Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0007131 (non-small cell lung cancer)
 22,601 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The pattern of inhibition of cell proliferation and cytotoxicity in vitro by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene (Naph-DNB) was evaluated by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) and the trypan blue (TB) dye exclusion assays in nine murine and human cell lines of different histologic origin. In our culture conditions Naph-DNB showed a good inhibiting activity against all cell lines tested, with IC(50)s varying within a narrow micromolar range of concentrations (2.0 +/- 0.2-14.3 +/- 2.3 microM). In particular, murine P388 (leukemia), human Jurkat (leukemia), A2780, PA-1 (ovarian carcinoma) and Saos-2 (osteosarcoma) cells showed the highest sensitivity to the inhibiting potential of Naph-DNB, while human A549 (non small cell lung cancer, NSCLC), MDA-MB-231 (breast cancer), HGC-27 (gastric cancer) and HCT-8 (colon carcinoma) were the least sensitive cell lines. Moreover, the analysis of cytotoxicity of Naph-DNB evaluated by the TB test showed that this compound was able to kill cells with IC(50)s ranging from 1.7 to 39.2 microM. The study of the induction of apoptosis was carried out by 4'-6-diamidine-2'-phenylindole (DAPI) staining of segmented nuclei, western blot of p53 protein and TdT-mediated dUTP-biotin nick end labeling (TUNEL) method, while the interaction with DNA was evaluated through the analysis of interstrand cross-link (ISCL) formation. Our data show that in all cell lines tested Naph-DNB was able to form ISCLs, to upregulate p53 oncosuppressor-protein and to induce apoptosis. Moreover, TUNEL analysis also suggested that Naph-DNB, similarly to other anticancer drugs, was able to block cells in the G (0)/ G (1) phase of the cell cycle. In conclusion our data suggest that Naph-DNB may be an effective novel lead molecule for the design of new anticancer compounds.
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PMID:Preliminary evaluation in vitro of the inhibition of cell proliferation, cytotoxicity and induction of apoptosis by 1,4-bis(1-naphthyl)-2,3-dinitro-1,3-butadiene. 1529 6

Non-small cell lung cancer (NSCLC) includes a group of tumors that respond poorly to drugs. cis-Diamminedichloroplatinum(II) (cis-DDP) toxicity still remains problematic, and not completely solved by the improvement of supportive care. Therefore, the cis-Pt(II) complex of 3-aminoflavone was selected from cis-DDP analogues with a more favourable toxic profile towards normal cells and at least similar or better anti-tumor activity in comparison with cis-DDP. The aim of this research is to compare the ability of the cis-Pt(II) complex of 3-aminoflavone and cis-DDP to induce apoptosis and necrosis in the human non-small cancer cell line A549. Trypan blue dye exclusion, fluorochrome staining (acridine orange/ethidium bromide double staining), MTT and TUNEL (TdT-mediated dUTP Nick-End Labeling) assays were used. The results obtained show that the cis-Pt(II) complex of 3-aminoflavone is more active in inducing apoptosis and necrosis and in decreasing viability in A549 cells than cis-DDP, which suggests that it could be a potential chemotherapeutic drug.
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PMID:Induction of apoptosis and necrosis in A549 cells by the cis-Pt(II) complex of 3-aminoflavone in comparison with cis-DDP. 1532 49

