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 antiproliferative effect of paclitaxel, docetaxel, gemcitabine, topotecan, SN-38 and cis-platin was studied on 5 non-small cell lung cancer (NSCLC) cell lines, 3 of which were adenocarcinoma (ADK) and 2 squamous cell carcinoma (SCC). Cellular chemosensitivity was determined using the MTT in vitro assay after 48, 72 and 96 h of exposure to drug in concentration ranging from 0.001 to 100 microM. A concentration-dependent cell growth inhibition was observed for paclitaxel, gemcitabine, topotecan, SN-38 and cis-platin in all cell lines tested. Docetaxel showed a concentration-independent cytotoxicity and was 104 times more potent than cis-platin (IC50 = 0. 001 vs. 10 microM). Paclitaxel, gemcitabine, topotecan and SN-38 were 102 times more potent than cis-platin, with median IC50 = 0.1 microM at 72 h. The level of drug-induced cell growth inhibition appeared to be correlated, for some of the six drugs tested, with the tumor histological subtype. In particular, topotecan and cis-platin were more active in squamous cell carcinoma than in adenocarcinoma cell lines (p=0.006 and 0.001 respectively at 0.1 microM concentration), while paclitaxel was more active in ADK than in SCC cell lines (p=0.004 at 0.01 microM concentration). Ca-Lu-6, a cell line that, contrary to most other lung cancer cell lines, is wild-type for most oncogenes/tumor suppressor genes, was by far the most sensitive cell line used (p=0.002, 0.003, 0.01 for paclitaxel, topotecan and cis-platin respectively, at 1 microM concentration), showing a >50% growth inhibition to new drugs at a concentration of 0.01 microM. In conclusion, all these new compounds tested were found to be more potent than cis-platin in affecting cellular proliferation of six NSCLC cell lines studied. We suggest that the specific histological subtype and molecular pattern of the cell line being treated could affect the antiproliferative effect of these drugs.
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PMID:Pre-clinical evaluation of new antineoplastic agents in NSCLC cell lines: evidence of histological subtype-dependent cytotoxicity. 1049 63

Peptides containing retinoblastoma protein (RB) fragment 649-654 (LFYKKV) were tested for their ability to block the proliferation of RB-negative and RB-positive human non-small cell lung cancer (NSCLC) cells. These peptides potently restrained the growth of both types of tumor cells, as measured by metabolic (MTT) and cellular viability (trypan blue exclusion) assays. As such, and remarkably, the peptides were able to overcome the resistance of RB-positive cells usually observed with RB gene or protein replacement therapy. Compared to the overall performance of conventional chemotherapy tested in parallel, the peptides were more cytotoxic against RB-negative neoplastic cells and equipotent toward RB-positive tumor cells, yet less toxic toward normal human cells. Thus, these new molecules hold great promise to evolve into an efficient therapy for human lung cancer, a common malignancy still defying treatment and holding a poor prognosis, as well as for other human neoplasias.
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PMID:Selective inhibition of human lung cancer cell growth by peptides derived from retinoblastoma protein. 1062 76

Cyclooxygenase (COX)-2 has been reported to play an important role in carcinogenesis. Meloxicam (preferential COX-2 inhibitor) inhibits the growth of COX-2 positive and COX-1 negative colorectal cancer cells. We evaluated the effects of meloxicam on the growth of lung cancer cells. By reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis, COX-2 but not COX-1 was expressed in human non-small cell lung cancer (NSCLC) cell lines (A549 and PC14). In human small cell lung cancer (SCLC) cell line (H841), both COX-1 and COX-2 were not detected. MTT assay and prostaglandin (PG) E2 enzyme immunoassay showed that meloxicam inhibited the growth and PGE2 production of both A549 and PC14, but not H841 cells. These findings suggest that COX-2 may play an important role in the pathogenesis and progression of NSCLC, and that meloxicam may be a useful therapeutic agents in the treatment of NSCLC.
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PMID:Meloxicam inhibits the growth of non-small cell lung cancer. 1106 95

