Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0699790 (colon cancer)
 28,837 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Derivatives of xanthenone-4-acetic acid (XAA) have been found to have similar activity to flavone-8-acetic acid against transplantable solid tumors. Some of these compounds were compared to flavone acetic acid (FAA) in their ability to induce cytokines as well as to mediate antitumor effects against murine renal cancer (Renca) and a mouse colon cancer (MCA-38). 5-Methyl-XAA and 5-chloro-XAA proved to be more potent than FAA on a mg/kg basis for induction of the genes for IFN alpha, IFN gamma, and TNF alpha, and for IFN and TNF activities in the sera of treated mice. These effects were sharply dose dependent. On the other hand, 7-methyl-XAA, which has no antitumor activity, did not induce these genes. In addition, 5-methyl-XAA and 5-chloro-XAA but not 7-methyl-XAA synergized with recombinant human interleukin-2 (rhIL-2) for the treatment of Renca and MCA-38. Doses of the active derivatives that failed to induce cytokines also exhibited no therapeutic synergy with rhIL-2. These results suggest that at least some of the antitumor effects of these XAA derivatives are related to their ability to induce cytokines.
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PMID:Cytokine induction and therapeutic synergy with interleukin-2 against murine renal and colon cancers by xanthenone-4-acetic acid derivatives. 147 76

TNF, a cytokine produced by macrophages, is able either to exert an antitumor activity, or to determine severe clinical complications, such as cachexia and septic shock. Increased blood levels of TNF have been described in cancer patients. The present study was performed to better define TNF secretion in patients with solid tumors. The study included 48 cancer patients (lung cancer: 22; colon cancer: 11; breast cancer: 10; renal cancer: 5), and among them 27 showed distant organ metastases. TNF serum levels were measured by IRMA method. The control group comprised 40 healthy subjects. TNF levels were also evaluated in relation to those of SIL-2R, whose increase seems to be associated with an unfavorable prognosis in cancer. High levels of TNF were seen in 27/48 (56%) patients. Mean levels of TNF were significantly higher in cancer patients than in controls. Moreover, within the cancer group, TNF mean values were significantly higher in metastatic patients than in those without metastases; the highest levels were observed in patients with visceral lesions as dominant metastasis sites. Finally, patients with high TNF concentrations showed significantly higher mean levels of SIL-2R than those with normal values. This study shows that the neoplastic metastatic disease is associated with an exaggerated TNF secretion.
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PMID:Tumor necrosis factor in solid tumors: increased blood levels in the metastatic disease. 149 96

Tumor-infiltrating lymphocytes (TIL) were isolated from 22 human primary and metastatic liver tumors, and expanded in vitro in the presence of either interleukin-2 (IL-2, 100 U/ml) plus tumor necrosis factor alpha (TNF alpha, 1000 U/ml), IL-2 (1000 U/ml) plus IL-4 (1000 U/ml) or IL-2 (1000 U/ml) alone. TIL proliferated in culture in 20/22 cases. Among different cytoline combination, TNF alpha and IL-2 were most effective in promoting the outgrowth of CD3+CD8+T lymphocytes (mean +/- SEM: 90% +/- 5) in the cultures of TIL from primary liver tumors. Cytotoxicity against autologous tumor cells was demonstrated in all early cultures of TIL from primary liver cancers in the presence of IL-2 plus TNF alpha. In contrast, cultures of TIL derived from colon cancer metastatic to liver had significantly lower levels of autotumor cytotoxicity and proportions of CD3+CD8+ cells (40% +/- 13) than those of TIL from primary liver tumors. The addition on day 0 of interferons (alpha or gamma) to TIL cultured in the presence of TNF alpha and IL-2, significantly augmented cytotoxicity against autologous tumor. In contrast, incubation of TIL in the presence of IL-4 and IL-2 did not result in increased autotumor responses in the cultures of TIL from primary liver tumors. The expansion (-fold) of TIL (day 30) cultured in the presence of IL-2 alone compared to that in the presence of TNF alpha and IL-2 was significantly greater for hepatocellular carcinoma (median, 280 vs 260) than for autologous peripheral blood lymphocytes (36 vs 27), cholangiocarcinoma (42 vs 51) or TIL from metastatic colon cancer (39 vs 30). Outgrowth of TIL in IL-2 plus TNF alpha offers an opportunity for in vitro enrichment in cells with autotumor cytotoxicity in primary liver tumors. However, this cytokine combination was unable to promote and sustain growth of autotumor effectors from TIL in metastatic liver cancer.
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PMID:Effects of cytokines on in vitro growth of tumor-infiltrating lymphocytes obtained from human primary and metastatic liver tumors. 184 44

