Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0684249 (lung carcinoma)
 23,830 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of substituted 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines was identified as potent and selective inhibitors of the tyrosine kinase activity of the growth factor receptors VEGFR-2 (Flk-1, KDR) and FGFR-1. The enzyme kinetics associated with the VEGFR-2 inhibition of compound 50 (K(i) = 52 +/- 3 nM) confirmed that the pyrrolo[2,1-f][1,2,4]triazine analogues are competitive with ATP. Several analogues demonstrated low-nanomolar inhibition of VEGF- and FGF-dependent human umbilical vein endothelial cell (HUVEC) proliferation. Replacement of the C6-ester substituent of the pyrrolo[2,1-f][1,2,4]triazine core with heterocyclic bioisosteres, such as substituted 1,3,5-oxadiazoles, afforded compounds with excellent oral bioavailability in mice (i.e., 50 F(po) = 79%). Significant antitumor efficacy was observed with compounds 44, 49, and 50 against established L2987 human lung carcinoma xenografts implanted in athymic mice. A full account of the synthesis, structure-activity relationships, pharmacology, and pharmacokinetic properties of analogues within the series is presented.
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PMID:Design, synthesis, and evaluation of orally active 4-(2,4-difluoro-5-(methoxycarbamoyl)phenylamino)pyrrolo[2,1-f][1,2,4]triazines as dual vascular endothelial growth factor receptor-2 and fibroblast growth factor receptor-1 inhibitors. 1594 73

Gefitinib (Iressa), an orally-active tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), is the first approved molecular-targeted drug for the management of patients with advanced non-small cell lung cancer (NSCLC). Two Phase II trials (IDEAL [Iressa Dose Evaluation in Advanced Lung Cancer]-1 and -2), evaluated the efficacy of gefitinib in advanced NSCLC patients who received < or = 2 (IDEAL1) or > or = 2 (IDEAL2) previous chemotherapy regimens. The response rate and disease control rate in IDEAL1 and -2 was 18/12% and 54/42%, respectively. The median survival time and one-year survival rate in both studies were approximately 7 months and 30%, respectively. As gefitinib has demonstrated antitumour activity and an acceptable tolerability profile not typically associated with cytotoxic adverse events, such as hematological toxicities, combinations with cytotoxic drugs have been evaluated. Disappointingly, in chemotherapy-naive patients with advanced NSCLC, gefitinib 250 and 500 mg/day combined with platinum-based chemotherapy (gemcitabine/cisplatin or paclitaxel/carboplatin) did not produce prolonged survival, compared with chemotherapy alone in two large, randomised, placebo-controlled, multi-centre Phase III trials (INTACT [Iressa NSCLC Trial Assessing Combination Treatment]-1 and -2). Furthermore, in a recent randomised, placebo-controlled, Phase III trial (ISEL: IRESSA Survival Evaluation in Lung cancer), gefitinib failed to prolong survival compared with placebo in patients with advanced NSCLC who had failed one or more lines of chemotherapy. Subgroup analysis of ISEL suggested improved survival in patients of Asian origin and non-smokers. In addition, subset analyses of IDEAL and several retrospective studies have indicated that female gender, adenocarcinoma histology (especially bronchial alveolar carcinoma), non-smoker status and Asian ethnicity are factors which predict to response to gefitinib. Two types of somatic mutation clustered around the ATP binding pocket in the tyrosine kinase domain of the EGFR gene have been reported as possible surrogate biological markers for predicting response to gefitinib. Appropriate patient selection by clinical characteristics or genetical information is needed, both for future clinical trials of gefitinib and its routine use in the clinic among patients with advanced NSCLC.
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PMID:Gefitinib in non-small cell lung cancer. 1595 26

Gefitinib (Iressa) is a selective epidermal growth factor receptor tyrosine kinase inhibitor and is used for the treatment of lung cancer. Recently, we discovered that it inhibits the breast cancer resistance protein, which is an ATP-binding cassette transporter. P-glycoprotein (Pgp) also pumps multiple types of drugs out of the cell using energy generated from ATP, and confers multidrug resistance on cancer cells. This study was designed to examine whether gefitinib inhibits the function of Pgp. We used multidrug resistant PC-6/PTX lung cancer and MCF-7/Adr breast cancer cells which overexpress Pgp and measured their drug sensitivity and drug-efflux function by tetrazolium assay and flowcytometry, respectively. In addition, the drug-stimulated ATPase activity of Pgp was measured using insect membranes that express human Pgp. Epidermal growth factor receptor was expressed in MCF-7/Adr, but not in PC-6/PTX cells, and the overexpression of Pgp did not confer resistance to gefitinib to both cell types. However, clinically achievable levels of gefitinib moderately reversed the Pgp-mediated resistance to paclitaxel and docetaxel in Pgp overexpressing cells. In addition, gefitinib increased the intracellular accumulation of the Pgp substrate rhodamine-123 in resistant cells, and activated ATPase in a preparation of pure Pgp-expressing membrane. These findings suggest that gefitinib directly interacts with Pgp and inhibits its function. Gefitinib may clinically inhibit the excretion of Pgp substrate drugs including anticancer agents, and its drug-interaction should therefore be considered.
Lung Cancer 2005 Sep
PMID:Gefitinib, an EGFR tyrosine kinase inhibitor, directly inhibits the function of P-glycoprotein in multidrug resistant cancer cells. 1595 94