Integration of chemotherapy and radiation is the standard practice in the management of locally advanced inoperable NSCLC. To assess the biological interaction between third generation chemotherapeutic agents and radiation in non-small cell lung cancer (NSCLC) in vitro, we tested a number of different drugs (paclitaxel, docetaxel, gemcitabine, topotecan, SN-38 and cisplatin) combined with radiation, in lung cancer cell lines. Cellular chemosensitivity was determined, using the semi-automated colorimetric MTT assay, after 48, 72 and 96 h of exposure to increasing drug concentrations, (0.001-100 microM) and radiation doses (100-400 cGy). Cell lines used were the adenocarcinoma (ADK), A-549, and the squamous-cell carcinoma (SCC), LX-1. Cells were pre-treated with anticancer agents at 24, 12 and 0 h before irradiation. Cytofluorimetric cell cycle analysis was performed. A significant S-phase block or a G(2)/M block was seen with gemcitabine and topotecan or paclitaxel pre-treatment, respectively. Apoptosis was seen only after paclitaxel exposure in the A-549 cell line. Despite a similar pattern of cell-kinetic changes induced by chemotherapy pre-treatment in all cell lines, the adenocarcinoma A-549 cell line was not radiosensitized by any of the anticancer agents tested, whereas synergism was observed in the LX-1 squamous carcinoma cell line, when exposed to gemcitabine, SN-38, topotecan and cisplatin. Paclitaxel, despite a favourable cell cycle effect, was not found to be synergistic with radiotherapy in our experimental model. In conclusion, the observed synergism appears to be dose- and timing-independent and seems to be related to the histological subtype being present in SCC only. Favourable perturbation of the cell cycle is evident with all the new agents tested in both cell types, but was not sufficient to produce synergism with radiation.
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PMID:Interaction between novel anticancer agents and radiation in non-small cell lung cancer cell lines. 1142 93

Despite recent developments, treatment outcome in advanced non-small cell lung cancer (NSCLC) remains far from satisfactory. Vinorelbine and irinotecan have shown good single-agent activity against NSCLC. These two anticancer agents target different phases of the cell cycle: the cytotoxicity of camptothecin occurs mainly in the S-phase while the cytotoxicity of vinca alkaloids occurs mainly in the M-phase. Thus, it seemed interesting to study the combined activity of these two drugs against human NSCLC cell lines in vitro. In this study, the cytotoxic interaction between vinorelbine and SN 38 (the active metabolite of irinotecan), administered at various schedules, was assessed against a human NSCLC cell line, NCI H460. Cell growth inhibition was determined by the MTT assay. The effects of drug combinations were analysed by the isobologram method. The mean IC50 was 2.06 x 10(-6) mg/ml or vinorelbine, 2.72 x x 10(-3) mg/ml for irinotecan and 2.76 x 10(-6) for SN 38. On simultaneous exposure to these two drugs, additive effects were observed, while antagonistic effects were observed on sequential exposure to vinorelbine followed by SN 38. On sequential exposure to SN 38 first followed by vinorelbine, a slight antagonistic effect was observed at the isoeffect 50%; at the isoeffect 70%, additive effects were observed. These findings suggested that simultaneous exposure to vinorelbine and SN 38 may be the optimum schedule for this combination, while sequential administrations may be less cytotoxic and inadequate. Further preclinical and clinical studies are required to elucidate the relationship between vinorelbine and SN 38 with regard to both anti-tumor activity and toxicity.
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PMID:In vitro schedule-dependent interaction between irinotecan and vinorelbine in NCI H460 non-small cell lung cancer cell line. 1201 70

