Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0242379 (lung cancer)
 71,905 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Loss of heterozygosity (LOH) on chromosome 18q is common in lung cancer. The genes involved in LOH on 18q in lung cancer have not been well characterized. Cables, a cyclin-dependent kinase (cdk) interacting protein, has recently been identified and mapped to human chromosome 18q11-12. Cables inhibits cell growth and suppresses tumor formation in nude mice, making it a candidate gene for 18q LOH in lung cancer. Little is known regarding Cables protein expression in human non-small cell lung cancer (NSCLC). In this study we examined Cables expression in 163 NSCLC and nonneoplastic lung specimens using tissue microarrays. Strong nuclear staining was present in normal lung and bronchial tissue. We also evaluated the Cables protein expression pattern and its correlation with histopathologic features and with clinical course of NSCLC. The results of the present study demonstrate for the first time that numerous NSCLCs (45%) lose Cables expression. Furthermore, more adenocarcinomas show a loss of this novel protein than do squamous counterparts. The relationship between tumor histology type and Cables expression appears to be statistically significant (P = 0.028). Our results suggest that Cables may be involved in the pathogenesis of NSCLC.
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PMID:Loss of cables protein expression in human non-small cell lung cancer: a tissue microarray study. 1261 82

The antisense inhibitor poly-2'-O-(2,4-dinitrophenyl)-5'-GGCUGCGUGCCUCCUCACUGG (antisense poly-DNP RNA-21) has been synthesized by in vitro transcription followed by chemical derivatization. Its base sequence is complementary to that of nucleotides 110-130 in the mRNA of the regulatory RIalpha subunit of PKA (RIalpha/PKA), which is overexpressed in MCF-7 breast cancer cells and A549 lung cancer cells. The bioavailable and RNase-resistant antisense poly-DNP RNA-21 was found to inhibit cell growth with 50% inhibitory concentration (IC50) values of 0.05 nM in MCF-7 cells and 4 nM in A549 cells. The control 21-nt RNAs with the same poly-DNP oligonucleotide (ODN) platform but with scrambled, sense, or mismatched base sequence are inactive. Treatment of MCF-7 cells with antisense poly-DNP RNA-21 abolishes both the steady-state concentration of RIalpha mRNA and the synthesis of RIalpha protein. At sufficiently high concentration, antisense poly-DNP RNA-21 selectively kills the targeted cancer cells by inducing apoptosis. The observed sequence specificity and extremely low IC50 values of antisense poly-DNP RNA-21 suggest that it is a promising candidate for in vivo testing as an effective anticancer agent.
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PMID:A high-efficacy antisense RIalpha poly-DNP 21-nt RNA. 1269 37

Gene methylation and K-ras mutations were examined in tumor and paired serum DNA of 50 resected non-small-cell lung cancer patients. RASSF1A, death associated protein kinase and target of methylation-induced silencing were methylated in 17/50 (34%), 23/50 (45%) and 18/50 (35%) tumors, respectively, and in 17/50 (34%), 20/50 (40%) and 17/50 (34%) sera, respectively. Methylation in tumor and serum were closely correlated (P=0.001), but no correlation was found with survival. Twelve K-ras mutations (cysteine) were found in serum and nine mutations were found in tumor (five cysteine, one alanine, one aspartic, one arginine, and one valine). K-ras mutations in serum correlated significantly with survival (P=0.01).
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PMID:Methylation patterns and K-ras mutations in tumor and paired serum of resected non-small-cell lung cancer patients. 1474 28

Cell adhesion to extracellular matrix (ECM) is thought to confer resistance against cell-damaging agents, that is, drugs and radiation, in tumour and normal cells in vitro. The dependence of cell survival on beta1-integrin-linked kinase (ILK), protein kinase Balpha/Akt (PKBalpha/Akt) and glycogen synthase kinase-3beta (GSK-3beta) activity, which participate in beta1-integrin signalling and cell cycle progression was investigated as a function of radiation exposure. Colony-formation assays on polystyrene, fibronectin (FN), laminin (LA), bovine serum albumin (BSA) or poly-L-lysine (poly-L) (0-8 Gy), kinase assays, flow cytometric DNA and annexin-V analysis and immunoblotting were performed in nonirradiated and irradiated (2 or 6 Gy) A549 human lung cancer cells and CCD32 normal human lung fibroblasts. Cell contact to FN in contrast to polystyrene elevated basal ILK, PKBalpha/Akt and GSK-3beta kinase activities in A549 and CCD32 cells, as well as the basal amount of A549 G2 phase cells. Irradiation on FN or LA as compared to polystyrene, BSA or poly-L significantly improved cell survival. Following irradiation, kinase activities were stimulated strongly on polystyrene but showed to be less prominent on FN, which was because of the FN-related basal induction. Following irradiation, FN compared to polystyrene enlarged and prolonged G2 arrest in both the cell lines. For the analysis of phosphatidylinositol-3 kinase (PI3-K) dependence of protein kinases and cell cycle transition, the PI3-K inhibitors LY294002 and wortmannin were used showing decreased kinase activities, antiproliferative and radiation-dependent G2 accumulation-abrogating effects accompanied by downregulation of cyclin D1 and phospho-pRb in cells attached to polystyrene. Fibronectin partly abrogated these effects PI3-K-independently. These findings suggest a novel pathway that makes direct phosphorylation of GSK-3beta by ILK feasible after irradiation. Conclusively, the data indicate that ILK, PKBalpha/Akt and GSK-3beta are involved in modulations of the cell cycle after irradiation. These interactions are strictly dependent on ECM components in a cell line-specific manner. Our findings provide molecular insights into mechanisms likely to be important for ECM-dependent cell survival and cellular radioresistance as well as tumour growth.
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PMID:Cell adhesion to the extracellular matrix protein fibronectin modulates radiation-dependent G2 phase arrest involving integrin-linked kinase (ILK) and glycogen synthase kinase-3beta (GSK-3beta) in vitro. 1277 79

