UMLS:C0684249 - FACTA Search

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Query: UMLS:C0684249 (lung carcinoma)
23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have identified the CD95 system as a key mediator of chemotherapy-induced apoptosis in leukemia and neuroblastoma cells. Here, we report that sensitivity of various solid tumor cell lines for drug-induced cell death corresponds to activation of the CD95 system. Upon drug treatment, strong induction of CD95 ligand (CD95-L) and caspase activity were found in chemosensitive tumor cells (Hodgkin, Ewing's sarcoma, colon carcinoma and small cell lung carcinoma) but not in tumor cells which responded poorly to drug treatment (breast carcinoma and renal cell carcinoma). Blockade of CD95 using F(ab')2 anti-CD95 antibody fragments markedly reduced drug-induced apoptosis, suggesting that drug-triggered apoptosis depended on CD95-L/receptor interaction. Moreover, drug treatment induced CD95 expression, thereby increasing sensitivity for CD95-induced apoptosis. Drug-induced apoptosis critically depended on activation of caspases (ICE/Ced-3-like proteases) since the broad-spectrum inhibitor of caspases zVAD-fmk strongly reduced drug-mediated apoptosis. The prototype substrate of caspases, poly(ADP-ribose) polymerase, was cleaved upon drug treatment, suggesting that CD95-L triggered autocrine/paracrine death via activation of caspases. Our data suggest that chemosensitivity of solid tumor cells depends on intact apoptosis pathways involving activation of the CD95 system and processing of caspases. Our findings may have important implications for new treatment approaches to increase sensitivity and to overcome resistance of solid tumors.
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PMID:Chemosensitivity of solid tumor cells in vitro is related to activation of the CD95 system. 953 69

The arachidonate 15-lipoxygenase is induced in peripheral human monocytes by culturing the cells for 3 days in the presence of interleukin 4 (IL-4) in concentrations as low as 40 pM. Linoleic acid is oxygenated by IL-4 treated monocytes to 13(S)-hydroxy-9Z, 11E-octadecadienoic acid [13(S)-HODE] with a specific activity of about 2 nmoles 13(S)-HODE/10(6) cells min. A screening of various permanent cell lines expressing the IL-4 receptor indicated that all monocyte/macrophage lines tested did not exhibit the effect of LOX induction. However, IL-4 treatment of the lung carcinoma cell line CCC 185 and of the colon carcinoma cell line HTB 38 induces the 15-LOX as shown by activity assay and immunohistochemistry. The IL-4 mutant Y124D which has been characterized as specific IL-4 receptor antagonist in human T-cells does not induce the 15-LOX but appears to act as competitive inhibitor for the induction. Subcellular fractionation of IL-4 treated monocytes indicated a cytosolic and a membrane bound enzyme pool. The intracellular action of the LOX leads to a specific oxygenation of the membrane phospholipids which is drastically increased after damage to the cells. The possible biological role of the 15-LOX for monocyte metabolism is discussed.
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PMID:Regulation of 15-lipoxygenase expression by cytokines. 954 9

The potential of the thymidylate synthase inhibitor, Tomudex to interact with ionizing radiation was assessed in vitro and in vivo in comparison with 5-fluorouracil. A concentration of 1 microM Tomudex decreased the shoulder of the radiation survival curves for normally oxygenated and hypoxic human HT-29 colon carcinoma cells and human SCC-25 head and neck squamous carcinoma cells, resulting in enhancement ratios of 10 and 2.8 for normally oxygenated and hypoxic HT-29 cells at 5 Gray, respectively, and enhancement ratios of 19.5 and 2.7 for normally oxygenated and hypoxic SCC-25 cell at 5 Gray, respectively. Two schedules of Tomudex administered to animals bearing the Lewis lung carcinoma resulted in additive tumor growth delay with the fractionated radiation therapy. In nude mice bearing the HT-29 colon carcinoma grown as a xenograft, administration of Tomudex daily for 5 days on a 1 or 2-week schedule resulted in increased tumor growth delay along with fractionated radiation therapy on the same schedules. However, administration of Tomudex intermittently on a 2-week schedule appeared to be more interactive with daily fractionated radiation therapy on the 2-week schedule. In each assay, the results obtained with Tomudex were equal to or exceeded those obtained with 5-fluorouracil. These findings indicate that clinical trial of Tomudex along with fractionated radiation therapy is warranted.
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PMID:Interaction of tomudex with radiation in vitro and in vivo. 968 75

