Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007097 (carcinoma)
 152,788 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The clinical application of anticancer cytokines (interferons, interleukin-1, interleukin-2 and tumor necrosis factor) are reviewed. Although anticancer cytokines have confirmed its usefulness against some tumors which are refractory to the treatment using anticancer drugs, the results of clinical trials have generally been disappointing because the target spectrum and efficiency is somewhat limited. Recently, combined efficacy between interferon and anticancer drugs was reported in some malignancies such as multiple myeloma and colorectal carcinoma. For the development of effective combination treatment, we need more basic and clinical information on dose, schedule and sequence of drug administration.
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PMID:[Clinical application of anticancer cytokines]. 127 41

The effect of the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA) and the cytokines interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNF-alpha) on matrix metalloproteinases (MMP) and metalloproteinase inhibitors was studied in a variety of human cell lines. Expression of the mammalian collagenase (MMP-1), 72-kD gelatinase/type IV collagenase (MMP-2), stromelysin (MMP-3), 92-kD gelatinase/type IV collagenase (MMP-9), and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) was assessed by zymography and Northern blot analysis. MMP-2 and TIMP-2 activities were refractory to TPA, IL-1 and TNF-alpha treatment in most of the cell lines. In contrast, MMP-3, MMP-9 and TIMP-1 activities were markedly stimulated by TPA in most of the tumor cell lines and human umbilical vein endothelial cells (HUVEC), whereas the fibroblast lines were minimally stimulated or unresponsive to TPA. The MMP-3, MMP-9 and TIMP-1 stimulation in response to IL-1 and TNF-alpha treatment was detected in some of the tumor cell lines and HUVEC. The increase in activity was less marked than in TPA. A breast carcinoma cell line, MDA-MB-231, which did not express MMP-2, had high expression of MMP-3 and MMP-9 which were unaffected by TPA and cytokine treatment. Northern blot analysis of MMP and TIMP mRNA expression reflected the zymogram findings for most of the cell lines. TPA-mediated stimulation of MMP-1 was similar to that of MMP-3 and MMP-9. Exceptions were the fibroblast cell lines which showed either a much more marked mRNA response of MMP-9 to TPA than observed at protein level, or a high constitutive MMP-9 mRNA when MMP-9 activity was not detectable by zymography. TPA-mediated stimulation of MMP-9 and TIMP-1 activity was blocked by staurosporine, an inhibitor of protein kinase C (PKC). A non-PKC-activating phorbol ester, 4 alpha-phorbol-12,13-didecanoate, did not stimulate MMP-9 and TIMP-1 activity. TPA treatment caused the increased expression of c-fos containing AP-1-specific binding activity in selected tumor cell lines. This activity was maximal at 6 h. An association was observed between AP-1 binding activity and increased expression of MMP-1, MMP-3 and MMP-9, which possess TPA-responsive elements (TRE). TPA-sensitive MMPs and TIMP-1 were variably stimulated by biologically relevant cytokines, such as IL-1 and TNF-alpha.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Effect of phorbol ester and cytokines on matrix metalloproteinase and tissue inhibitor of metalloproteinase expression in tumor and normal cell lines. 128 26

Human papillary thyroid carcinoma (PTC) has a relatively benign prognosis despite a high frequency of lymphatic metastasis. This suggests that local anticancer factors, generated in lymph nodes, control PTC progression. The cytokine, tumor necrosis factor-alpha (TNF-alpha), may be one such factor. We have previously shown that a human PTC cell line (NP-PTC) has high affinity TNF-alpha receptors. We now report on the action of TNF-alpha in these cells. TNF-alpha decreased [3H]thymidine incorporation as well as cellular DNA content and cell number in a dose-dependent manner. The abundance of phosphodiesterase and manganous superoxide dismutase mRNA species was increased in a time- and dose-dependent manner in the NP-PTC cells after TNF-alpha treatment. TNF-alpha activated NF-kappa B, a nuclear factor thought to mediate multiple actions of TNF-alpha, in these cells with a maximum effect observed after 30 min of treatment. Thus, TNF-alpha has an antiproliferative action on NP-PTC cells, despite its ability to induce the accumulation of mRNA that encodes an enzyme (manganous superoxide dismutase), thought to be cytoprotective. The net antiproliferative effect must therefore be explained by a balance of protective and tumoricidal or static effects that ultimately result in control of tumor spread. These antiproliferative effects may be in part mediated by NF-kappa B and PDE.
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PMID:Tumor necrosis factor-alpha activates nuclear factor kappa B and induces manganous superoxide dismutase and phosphodiesterase mRNA in human papillary thyroid carcinoma cells. 132 6