Most of the signal transduction pathways are mediated by protein kinases regulating every aspect of cell function. Mutations which deregulate their expression or their function or both result in cancers. Therefore, protein kinase inhibitors has become the focus of development of new therapies for cancer. Almost all 120 protein tyrosine kinases are involved in signaling, whereas only a handful of Ser/Thr kinases are involved. Thus, most of the effort is directed toward the development of tyrosine phosphorylation inhibitors. The success of Gleevec in the treatment of chronic myeloid leukemia and of Iressa for lung cancer validates the approach.
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PMID:Protein kinase inhibitors as a therapeutic modality. 1280 33

Abnormalities in the cell cycle are responsible for the majority of human neoplasias. Most abnormalities occur due to hyperphosphorylation of the tumor suppressor gene Rb by the key regulators of the cell cycle, the cyclin-dependent kinases (CDKs). Thus, a pharmacological CDK inhibitor may be useful in the prevention and/or treatment of human neoplasms. Flavopiridol is a flavonoid with interesting preclinical properties: (1) potent CDK inhibitory activity; (2) it depletes cyclin D1 and vascular endothelial growth factor mRNA by transcriptional and posttranscriptional mechanisms, respectively; (3) it inhibits positive elongation factor B, leading to transcription "halt"; and (4) it induces apoptosis in several preclinical models. The first phase I trial of a CDK inhibitor, flavopiridol, has been completed. Dose-limiting toxicities included secretory diarrhea and proinflammatory syndrome. Antitumor activity was observed in some patients with non-Hodgkin's lymphoma and renal, colon, and prostate cancers. Concentrations between 300 and 500 n M-necessary to inhibit CDK-were achieved safely. Phase II trials with infusional flavopiridol and phase I infusional trials in combination with standard chemotherapy are being completed with encouraging results. A novel phase I trial of 1-h flavopiridol administration was recently completed. The maximum tolerated doses using flavopiridol daily for 5, 3, and 1 consecutive days are 37.5, 50, and 62.5 mg/m(2) per day. Dose-limiting toxicities include vomiting, neutropenia, proinflammatory syndrome, and diarrhea. Plasma flavopiridol concentrations achieved were in the range 1.5-3.5 MICRO M. Phase II/III trials using this 1-h schedule in several tumor types including non-small-cell lung cancer, chronic lymphocytic leukemia, mantle cell lymphoma, and head and neck cancer are being conducted worldwide. UCN-01, the second CDK modulator that has entered clinical trials, has unique preclinical properties: (1) it inhibits protein kinase C (PKC) activity; (2) it promotes cell-cycle arrest by accumulation in p21/p27; (3) it induces apoptosis in several preclinical models; and (4) it abrogates the G(2) checkpoint by inhibition of chk1. The last of these represents a novel strategy to combine UCN-01 with DNA-damaging agents. In the initial UCN-01 clinical trial (continuous infusion for 72 h), a prolonged half-life of about 600 h (100 times longer than in preclinical models) was observed. The maximum tolerated dose was 42.5 mg/m(2) per day for 3 days. Dose-limiting toxicities were nausea/vomiting, hypoxemia, and symptomatic hyperglycemia. One patient with melanoma achieved a partial response (8 months). Another patient with refractory anaplastic large-cell lymphoma had no evidence of disease at >4 years. Bone marrow and tumor samples obtained from some patients revealed loss in adducin phosphorylation, a substrate of PKC. Phase I trials with shorter infusions are being completed. In summary, the first two CDK modulators have shown encouraging results in early clinical trials. A question that remains unanswered is "Which is the best schedule for combination with standard antitumor agents?" Moreover, it is still unclear which pharmacodynamic endpoint reflects loss of CDK activity in tissue samples from patients in these trials. Despite these caveats, we feel that CDKs are sensible targets for cancer therapy and that there are several small-molecule CDK modulators in clinical trials with encouraging results.
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PMID:Novel direct and indirect cyclin-dependent kinase modulators for the prevention and treatment of human neoplasms. 1281 36

