role in modulating macrophage responses to inflammatory stimuli in vivo.
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PMID:Macrophage inflammatory protein 1 modulates macrophage function. 157 67

Local inflammation induces increased expression of MHC and other genes in the affected tissue because of the paracrine effects of cytokines such as IFN-gamma. We previously reported that one such process--local allograft rejection--was accompanied by increased expression of MHC in a remote tissue, namely kidney. To explore how local inflammation affects gene expression in remote tissues, we studied MHC, beta 2-microglobulin, and IFN-gamma expression in mice undergoing either of two T cell-dependent localized inflammatory processes: rejection of an ascites tumor allograft, and skin sensitization by oxazalone. As assessed by binding of radiolabeled mAb and by immunohistology, each stimulus increased MHC expression in many remote tissues, including liver, heart, pancreas, and kidney. This was associated with increases in steady state mRNA for class I, class II, and beta 2-microglobulin. MHC induction was inhibited by the in vivo administration of cyclosporine or anti-IFN-gamma mAb and did not occur in nude mice, confirming the key role of IFN-gamma released from T cells. When we examined tissues of mice with these localized inflammatory lesions for IFN-gamma mRNA levels by polymerase chain reaction, we found that IFN-gamma steady state mRNA levels were increased in the spleen and, more surprisingly, in the kidney, and in uninvolved skin. Moreover, anti-IFN-gamma inhibited the induction of IFN-gamma mRNA in the kidney, suggesting that IFN-gamma expression was induced by IFN-gamma in an autoregulatory fashion. Thus the systemic MHC induction accompanying local T cell-mediated inflammation reflects the release of IFN-gamma from the site of inflammation, but may be amplified by the ability of IFN-gamma to induce its own expression in remote tissues. This self-amplification of IFN-gamma may contribute to the ability of local inflammation to induce extensive systemic effects.
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PMID:Local T cell responses induce widespread MHC expression. Evidence that IFN-gamma induces its own expression in remote sites. 160 32

The GG2EE macrophage tumor cell line was previously established by immortalization of C3H/HeJ mouse bone marrow cells with the J2 retrovirus which contains the v-myc and v-raf oncogenes. Studies on the control of GG2EE cell proliferation in vitro have recently been performed. We observed that the combination of 5-25 U/ml recombinant mouse interferon-gamma (rmIFN-gamma) plus 0.03-0.3 micrograms/ml lipopolysaccharide (LPS) markedly inhibited the proliferation of GG2EE cells (by greater than 95%) in vitro, while either agent alone inhibited only by less than 40% and 0-10%, respectively. Subsequent studies established that biologically active IL1-like (2-4 U/ml) and TNF alpha-like (50-100 U/ml) activities were released into the supernatants of LPS-treated GG2EE cells. The combination of IFN-gamma + LPS induced more (6-8 U/ml) IL1 release. These results suggested that the inhibition of proliferation of GG2EE cells by IFN-gamma + LPS could have been mediated in part by cytokines produced by the cells themselves. rhIL1 alpha at a concentration of 10 U/ml inhibited GG2EE proliferation by 25-30%, while rmIFN-gamma (25 U/ml) + rhIL1 alpha (10 U/ml) inhibited proliferation by 98%. Thus, 10 U/ml rhIL1 alpha could completely replace LPS in the LPS + rmIFN-gamma combination. Further, the combination of low doses of rhIL1 alpha (0.1 to 1 U/ml) plus rmTNF alpha (250 U/ml), which together inhibited proliferation by less than 20% synergized with doses of 5 to 25 U/ml rmIFN-gamma to inhibit proliferation of GG2EE cells by 98-99%. These results suggest that cytokines produced by the cells themselves can synergize with rmIFN-gamma to inhibit the oncogene-driven proliferation of GG2EE cells.
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PMID:Inhibition of proliferation of retrovirus-immortalized macrophages by LPS and IFN-gamma: possible autocrine down-regulation of cell growth by induction of IL1 and TNF. 162 40


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