Because of the observed immunostimulatory actions of a new fermented wheat germ extract--with standardized benzoquinone composition--we have investigated the eventual tumor growth- and metastasis-inhibiting effects of this preparation (Avemar) applied alone or in combination with vitamin C. Tumor models of different origin [a highly metastatic variant of the Lewis lung carcinoma (3LL-HH), B16 melanoma, a rat nephroblastoma (RWT-M) and a human colon carcinoma xenograft (HCR25)]--kept in artificially immunosuppressed mice were applied. The metastasis-inhibiting effects of the treatments have been studied both in the presence and in the absence (following surgical removal) of the transplanted primary tumors. Combined treatments with Avemar and vitamin C--administered synchronously--profoundly inhibited the metastasis formation in all the applied tumor models while, treatments with vitamin C alone did not exert such an inhibiting effect on the metastasizing process. The degree of the observed metastasis inhibition in certain models was significant, while in others--although it was meaningful--did not prove to be significant. It is noteworthy that treatment with Avemar alone in certain models exerted a more pronounced inhibiting effect on metastasis formation than the synchronous combined treatment with Avemar and vitamin C. Furthermore, if the time schedule of the combined treatment was changed (vitamin C--instead of being administered synchronously--was given one hour after the treatments with Avemar), the vitamin C rather decreased the metastasis inhibiting effect of Avemar. It should be mentioned however, that in the case of rat nephroblastoma, a different response was observed: while, in the case of synchronous combination significant inhibition of metastasis formation was observed, treatment with Avemar alone did not produce metastasis-inhibition. It is noteworthy that in this model the metastasis-inhibiting effect of the synchronous combination treatment proved to be even more pronounced if Avemar was administered in a 100 times smaller dose than its regularly applied dosage. Treatment with Avemar and vitamin C--administered in combination or separately--in the majority of experimental models (with the exception of rat nephroblastoma) did not inhibit the growth of the primary tumors. It is reasonable, therefore, to suppose that in the observed metastasis-inhibiting effect the eventual proliferation inhibiting effect of these remedies does not play an important role. According to the results of other experiments--carried out in our laboratory in parallel with those described here--Avemar proved to have a meaningful immunostimulatory effect. It might therefore be suggested that the observed metastasis-inhibiting effect of this preparation may be mainly due to its immunostimulatory properties. The possible therapeutic benefits of Avemar and Avemar plus vitamin C are also discussed.
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PMID:Effect of Avemar and Avemar + vitamin C on tumor growth and metastasis in experimental animals. 970 78

Illudins are a novel class of agents with a chemical structure entirely different from current chemotherapeutic agents. A new semisynthetic derivative, MGI 114 (NSC 683,863, 6-hydroxymethyl-acylfulvene, HMAF), is markedly effective in a variety of lung, breast and colon carcinoma xenograft models. This analogue, MGI 114, is currently in phase I human clinical trials, and is scheduled for two different phase II trials. To determine if MGI 114 could be effective in vivo against mdr tumour cells, we generated an mdr1/gp170-positive clone of the metastatic MV522 human lung carcinoma line by transfecting a eukaryotic expression vector containing the cDNA encoding for the human gp170 protein. This MV522/mdr1 daughter line retained the metastatic ability of parental cells. The parental MV522 xenograft is mildly responsive in vivo to mitomycin C and paclitaxel, as evidenced by partial tumour growth inhibition and a small increase in life span, whereas MV522/mdr1 xenografts were resistant to these agents. In contrast to mitomycin C and paclitaxel, MGI 114 produced xenograft tumour regressions in 32 of 32 animals and completely eliminated tumours in more than 30% of MV522/mdr1 tumour-bearing mice. Thus, MGI 114 should be effective in vivo against mdr1/gp170-positive tumours.
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PMID:Efficacy of MGI 114 (6-hydroxymethylacylfulvene, HMAF) against the mdr1/gp170 metastatic MV522 lung carcinoma xenograft. 979 6