Bayer and Onyx are developing BAY-43-9006, an oral cytostatic Raf kinase inhibitor for the potential treatment of colorectal and breast cancers, hepatocellular carcinoma and non-small-cell lung cancer, in addition to acute myelogenous leukemia, myelodysplastic syndrome and other cancers. A US IND was filed in May 2000 and by February 2003 BAY-43-9006 was in phase II trials, with phase III trials expected to begin later in 2003.
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PMID:BAY-43-9006 Bayer/Onyx. 1290 Dec 37

We have previously shown that tamoxifen (Tam) inhibits proliferation of estrogen receptor-negative human non-small cell lung cancer cells and this inhibition is associated with induction of p27(Kip1). In this study, we investigated the mechanism by which Tam increases p27(Kip1) expression. Because intracellular p27(Kip1) protein level is mainly controlled via posttranslational regulation, we first tested whether Tam might affect protein stability of p27(Kip1). Metabolic labeling and pulse chase assays showed that Tam did not affect the half-life of this protein. We next examined whether Tam enhanced p27(Kip1) expression through transcriptional activation. Our results demonstrated that Tam directly stimulated the p27(Kip1) promoter in lung cancer cells. Deletion and mutation analysis revealed that two Sp1 consensus sites located between -545 and -532bp from the transcription start site were crucial for the induction of p27(Kip1) by Tam. Conversely, mutation in a CTF site (-525/-520) nearby these two Sp1 sites had little effect. Electromobility shift assays showed that Sp1 transcription factor bound to these consensus sites and the DNA binding activity of Sp1 was enhanced by Tam. Our data also demonstrated that induction of p27(Kip1) by Tam was inhibited by protein kinase A inhibitor H89, but not by protein kinase C inhibitor calphostin C and mitogen-activated kinase kinase inhibitor PD98059. Taken together, our results suggest that Tam transcriptionally activates p27(Kip1) expression via the Sp1 consensus sites in the p27(Kip1) promoter and PKA is involved in this process.
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PMID:Involvement of PKA and Sp1 in the induction of p27(Kip1) by tamoxifen. 1290 35

Resveratrol, a polyphenolic phytoalexin found in grapes, may have the potential for prevention and therapy for human cancer. We report here that resveratrol inhibits the growth of human lung carcinoma A549 cells and provides molecular understanding of this effect. Resveratrol treatment of A549 cells resulted in a concentration-dependent induction of S phase arrest in cell cycle progression. This anti-proliferative effect of resveratrol was associated with a marked inhibition of the phosphorylation of the retinoblastoma protein (pRB) and concomitant induction of cyclin-dependent kinase (Cdk) inhibitor p21WAF1/CIP, which appears to be transcriptionally upregulated and is p53- dependent. In addition, resveratrol treatment resulted in induction of apoptosis as determined by fluorescence microscopy and flow cytometric analysis. These effects were found to correlate with an activation of caspase-3 and a shift in Bax/Bcl-xL ratio more towards apoptosis. Resveratrol treatment also inhibited the transcriptional activity of nuclear transcription factor kappaB (NF-kappaB). Taken together, these findings suggest that resveratrol has strong potential for development as an agent for prevention against human lung cancer.
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PMID:Involvement of p21WAF1/CIP1, pRB, Bax and NF-kappaB in induction of growth arrest and apoptosis by resveratrol in human lung carcinoma A549 cells. 1296 97

It has become clear in the past decade that most human malignancies, including lung neoplasms, have aberrations in cell cycle control. The tumor suppressor gene retinoblastoma is an important player in the G1/S transition and its function is abnormal in most human neoplasms. Retinoblastoma function is lost as a result of phosphorylation by the cyclin-dependent kinases (CDKs). Thus, modulation of CDKs may have an important use for the therapy and prevention of human neoplasms. Direct CDK modulators are small molecules that target specifically the adenosine triphosphate binding site of CDKs. In contrast, indirect CDK modulators affect CDK function by modulation of upstream pathways required for CDK activation. The first example of a direct small-molecule CDK modulator tested in the clinic, flavopiridol, is a pan-CDK inhibitor that not only promotes cell cycle arrest but also halts transcriptional elongation, promotes apoptosis, induces differentiation, and has antiangiogenic properties. The second example of direct small-molecule CDK modulators tested in clinical trials is UCN-01 (7-hydroxystaurosporine). UCN-01 has interesting preclinical features: it inhibits Ca2+-dependent protein kinase C, promotes apoptosis, arrests cell cycle progression at G1/S, and abrogates checkpoints upon DNA damage. In summary, novel small-molecule CDK modulators are being tested in the clinic with interesting results. Although these small molecules are directed toward a very prevalent cause of carcinogenesis, their role in the clinical armamentarium is still uncertain.
Clin Lung Cancer 2003 Nov
PMID:Cell cycle modulators for the treatment of lung malignancies. 1466 71


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