Human blood monocytes isolated by centrifugal elutriation from healthy donors were tested for ability to produce membrane-associated antitumor monokine(s) in response to activation stimuli such as various types of interferon (IFN) and/or synthetic desmethyl muramyl dipeptide (norMDP). IFNs (alpha, beta, and gamma) and norMDP rendered blood monocytes cytotoxic to allogeneic A375 melanoma cells, as assayed by measuring release of [125I]iododeoxyuridine in 72 h. When monocytes were treated with any type of IFN for 16 h, and then fixed with paraformaldehyde, they did not show cytotoxicity to A375 cells, but when they were fixed after treatment with norMDP or lipopolysaccharide they showed significant cytotoxicity to A375 melanoma cells. This membrane-associated antitumor monokine induced by the synergistic actions of suboptimal concentrations of IFN-gamma and norMDP, was cytotoxic to HT-29 colon cancer cells as well as A375 melanoma cells, but not to actinomycin D-treated L-929 cells. The fixed monocyte-mediated cytotoxicity against A375 melanoma cells was completely inhibited by a specific anti-interleukin 1 alpha antiserum, but not by a specific anti-interleukin 1 beta antiserum or monoclonal anti-TNF antibody. These results suggest that membrane-associated interleukin 1 alpha is involved through cell-to-cell contact in the host defense mechanism against cancer.
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PMID:Membrane-associated interleukin 1 alpha as a mediator of tumor cell killing by human blood monocytes fixed with paraformaldehyde. 246 72

rTNF was administered to 28 patients with advanced metastatic cancers by continuous intravenous infusion for 5 consecutive days every 2 weeks. The dose levels were 30, 40, 70, 110, 180 and 290 micrograms/M2/day. Groups of 3 patients were started at each successive dose level and then on subsequent courses treated with the next dose level through 4 escalations as tolerated. Tumor types were: colon cancer 14; adenocarcinoma of unknown primary, 2; renal cancer, 2; leiomyosarcoma, 2; lung cancer, 1; prostate cancer, 1; thymona, 1; bladder cancer; 1; parotid, 1; Kaposi's sarcoma 2; ovarian 1. Toxicities included fever and chills (usually within the first 8 hours of infusion), fatigue, headache, decreased performance status, hypotension and CNS. All patients experienced leukopenia and thrombocytopenia within 24 hours or less after start of infusion with return of baseline by 72 hours after rTNF was stopped. The fall in these counts averaged 50% and was not dose related. No major changes in liver or renal function, coagulation or blood lipids were seen. Major dose limiting toxicities were fatigue, confusion, thrombocytopenia, seizures, hypotension and decreased performance status. NK cell activity measured against K562 target cells was augmented from about 30% target cell lysis to about 70% target cell lysis over the first 7 days of treatment. Two patients, both with metastatic colon cancer showed transient, objective tumor regression which did not qualify as a partial response. One patient with ovarian cancer had a stable partial response but progressed after 13 courses of treatment. Continuous infusion of TNF can be safely administered to patients with a maximum tolerated dose of only between 30 and 40 micrograms/M2/day.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:A phase I trial of recombinant tumor necrosis factor (rTNF) administered by continuous intravenous infusion in patients with disseminated malignancy. 264 24

Mouse mAb M111 identifies a cell surface glycoprotein of 115,000 to 135,000 Da. M111 was expressed constitutively in subsets of cells of multiple lineages at discrete stages of cell maturation, suggesting that M111 is a differentiation Ag of the three germ layers. Ag expression could be induced by IFN-gamma but not by IFN-alpha, IFN-beta, or TNF. Induction of M111 expression was maximal at 48 h of culture in 200 U/ml of IFN-gamma and was independent of induction of class II MHC Ag. Induction was dependent on the cell type used. Nine colon cancer cell lines of undifferentiated phenotype were constitutively M111-; IFN-gamma induced M111 expression in seven of them. In contrast, IFN-gamma failed to induce M111 expression in six of six M111- ovarian cancer cell lines. Eight normal fibroblast cultures tested were M111-; they could not be induced to express M111. Three of five sarcoma cell lines were M111+; culture in IFN-gamma induced an increase in M111 expression in all of them. Constitutive and IFN-gamma-induced expression of M111 was independent of constitutive and induced expression of HLA class I and II molecules. IFN-gamma-mediated induction of M111 expression was not accompanied by coordinate changes in the expression of other differentiation traits. These results suggest that expression of the M111 gene is controlled by two mechanisms, one related to differentiation and the other activated by IFN-gamma.
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PMID:IFN-gamma-regulated expression of a differentiation antigen of human cells. 312 30