In this study, we have synthesized several compounds and examined their cytotoxic effects on human non-small cell lung cancer A549 cells. We found that GO-13 ((E,E)-2,5-bis[4-(3-dimethyl-aminopropoxy)styryl]-1,3,4-thiadiazole) is the most effective one by the MTT assay. Furthermore, the GO-13-induced apoptotic reaction was identified based on several criteria, such as negative release reaction of lactate dehydrogenase and positive labeling of annexin V and terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) techniques. GO-13 induced the apoptosis in A549 cells in a concentration- and time-dependent manner. The data demonstrate that the regulations of p38 mitogen-activated protein kinase and protein kinase C was not involved in the GO-13-mediated mechanism. However, GO-13 significantly induced a down-regulation of Bcl-X(L) expression in a short-term treatment (less than 3hr), whereas stimulated up-regulation of Bax expression in a long-term treatment (24hr) indicating their involvement in GO-13 action. GO-13-mediated apoptosis is also positively correlated with the increase in caspase-3 activity. Worth noting is the fact that GO-13 did not modify the phosphorylation level of Akt/protein kinase B (PKB) until a 24-hr exposure was carried out indicating that the inhibition of Akt/PKB activation was involved in the late-phase apoptosis. Besides the anticancer activity, GO-13 also showed equivalent anti-angiogenic activity in the nude mice angiogenesis model. In summary, we conclude that GO-13 is the most effective anticancer compound in our screening tests. It induced the early-phase apoptosis in A549 cells via the Bcl-X(L) down-regulation, and that of the late-phase through up-regulation of Bax expression as well as inhibition of Akt/PKB activation.
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PMID:Investigation of anticancer mechanism of thiadiazole-based compound in human non-small cell lung cancer A549 cells. 1281 71

The in vitro cytotoxic activity profile of nine novel phenylarsonic acid (CAS 98-05-5, PAA) compounds against 17 human cancer cell lines including (a) ovarian cancer cell lines ES-2, PA-1, CAOV-3, OVCAR-3, (b) testicular cancer cell lines Ntera-2, Tera-2, N2NICP, 833K, and 64CP, (c) multiple myeloma cell lines ARH77, HS-Sultan, RPMI-8226, and U266, and (d) acute lymphoblastic leukemia (ALL) cell lines NALM-6, MOLT-3, ALL-1, and RS4; 11, was determined by the MTT assay. The lead compounds, 2-methylthio-4-[(4'-aminophenylazo)-phenylarsonic acid] pyrimidine (PHI-370) and 2-methylthio-4-(4'-phenylarsonic acid)-aminopyrimidine (PHI-380) caused apoptotic death in all 17 cancer cell lines at low micromolar concentrations, as documented by TUNEL assays and confocal laser scanning microscopy. PHI-380 was also tested and found to be very active against primary tumor cells isolated from surgical biopsy specimens of 14 patients with therapy-refractory non-small cell lung cancer, breast cancer, colon cancer, lymphoma, hepatoblastoma, or Wilm's tumor as well. Because of their broad-spectrum and potent anticancer activity and ability to induce apoptosis in primary tumor cells from therapy-refractory cancer patients, PAA compounds such as PHI-370 and PHI-380 may provide the basis for effective salvage regimens for patients with recurrent cancer.
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PMID:Phenylarsonic acid compounds with broad-spectrum and potent cytotoxic activity against human cancer cells. 1287 14

K-ras alterations have been reported in 20-30% of non-small cell lung cancer (NSCLC) and represent a suitable target for the development of novel anticancer agents, such as Farnesyl transferase inhibitors (FTi), a new class of agents inhibiting the post-translational modification of the K-ras proteins. The effectiveness of FTi SCH66336 in inhibiting cell proliferation and deranging cell cycle of NSCLC cell lines as well as its interaction with chemotherapy or radiation have been evaluated. The activity of FTi SCH66336, alone or in combination with paclitaxel, gemcitabine, and radiotherapy, was examined in 3 cell lines, A-549, LX-1 and CaLu-6, by colorimetric MTT assay. Cell cycle perturbation and apoptosis were also assessed by cytofluorimetric analysis. The activity of SCH 66336 was found to be concentration- and time-dependent. The effect of SCH 66336, as demonstrated by cell growth recovery experiments, resulted cytostatic and it was superimposable in both cell lines bearing 2 different K-ras mutations (A-549 and LX-1) and in K-ras wild-type Ca-Lu-6. In all cell lines the combination of SCH 66336 and paclitaxel resulted in a synergism of action when SCH 66336 followed paclitaxel treatment, whereas, antagonism was found when SCH 66336 preceded paclitaxel treatment. No significant synergism or addition with SCH 66336 followed by radiation treatment was noted. Different cell cycle phase blocks at various drug concentrations were observed. In conclusion, SCH 66336 displays concentration-dependent cytostatic antitumour activity and schedule-dependent synergy with 2 commonly used anticancer agents in NSCLC cell lines. Further clinical testing of these combinations is warranted.
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PMID:In vitro study of farnesyltransferase inhibitor SCH 66336, in combination with chemotherapy and radiation, in non-small cell lung cancer cell lines. 1471 76