The purpose of this study was to determine whether sustained local production of murine IFN-beta (mIFN-beta) could inhibit the tumorigenicity and metastasis of human and murine tumor cells implanted into nude mice. Human melanoma cells (A375SM), renal carcinoma cells (SN12PM6), and colon carcinoma cells (KM12SM) were transfected with mIFN-beta or a control neomycin resistance vector. All cell lines grew well in culture. Tumor cells were injected into the subcutis, kidney, spleen, or lateral tail vein of nude mice. Parental or control transfected cells produced local tumors and experimental or spontaneous lung metastases, whereas mIFN-beta-transfected cells did not. In vivo survival experiments using [125I]IdUdR-labeled cells showed that by day 7 after s.c. implantation, all IFN-beta-transfected cells died. IFN-beta transfection prevented the outgrowth of parental or control-transfected cells only when they were injected together with transfected cells into one site, suggesting that IFN-beta promoted a local lysis of the bystander cells. Similar indirect antitumor activity was demonstrated in various human (KM12SM and SN12PM6) and murine (CT-26 colon carcinoma, RENCA renal cell carcinoma, and 3LL Lewis lung carcinoma) tumors. The IFN-beta-transfected tumor cells stimulated a high level of nitric oxide production by murine macrophages under in vitro and in vivo conditions, which correlated with the vigorous nonspecific antitumor activity. Collectively, these results demonstrate that local production of IFN-beta can eradicate tumor cells of different histology by inducing inducible nitric oxide synthase expression in infiltrating cells.
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PMID:Abrogation of tumorigenicity and metastasis of murine and human tumor cells by transfection with the murine IFN-beta gene: possible role of nitric oxide. 981 26

2',2'-Difluorodeoxycytidine (dFdC; gemcitabine) is a new antineoplastic agent that is active against ovarian carcinoma, non-small-cell lung carcinoma, and head and neck squamous cell carcinoma. cis-diamminedichloroplatinum (CDDP; cisplatin) is used commonly for the treatment of these tumors. Because the two drugs have mechanisms of action that might be complementary, we investigated a possible synergism between dFdC and CDDP on growth inhibition. The combination was tested in the human ovarian carcinoma cell line A2780, its CDDP-resistant variant ADDP and its dFdC-resistant variant AG6000, the human head and neck squamous cell carcinoma cell line UMSCC-22B, and the murine colon carcinoma cell line C26-10. The cells were exposed to dFdC and CDDP as single agents and to combinations in a molar ratio of 1:500 for 1, 4, 24, and 72 h with a total culture time of 72 h. Synergy was evaluated using the multiple drug effect analysis. In A2780 and ADDP cells, simultaneous exposure to the drugs for 24 and 72 h resulted in synergism, but shorter exposure times were antagonistic. No synergism was found in the UMSCC-22B and C26-10 cell lines at prolonged simultaneous exposure. However, a preincubation with CDDP for 4 h followed by a dFdC incubation for 1, 4, 24, and 72 h was synergistic in all cell lines except C26-10 cells. A 4-h preincubation with dFdC followed by an incubation with the combination for 20 and 68 h was synergistic in all cell lines. Initial studies of the mechanism of interaction concentrated on the effect of CDDP on dFdCTP accumulation and DNA strand break formation. In all cell lines, CDDP failed to increase dFdCTP accumulation at 4- or 24-h exposure to dFdC; in two cell lines, CDDP even tended to decrease dFdCTP accumulation. Neither dFdC nor CDDP caused more than 25% double strand break formation, whereas in the combination, CDDP even tended to decrease this type of DNA damage. The synergistic interaction between the two drugs is possibly the result of dFdC incorporation into DNA and/or CDDP-DNA adduct formation, which may be affected by each other.
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PMID:Synergistic interaction between cisplatin and gemcitabine in vitro. 981 99

AdmATF is a recombinant adenovirus encoding a secreted version of the amino-terminal fragment (ATF) of murine urokinase (uPA). This defective adenovirus was used in three murine models to assess the antitumoral effects associated with local or systemic delivery of ATF, a broad cell invasion inhibitor that antagonizes uPA binding to its cell surface receptor (uPAR). A single intratumoral injection of AdmATF into pre-established MDA-MB-231 human breast xenografts grown in athymic mice, or into pre-established C57/BL6 syngeneic Lewis lung carcinoma resulted in a specific arrest of tumor growth. Neovascularization within and at the vicinity of the injection site was also suppressed, suggesting that AdmATF inhibited primary tumor growth by targeting angiogenesis. AdmATF also interfered with tumor cell establishment at distant sites: (1) lung dissemination of Lewis lung carcinoma cells was significantly reduced following intratumoral injection at the primary site; and (2) systemic administration of AdmATF inhibited subsequent liver metastasis in a LS174T human colon carcinoma xenograft model. These data outline the potential of using a recombinant adenovirus directing the secretion of an antagonist of cell-associated uPA for cancer gene therapy.
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PMID:Adenovirus-mediated delivery of a uPA/uPAR antagonist suppresses angiogenesis-dependent tumor growth and dissemination in mice. 1032 34