Elderly patients with advanced non-small cell lung cancer (NSCLC) require chemotherapy that is effective and minimally toxic. We evaluated the activity of a combination of vinorelbine and 5-fluorouracil (5-FU)/UFT (a fixed combination of tegafur and uracil) in vitro and in vivo to establish a rationale for clinical use. The cytotoxic activities of various combinations of vinorelbine and 5-FU, the active metabolite of tegafur, were analyzed by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazlium bromide (MTT) assay and isobologram technique in vitro, using 3 NSCLC cell lines (A549, PC14, and Ma10). Sequential exposure to vinorelbine followed by 5-FU showed additive or synergistic activity against all 3 NSCLC cell lines tested. The reverse sequence showed no synergism. Antitumor activity and survival prolongation after treatment with different combinations of vinorelbine and UFT were evaluated in nude mice bearing PC14 xenografts. Treatment with vinorelbine before UFT was associated with higher antitumor activity, less toxicity, and longer survival than the reverse sequence. To clarify the underlying mechanism by which the combination exerts the synergistic effects, the expression of thymidylate synthase (TS) was assessed by Western blot analysis in vitro and by immunohistochemical analysis in an animal model. Vinorelbine suppressed the 5-FU-induced increase in TS protein in A549 cells. In PC14 tumor tissues of animal models, TS expression in cancer cells was suppressed by vinorelbine. Our data suggest that treatment with vinorelbine injection before oral UFT may have synergistic activity against NSCLC. This synergistic activity may be attributed to increased chemosensitivity to UFT caused by vinorelbine-induced suppression of TS.
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PMID:Schedule-dependent synergism of vinorelbine and 5-fluorouracil/UFT against non-small cell lung cancer. 1549 20

CI-994 (N-acetyldinaline) is a novel oral compound with a wide spectrum of antitumor activity in preclinical models, in vitro and in vivo. The mechanism of action may involve inhibition of histone deacetylation and cell cycle arrest. We studied the action of CI-994 on two non-small cell lung cancer (NSCLC) cell lines: A-549 (adenocarcinoma) and LX-1 (squamous cell carcinoma). Different drug concentrations were tested, ranging from 0.01 to 160 microM at 24, 48, and 72 h of treatment, with MTT assay. A concentration-dependent cell survival inhibition was observed, with an IC50 at 80 microM. The effect of CI-994, as demonstrated by recovery experiments, was cytostatic and seemed to be superimposable in both cell lines. Cytofluorimetric analysis to assess cell cycle perturbation and apoptosis was performed after 24 h of treatment, indicating a cell block with concomitant increase at G0/G1 phase, a reduction at S phase level at 20, 40, 80, and 160 microM, and apoptosis at the higher concentration (160 microM). When CI-994 was combined with antineoplastic agents commonly used in NSCLC management, a marked synergism of action (R = 1.8, R = 1.5) was observed between CI-994 (40 microM) and gemcitabine (0.01 microM) at 48 and 72 h of treatment. The same result was obtained with docetaxel (0.001 microM) combination (R = 1.4, R = 1.2), but no synergism of action was noted with paclitaxel. CI-994 showed no radiopotentiating effects, when combined with 100, 200, or 400 cGy irradiation. In conclusion, our experiments indicate that CI-994 is a promising novel cytostatic for the treatment of NSCLC. Its use in combination with standard anticancer agents, such as gemcitabine and docetaxel, is warranted.
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PMID:In vitro study of CI-994, a histone deacetylase inhibitor, in non-small cell lung cancer cell lines. 1583 4

Interleukin-6 (IL-6) has been shown to regulate both growth and neuroendocrine (NE) differentiation in some types of human cancer cells, and erbB2 may be a critical component of IL-6 signaling. Non-small cell lung cancer (NSCLC) tumors that demonstrate NE properties have been suggested to have biological characteristics similar to small cell lung cancers with initial responsiveness to chemotherapy. We investigated whether IL-6 is implicated in the cell growth, NE differentiation, and chemosensitivity of NSCLC-NE cells. NSCLC-NE cells were treated with exogenous IL-6, and a subclone of an IL-6-transfected NSCLC cell line that constitutively expressed IL-6 receptor was also generated. These cells were assessed for cell proliferation by cell counting and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide (MTT) assays, chemosensitivity to cisplatin and etoposide by MTT assays, and NE differentiation by observing morphological changes and immunoblotting for neuron-specific enolase (NSE). The IL-6-treated cells and the IL-6-transfected cells showed enhanced cell proliferation and downregulated NSE expression, but little change in chemosensitivity. In the culture medium, IL-6-transfected cells grew as looser aggregates than the parental cells. IL-6 could not activate the erbB genes. In conclusion, IL-6 can induce cell proliferation and NE dedifferentiation but has little effect on chemosensitivity in IL-6 receptor-expressing NSCLC-NE cells. The status of NSE expression is unlikely to be a crucial factor for chemosensitivity in NSCLC cells.
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PMID:Role of IL-6 in neuroendocrine differentiation and chemosensitivity of non-small cell lung cancer. 1589 59