Mammalian bombesin (BN) receptors are among those most frequently overexpressed by a number of common tumors including prostate, breast, lung, and colon cancers. The aim of this study was to develop a camptothecin-bombesin (CPT-BN) conjugate that interacts with all classes of BN receptors and possibly functions as a prodrug via a labile linker with site-specific cytotoxicity for cancer cells bearing these receptors. CPT was coupled to analogs of [D-Tyr6,beta-Ala11,Phe13,Nle14]BN-(6-14) (BA0) using carbamate linkers (L1 and L2) with built-in nucleophile-assisted releasing groups for intracellular cleavage of free cytotoxic agents. One conjugate, CPT-L2-BA3, bound to all three BN receptor classes with high affinity and functioned as a full agonist at each. 125I-CPT-L2-BA3 was rapidly internalized by cells expressing each BN receptor class and, using fluorescent imaging, was found to co-localize with BN receptors initially and later to be internalized in cytoplasmic compartments. HPLC analysis of internalized ligand showed that 40% was intact, 25% was metabolized by releasing free CPT, and 35% was metabolized to other breakdown products. CPT-L2-BA3 inhibited the growth of NCI-H1299 non-small cell lung cancer cells in 3-(4,5-dimethylthiazol-2-yl)-2.5-diphenyl-2H-tetrazolium bromide (MTT) and clonal growth assays. CPT-L2-BA3 was cytotoxic in an MTT assay for cells transfected with each class of BN receptor; however, it had significantly less effect in cells lacking BN receptors. These results indicate that CTP-L2-BA3 is a potent agonist that is cytotoxic for cells overexpressing any of the three BN receptor classes and functions as a prodrug for receptor-mediated cytoxicity. It therefore should be a useful prototype to explore the effectiveness of tumor-specific cytotoxicity delivery using a receptor-mediated mechanism.
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PMID:Development of high affinity camptothecin-bombesin conjugates that have targeted cytotoxicity for bombesin receptor-containing tumor cells. 1501 26

Gefitinib ("Iressa", ZD1839) is a selective epidermal growth factor receptor-tyrosine kinase inhibitor, which blocks signal transduction pathways implicated in proliferation and survival of cancer cells. However, in vitro and in vivo studies concerning cell growth after withdrawal of gefitinib are limited. To determine whether cancer cells would resume proliferation upon removal of gefitinib, an in vitro study was undertaken using 4 human non-small cell lung cancer cell lines. With immunocytochemical staining and Western blot analysis, we confirmed positive expression of EGFR in these cell lines. We next evaluated growth inhibition before and after withdrawal of gefitinib. After incubation with 0-100 microM gefitinib for 24 h, medium containing gefitinib was removed, followed by addition of fresh growth medium to cell cultures. MTT assays were performed daily over a 6-day time course. Even at very low levels of gefitinib (<1 microM), these 4 TKB cells had 1-10% growth inhibition, respectively. With these levels of gefitinib, continued inhibitory effects after withdrawal of getitinib were observed in 3 of the 4 cell lines. Furthermore, none of the 4 cell lines, including the cell line which had abolished growth inhibition, showed accelerated re-growth rate after the withdrawal of gefitinib even in these exposure conditions. Based on our in vitro experiments, additional in vivo studies, which can compare the pre- and post-treatment growth rate, will be necessary to help better understand the mechanisms behind cell growth recovery after temporary gefitinib treatment.
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PMID:Cell growth after withdrawal of gefitinib ("Iressa", ZD1839) in human lung cancer cells. 1528 46


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