Using polymerase chain reaction (PCR), we confirmed the expression of interleukin-1 alpha (IL-1 alpha) by the human nasopharyngeal carcinoma (NPC) cell line C15 without contribution of either human IL-1 beta or mouse IL-1 alpha in the biological activity previously found in C15. However we showed that IL-1 alpha was not expressed in all NPCs. IL-1 beta and/or tumor necrosis factor (TNF)-alpha genes could also be activated, independently from the number of Epstein Barr Virus (EBV) copies harbored by the cells. Interestingly, the primary tumor C15 showed a profile of TNF-sensitive tumor while C17, C18 and C19 which were derived from metastasis have a typical profile of TNF-resistant cells. Furthermore, the inflammatory cytokines whose genes are classically induced by IL-1 and TNF were found expressed only in C17 and C19 suggesting another level of heterogeneity among NPCs.
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PMID:Heterogeneity among human nasopharyngeal carcinoma cell lines for inflammatory cytokines mRNA expression levels. 132 86

Alterations in cellular biochemistry which are associated with the development of resistance to cytotoxic peptides, such as tumor necrosis factor (TNF), may also be responsible for changes in the response of cells to cytotoxic agents. Culturing ME-180 cervical carcinoma cells in the presence of escalating concentrations of TNF resulted in the development of an ME-180 cell variant (ME-180R) resistant to TNF but expressing a 3-5-fold increased sensitivity to cisplatin (CDDP) when measured following continuous exposure (low doses) or short-term incubation with CDDP (high doses) and clonogenic analysis. Cellular platinum uptake, efflux, and nuclear platinum content as well as the extent of DNA platination were examined and found to be identical in both ME-180 parental and ME-180R cell lines. Although ME-180R cells showed a relatively higher glutathione content than ME-180 parental cells, the effect of buthionine sulfoximine on the cellular sensitivity to CDDP and glutathione S-transferase activities of both cell lines were almost identical, suggesting that glutathione content or its metabolism did not appear to play a major role in differential CDDP cytotoxicity. Unscheduled DNA synthesis following exposure to CDDP was more inducible in ME-180 parental cells than in CDDP-sensitive ME-180R cells. Alkaline elution studies of cross-linked DNA in CDDP-treated ME-180 cells suggested that accumulation of DNA adducts reached maximal levels 10-15 h after CDDP treatment and was similar in both TNF-resistant and parental cells. Within 24 h after CDDP exposure, the extent of DNA cross-linking was markedly reduced in parental cells but remained elevated in the CDDP-sensitive ME-180R cell line. To examine the proposed regulatory role of phosphorylation in CDDP and TNF-mediated cytotoxicity, epidermal growth factor (EGF) receptor tyrosine kinase activity was measured in both TNF-resistant and parental ME-180 cells. Analysis of cell lysates demonstrated a 3-4-fold higher EGF receptor tyrosine kinase activity in ME-180R cells when compared to the parental population which correlated with increased expression of EGF receptor protein by immunoblot analysis. Based upon colony-forming assays, EGF treatment of ME-180 parental cells resulted in an increased sensitivity to CDDP (similar to ME-180R cells) and 3-fold stimulation of EGF receptor tyrosine kinase activity. Taken together, these results suggest that TNF resistance in ME-180 cervical carcinoma cells correlates with both increased EGF receptor expression and enhanced CDDP cytotoxicity.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Resistance of human cervical carcinoma cells to tumor necrosis factor correlates with their increased sensitivity to cisplatin: evidence of a role for DNA repair and epidermal growth factor receptor. 138 Aug 90

One molecular alteration that has been observed in the majority of colorectal carcinomas is the activation of pp60c-src kinase. To address the role of pp60c-src in growth control of colon carcinoma cell lines, the effects of the biologic response modifier, tumor necrosis factor (TNF)-alpha were studied on the established HT29 colorectal carcinoma cell line and two clonal variants derived from the parental line. In one clone, HT29-A34, approximately 55% growth inhibition was observed following a 120-h incubation period with 10(3) U/ml TNF. In this TNF-sensitive cell line, pp60c-src immune complex kinase activity was reduced 3.9-fold accompanied by only a slight reduction in pp60c-src protein levels. Growth inhibition and decreased pp60c-src kinase activity correlated in a dose-dependent manner. The HT29-A14 TNF-resistant clone was not growth-inhibited by TNF, and no changes in pp60c-src were observed following treatment. Growth inhibition also correlated with reduced pp60c-src kinase specific activity in a number of other established colon carcinoma cell lines that were TNF-sensitive. In TNF-resistant colon carcinoma cell lines, pp60c-src kinase activity and levels remained unchanged. When changes in specific activity of pp60c-src were observed in sensitive cells, they occurred after decreased [3H]-thymidine uptake was observed. Therefore, these changes in pp60c-src activity are not the earliest event in TNF-induced growth inhibition. Nevertheless, our results suggest that modulation of pp60c-src kinase activity may be important in growth control of colorectal carcinoma cell lines.
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PMID:Growth inhibition of human colorectal carcinoma cell lines by tumor necrosis factor-alpha correlates with reduced activity of pp60c-src. 138 Dec 17