Lung cancer has emerged as a leading cause of cancer death in the world. Non-small cell lung cancer (NSCLC) accounts for 75-80% of all lung cancers. Current therapies are ineffective, thus new approaches are needed to improve the therapeutic ratio. Double stranded RNA (dsRNA)-mediated RNA interference (RNAi) has shown promise in gene silencing, the potential of which in developing new methods for the therapy of NSCLC needs to be tested. We report here RNAi induced effective silencing of the epidermal growth factor receptor (EGFR) gene, which is over expressed in NSCLC. NSCLC cell lines A549 and SPC-A1 were transfected with sequence- specific dsRNA as well as various controls. Immune fluorescent labeling and flow cytometry were used to monitor the reduction in the production of EGFR protein. Quantitative reverse-transcriptase PCR was used to detect the level of EGFR mRNA. Cell count, colony assay, scratch assay, MTT assay in vitro and tumor growth assay in athymic nude mice in vivo were used to assess the functional effects of EGFR silencing on tumor cell growth and proliferation. Our data showed transfection of NSCLC cells with dsRNA resulted in sequence specific silencing of EGFR with 71.31% and 71.78 % decreases in EGFR protein production and 37.04% and 54.92% in mRNA transcription in A549 and SPC-A1 cells respectively. The decrease in EGFR protein production caused significant growth inhibition, i.e.: reducing the total cell numbers by 85.0% and 78.3%, and colony forming numbers by 63.3% and 66.8%. These effects greatly retarded the migration of NSCLC cells by more than 80% both at 24 h and at 48 h, and enhanced chemo-sensitivity to cisplatin by four-fold in A549 cells and seven-fold in SPC-A1. Furthermore, dsRNA specific for EGFR inhibited tumor growth in vivo both in size by 75.06% and in weight by 73.08%. Our data demonstrate a new therapeutic effect of sequence specific suppression of EGFR gene expression by RNAi, enabling inhibition of tumor proliferation and growth. However, in vivo use of dsRNA for gene transfer to tumor cells would be limited because dsRNA would be quickly degraded once delivered in vivo. We thus tested a new bovine lentiviral vector and showed lentivector-mediated RNAi effects were efficient and specific. Combining RNAi with this gene delivery system may enable us to develop RNAi for silencing EGFR into an effective therapy for NSCLC.
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PMID:Silencing the epidermal growth factor receptor gene with RNAi may be developed as a potential therapy for non small cell lung cancer. 1598 32

The aquaporins represent a family of transmembrane water channel proteins that play a major role in trans-cellular and transepithelial water movement. Most tumors have been shown to exhibit high vascular permeability and interstitial fluid pressure, but the transport pathways for water within tumors remain unknown. Here, we tested 10 non-small cell lung cancer cell lines of various origins by reverse transcriptase-polymerase chain reaction and Western blot analysis and identified clear expression of aquaporin 1 (AQP1) in seven cell lines. We next examined the distribution of the AQP1 protein in several types of primary lung tumors (16 squamous cell carcinomas, 21 adenocarcinomas, and 7 bronchoalveolar carcinomas) by immunohistochemical staining. AQP1 was overexpressed in 62% (13 of 21) and 75% (6 of 8) of adenocarcinoma and bronchoalveolar carcinoma, respectively, whereas all cases of squamous cell carcinoma and normal lung tissue were negative. Forced expression of full-length AQP1 cDNA in NIH-3T3 cells induced many phenotypic changes characteristic of transformation, including cell proliferation-enhancing activity by the MTT assay and anchorage-independent growth in soft agar. Although further details on the molecular function of AQP1 related to tumorigenesis remain to be elucidated, our results suggest a potential role of AQP1 as a novel therapeutic target for the management of lung cancer.
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PMID:Aquaporin 1 is overexpressed in lung cancer and stimulates NIH-3T3 cell proliferation and anchorage-independent growth. 2290 56