Adozelesin, bizelesin and carzelesin are synthetic cyclopropylpyrroloindole (CPI) analogs, a class of potent antineoplastic agents modeled on the antitumor antibiotic CC-1065, that specifically bind to the minor groove of DNA and preferentially alkylate AT-rich regions. These compounds were evaluated against fresh human tumors in a human tumor colony-forming assay (HTCFA) to assess and to compare their relative antitumor spectra, concentration-response relationships and schedule-dependence. Human tumor colony-forming units were treated with adozelesin and bizelesin at concentrations of 0.02, 0.1 and 0.5 ng/ml as a continuous exposure for 14 days, and to 0.2, 1.0 and 5.0 ng/ml as a 1 h exposure. Carzelesin concentrations were 0.04, 0.2 and 1 ng/ml as a continuous exposure, and 0.6, 3.0 and 15.0 ng/ml as a 1 h exposure. A response was scored if there was 50% or less colony survival. The three analogs had similar antitumor activity against colon carcinoma, kidney carcinoma and melanoma colony-forming units. Adozelesin also displayed activity against both breast and non-small cell lung carcinoma colony-forming units, and carzelesin was active against ovarian carcinoma colony-forming units. Significantly positive concentration-response relationships were apparent with all three agents. Responses increased from below 15% at the lowest concentration to above 45% at the highest concentration for the three drugs on all schedules (p < 0.01). At the highest concentration, the overall response rate was significantly higher (p < 0.01) with carzelesin on the continuous schedule (71%) compared to the 1 h schedule (46%). However, overall response rates for adozelesin and bizelesin were similar on both schedules (1 h/continuous: adozelesin, 67/58%; bizelesin, 49/44%), indicating that adozelesin and bizelesin are less schedule dependent than carzelesin in the HTCFA. These results demonstrate that the CPIs have broad-spectrum activity against human tumor colony-forming units in the HTCFA at very low concentrations, as well as differences with regard to schedule dependence which may help guide the optimal clinical development of these agents.
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PMID:Comparative activity of the cyclopropylpyrroloindole compounds adozelesin, bizelesin and carzelesin in a human tumor colony-forming assay. 1032 36

Based on LOH studies protein tyrosine phosphatasegamma (PTPgamma) has been suggested as a candidate tumor suppressor gene involved in the oncogenesis of lung and renal cancers. In order to assess the involvement of PTPgamma in tumor development we developed a PTPgamma-specific monoclonal antibody (gammaTL1) (IgM isotype) by immunization with a synthetic peptide of 15 amino acids corresponding to the amino acid sequence nos. 1423-1438 just outside the phosphatase domain-II. In line with the fact that the antibody was raised to an intracellular domain of the PTPgamma molecule the antibody labeled the cell membrane of fixed cells but did not stain the outside of the cell membrane in the immunofluorescence assay. The Mab gammaTL1 recognized a full-length baculovirus recombinant PTPgamma protein of 185 kDa, in addition to putative cleavage products of 120 kDa, 114/110 kDa and 80 kDa, on Western blots of lysates of PTPgamma-gene transfected Sf9 insect cells but not of tumor cell lysates. Based on immunoperoxidase and immunofluorescence assays on cryostat sections, however, PTPgamma was expressed in more than 90% of both normal, human tissue samples and in the (non-) tumor cells of carcinoma samples. However, PTPgamma was not found in 28% of the overall lung tumor samples, i.e. in 50% of the lung adenocarcinoma samples, while the expression was weak and heterogeneous in 71% of squamous lung cell carcinomas. PTPgamma was not suppressed in the normal cells between the lung carcinoma cells. The presence of PTPgamma, assayed by immunofluorescence in lung tumor cell lines (H69, H128, H82, C3) was confirmed by RT-PCR assay. Interestingly, the 90% expression score of PTPgamma protein in normal ovarian tissue samples was reduced dramatically to 44 and 38% in both the non-tumorous and tumorous cells, respectively, in ovarian tumor samples. PTPgamma was absent in the HT29 human colon carcinoma cell line both by immunofluorescence and RT-PCR assay. In summary, we have developed a PTPgamma-specific monoclonal antibody, that demonstrated that the expression of PTPgamma is severely reduced (>50%) in lung tumors and ovarian tumors.
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PMID:Reduced expression of protein tyrosine phosphatase gamma in lung and ovarian tumors. 1037 95

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