Treatment of human carcinoma xenotransplants in athymic mice with recombinant human tumor necrosis factor (rh TNF) causes necrosis mainly in the central parts of the tumors, while peripheral sections remain mitotically active. As tumors are known to be supplied with adequate glucose exclusively in their periphery, the influence of the lack of glucose on the cytotoxic activity of rh TNF was studied. The absence of glucose enhanced the killing of tumor cell lines by rh TNF in tissue culture. Meth-A, a cell line known to be resistant to TNF in vitro but highly sensitive to it in vivo, was readily killed in tissue-culture medium lacking glucose. All non-transformed cell lines tested were found to be resistant to rh TNF, regardless of the presence or absence of glucose. In tumor-bearing mice a reduction of the blood glucose content augmented by insulin led to increased anti-tumor efficiency of rh TNF. The enhanced anti-tumor activity was reflected both in histological sections of the tumor xenotransplants, by extensive central necroses, and by reduction of the tumor volumes.
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PMID:Glucose depletion enhances the anti-tumor effect of TNF. 139 14

The effects of the i.v. administration of endotoxin (6.25-50 micrograms/mouse on day 13 after tumor implantation) in mice treated orally with lysozyme hydrochloride (100 mg/kg on days 5-12 from tumor implantation) were examined using Lewis lung carcinoma in the C57Bl mouse and MCa mammary carcinoma of CBA mice. On primary tumor growth, endotoxin alone causes a dose-dependent and statistically significant reduction with a nadir on day +2 from endotoxin treatment. Combined with lysozyme, endotoxin causes an effect independent of the dose used, corresponding to the effect caused by endotoxin alone at the dose of 25 micrograms/mouse. No tumor regression was recorded in any of the treated groups. Endotoxin is virtually devoid of effects at the metastatic level. In the same conditions, lysozyme causes a reduction of primary tumor growth and a more pronounced inhibition of lung metastasis formation as expected from its already reported effects. The antitumor activity of endotoxin, unlike lysozyme, can be ascribed to tumor hemorrhagic necrosis due to tumor necrosis factor (TNF) production, as determined in tumor homogenates. Endotoxin does not increase the antitumor effects in mice treated with lysozyme, as expected from the data obtained with the more immunogenic SA1 sarcoma, although lysozyme increased the mitogenic response to ConA of ex vivo isolated splenocytes, in vitro cultured in the presence of IL-2.
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PMID:Effects of endotoxin in mice bearing solid metastasizing tumors and treated with lysozyme hydrochloride. 140 79

The antineoplastic properties of suramin, a polyanionic agent with demonstrated antigrowth factor activity, are under evaluation in vitro, in vivo, and in clinical trials. Suramin has been shown to have antitumor activity in patients with advanced, hormone refractory prostate cancer. During these trials, significant resolution of osseous pain was observed in nearly three quarters of the patients treated with suramin. To evaluate the effect of suramin on bone cells, we studied the effect of suramin on bone resorption in a neonatal mouse calvarial assay. Suramin inhibited bone-resorbing activity in a dose-related fashion and had an additive effect with calcitonin. Calvaria pretreated with suramin had less bone-resorbing activity, fewer attached osteoblasts, and less medium alkaline phosphatase activity than control calvaria. Suramin also inhibited osteoclastic release of tritiated proline from labeled bone in a dose-dependent fashion. The effect of metastatic prostate carcinoma on bone is incompletely understood, but may be moderated by tumor-produced factors and/or cytokines. The effects of several such agents, therefore, were examined in combination with suramin. Bone resorption induced by PTH, epidermal growth factor, tumor necrosis factor, and a tumor-produced factor, PTH related-protein, was blocked by suramin. The ability of suramin to inhibit the bone-resorbing effects of several cytokines suggests that its mechanism may involve direct action on bone metabolism. Autoradiography performed on calvaria treated with labeled suramin demonstrated heavy deposition of suramin on the outer surface of the matrix, adjacent to osteoblasts and osteoclasts lining the outer table, suggesting that bone cells may be subject to high local concentrations of the drug, in keeping with this hypothesis.
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PMID:Suramin inhibits bone resorption and reduces osteoblast number in a neonatal mouse calvarial bone resorption assay. 142 26

The antitumor effect of tumor necrosis factor (TNF) in combination with Cis-diammine-dichloroplatinum (II) (Cisplatin) upon implanted bladder carcinoma (MBT-2) in mice was analysed together with the toxicity. Mice were implanted into the bladder wall with about 10(4) cells MBT-2 viable cells. TNF was the purified human natural tumor necrosis factor. The antitumor effects were evaluated by the volume of the tumor thus implanted and the drug-toxicity by the body weight of mice and microscopic as well as macroscopic findings of the main organs. As a result, 1) The toxicity of TNF to mice was not enhanced in a dose-dependent fashion when combined with Cisplatin. 2) The antitumor effect by combination of TNF and Cisplatin was significantly increased compared to control group. 3) The effects of TNF was enhanced in a dose-dependent fashion when combined with Cisplatin. 4) The antitumor effects was confirmed by pathological findings. These results suggest that the combined use of n-TNF and Cisplatin is promising as a clinically effective treatment against bladder cancer in human.
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PMID:[Antitumor effect of combined use of purified human natural tumor necrosis factor (N-TNF) and cis-diamminedichoroplatinum (II) (cisplatin) on the implanted bladder carcinoma (MBT-2) in mice]. 143 74


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