A new series of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone were synthesized via four steps starting from 2-amino-5-methylbenzoic acid and initially screened against A-549 (human non-small cell lung cancer), HCT-8 (human colon cancer), and Bel-7402 (human liver cancer) cell lines at the single concentration of 5 microg/mL using the colorimetric MTT assay. The IC50 values were determined for the compounds reaching > or = 70% inhibition in primary screening by serial dilution. Among the newly synthesized compounds, 9n exhibited potent in vitro cytotoxicity against A-549, HCT-8, and Bel-7402 cell lines with the IC50 values of 1.65, 0.93, and 1.43 microM, respectively.
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PMID:Synthesis of substituted benzylamino- and heterocyclylmethylamino carbodithioate derivatives of 4-(3H)-quinazolinone and their cytotoxic activity. 1661 82

In this study we have investigated a spatial distribution of cell growth after their irradiation using a modulated x-ray intensity pattern. An A549 human non-small cell lung cancer cell line was grown in a 6-well culture. Two of the wells were the unirradiated control wells, whilst another two wells were irradiated with a modulated x-ray intensity pattern and the third two wells were uniformly irradiated. A number of plates were incubated for various times after irradiation and stained with crystal violet. The spatial distribution of the stained cells within each well was determined by measurement of the crystal violet optical density at multiple positions in the plate using a microplate photospectrometer. The crystal violet optical density for a range of cell densities was measured for the unirradiated well and this correlated with cell viability as determined by the MTT cell viability assay. An exponential dose response curve was measured for A549 cells from the average crystal violet optical density in the uniformly irradiated well up to a dose of 30 Gy. By measuring the crystal violet optical density distribution within a well the spatial distribution of cell growth after irradiation with a modulated x-ray intensity pattern can be plotted. This method can be used for in vitro investigation into the changes in radiation response associated with treatment using intensity modulated radiation therapy (IMRT).
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PMID:A preliminary investigation of cell growth after irradiation using a modulated x-ray intensity pattern. 1686 71

DNA repair enzyme expression in tumor cells possibly affects sensitivity to anti-cancer agents. The aim of this study was to determine the relationship between expression status of DNA repair enzymes and chemosensitivity in patients with non-small cell lung cancer (NSCLC). NSCLC tissues prepared from the surgical specimens of 41 patients were subjected to immunohistochemical analysis for Rad51 and ERCC1 proteins and to a chemosensitivity test using the MTT assay. The relationships between the expression status of the DNA repair enzymes and ex vivo chemosensitivity to various agents were evaluated. A positive expression for Rad51 and ERCC1 was observed in 17 cases (41%) and 20 cases (49%), respectively. The positivity of Rad51 was closely related to a certain histologic type of squamous cell carcinoma and poor differentiation, and the positivity of ERCC1 tended to be related to squamous cell carcinoma. In chemosensitivity tests, sensitivities to CDDP and CBDCA were significantly lower when both 2 enzymes were positive (p = 0.012 and 0.04 in CDDP, 0.014 and 0.03 in CBDCA). Both Rad51 and ERCC1 expressions showed no significant relationship with sensitivities to paclitaxel, etoposide, vinorelbine, gemcitabine, 5-FU, or irinotecan. In conclusion, combined expression of Rad51 and ERCC1 expression is associated with resistance to platinum agents in the ex vivo study of clinical NSCLC, and evaluation of expression status of both DNA repair enzymes would be a predictor for clinical response to platinum-based chemotherapies.
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PMID:Combined evaluation of Rad51 and ERCC1 expressions for sensitivity to platinum agents in non-small cell lung cancer. 1741 81


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