Recent reports demonstrating that the lethal effects of radiation on tumour cells can be augmented by tumour necrosis factor-alpha (TNF-alpha) prompted us to investigate whether this premise holds true for the LS174T human colon adenocarcinoma cell line. Three different techniques were used to assess cell damage: 3H-thymidine (3H-TdR) uptake, clonogenic survival, and vital dye exclusion. In these assays human recombinant TNF-alpha treatment was administered before single-dose-gamma-radiation at 4, 6, 8, or 10 Gy. Oxygen radical formation by the tumour cells in the presence of TNF-alpha and radiation, alone and in combination, was also investigated. TNF-alpha and radiation, when used as single modalities, decreased LS174T cell viability with time. However, treatment with TNF-alpha before irradiation resulted in highly significant reductions in 3H-TdR uptake and decreased clonogenic survival compared to their counterparts receiving only radiation. Our data show that these two measurements of tumour-cell damage correlate well. No difference was noted in vital dye exclusion when comparisons were made between TNF-alpha+radiation and radiation alone. This latter finding may be partly due to the fact that although apoptotic cells are 'dead', they generally do not become more permeable to normally excluded macromolecules. Chemiluminescence measurements indicate that the radiation-enhancing mechanism of TNF-alpha may be related to oxygen radical production by the LS174T cells. Taken together our results suggest that TNF-alpha may be useful as an adjunctive modality in the radiotherapy of colon cancer.
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PMID:Interaction of tumour necrosis factor-alpha and radiation against human colon tumour cells. 758 76

The modulation of urokinase plasminogen activator receptor (uPAR) gene expression by tumor necrosis factor alpha (TNF alpha), phorbol ester (PMA) and amiloride was studied in three colon cancer cell lines. uPAR mRNA and protein were induced by TNF alpha and by PMA but were inhibited by amiloride at concentrations of 0.1 to 1 mM in the presence or absence of TNF alpha and PMA. Nuclear run-on transcription assay indicated that the effects of amiloride and TNF alpha were mediated at least in part at the transcriptional level, whereas PMA may act in part via a posttranscriptional mechanism. These results suggested that uPAR gene expression is modulated by multiple signal transduction pathways.
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PMID:Human urokinase receptor expression is inhibited by amiloride and induced by tumor necrosis factor and phorbol ester in colon cancer cells. 792 38

Tumor necrosis factor-alpha receptors (TNFR-55 and TNFR-75) were inserted into retrovirus derived vector. They were transfected into a packaging cell line. The high titer of transfectants, which produced virus containing TNFR-55 or TNFR-75, was obtained. TNFR-55 and TNFR-75 negative human colon cancer cells were infected with this virus as a model experiment of gene therapy. Although the original colon cancer cell line did not express TNFR-55 or TNFR-75, the colon cancer cells, which were infected by recombinant virus, expressed a high level of TNFR-55 or TNFR-75. TNFR-55 or TNFR-75 transformed colon cancer cells were killed by recombinant TNF.
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PMID:Gene transfer of TNF receptor for treatment of cancer by TNF. 806 Mar 37

Recombinant human tumor necrosis factor and recombinant human gamma interferon (IFN-gamma) exert synergistic growth inhibitory effects in WiDR human colorectal carcinoma cells. In this cell line, tumor necrosis factor increases IFN-gamma binding. Interleukin 1 (IL-1) is a cytokine that mimics many of the biological actions of TNF. Therefore, in the present study, we investigated the effects of recombinant human IL-1 on cell growth and IFN-gamma receptor expression in WiDR cells. IL-1 slightly inhibited the growth of WiDR cells, and exerted additive growth inhibitory effects in the presence of IFN-gamma. IL-1 caused a time- and dose-dependent increase in 125I-labeled IFN-gamma binding that was maximal at 6 h, persisted for at least 24 h, and was blocked by both actinomycin D and cycloheximide. The increase in binding was associated with an increase in cell surface IFN-gamma receptor protein expression as determined by Scatchard analysis of equilibrium binding data and by immunofluorescent staining with an anti-human IFN-gamma receptor monoclonal antibody. IL-1 also produced a time- and dose-dependent increase in IFN-gamma receptor mRNA levels that was maximal at 3 h and persisted for at least 24 h. Actinomycin D, but not cycloheximide, completely blocked the IL-1-mediated increase in IFN-gamma receptor mRNA levels. However, IL-1 did not alter IFN-gamma receptor mRNA half-life. These data indicate that IL-1 and IFN-gamma exert additive growth inhibitory effects on colon cancer cell growth, and suggest that IL-1 increases IFN-gamma receptor expression in these cells by enhancing IFN-gamma mRNA levels.
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PMID:Growth inhibition of a human colorectal carcinoma cell line by interleukin 1 is associated with enhanced expression of gamma-interferon receptors. 842 99


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