The protein-kinase family is the most frequently mutated gene family found in human cancer. Gefitinib, an ATP-competitive inhibitor of epidermal growth factor receptor (EGFR), also appears to be particularly effective in adenocarcinoma of the lung and in patients without smoking history. To determine whether lung tumors sensitive to gefitinib contained mutations within the tyrosine kinase (TK) domain of EGFR, we screened exons 18-23 of EGFR of tumors in 20 patients with non-small cell lung cancer (NSCLC) who had been treated with gefitinib. Nine (45%) tumors had TK domain mutations. All mutations were observed in adenocarcinoma. Seven (77.8%) of 9 cases with mutated types showed sensitivity to gefitinib, while no cases of 11 with wild type showed gefitinib sensitivity. Such mutations were more frequently observed in patients who had never smoked (5/8 or 62.5%) than in smokers (4/12 or 33.3%). The patients with mutations of EGFR to have a more favorable prognosis than those with wild type (p=0.033). These data show that adenocarcinomas from patients who had never smoked comprise a specific subset of patients with NSCLC sensitive to gefitinib treatment.
Lung Cancer 2006 Jan
PMID:Epidermal growth factor receptor mutations are associated with gefitinib sensitivity in non-small cell lung cancer in Japanese. 1619 42

Mammalian chromatin remodeling factor, SWI/SNF complex contains a single molecule of either Brm or BRG1 as the ATPase catalytic subunit. Here, we show that the SWI/SNF complex forms a larger complex with neuron-restrictive silencer factor (NRSF) and its corepressors, mSin3A and CoREST, in human nonsmall cell lung carcinoma cell lines. We also demonstrate that the strong transcriptional suppression of such neuron-specific genes as synaptophysin and SCG10 by NRSF in these non-neural cells requires the functional SWI/SNF complex; these neuronal genes were elevated in cell lines deficient in both Brm and BRG1, whereas retrovirus vectors expressing siRNAs targeting integral components of SWI/SNF complex (Brm/BRG1 or Ini1) induced expression of these neuronal genes in SWI/SNF-competent cell lines. In cell lines deficient in both Brm and BRG1, exogenous Brm or BRG1 suppressed expression of these neuronal genes in an ATP-dependent manner and induced efficient and specific deacetylation of histone H4 around the NRSF binding site present in the synaptophysin gene by a large complex containing the recruited functional SWI/SNF complex. Patients with Brm/BRG1-deficient lung carcinoma have been reported to carry poor prognosis; derepression of NRSF-regulated genes including these neuron-specific genes could contribute to enhance tumorigenicity and also would provide selective markers for Brm/BRG1-deficient tumors.
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PMID:SWI/SNF complex is essential for NRSF-mediated suppression of neuronal genes in human nonsmall cell lung carcinoma cell lines. 1624 81

Somatic mutations in the tyrosine kinase domain of the epidermal growth factor receptor (EGFR) gene are associated with increased sensitivity to tyrosine kinase inhibitors (TKIs) and are present in 10-30% of non-small cell lung carcinoma depending on ethnic origin. EGFR protein is also overexpressed in about 90% of squamous cell carcinoma of head and neck (HNSCC), and treatment with TKIs has shown clinical benefit in a subgroup of these patients. Recently, EGFR mutations were described in three Asian patients with larynx cancer. We screened for EGFR tyrosine kinase mutations in tumour DNA of 100 patients of Caucasian origin with HNSCC by direct sequencing of the hotspot regions. Only one patient with larynx cancer displayed a novel, somatic EGFR missense mutation, K745R, affecting a highly conserved residue within the ATP cleft. Similar to reports in lung cancer, EGFR kinase domain mutations in HNSCC patients seem to show a lower incidence in patients of Caucasian origin.
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PMID:Low incidence of mutations in EGFR kinase domain in Caucasian patients with head and neck squamous cell carcinoma. 1632 36

Several groups have reported in recent years that members of the plant stress hormones family of jasmonates, and some of their synthetic derivatives, exhibit anti-cancer activity in vitro and in vivo. Jasmonates increased the life span of EL-4 lymphoma-bearing mice, and exhibited selective cytotoxicity towards cancer cells while sparing normal blood lymphocytes, even when the latter were part of a mixed population of leukemic and normal cells drawn from the blood of chronic lymphocytic leukemia (CLL) patients. Jasmonates join a growing number of old and new cancer chemotherapeutic compounds of plant origin. Three mechanisms of action have been proposed to explain the anti-cancer activity of jasmonates. These include: (1) The bio-energetic mechanism-jasmonates induce severe ATP depletion in cancer cells via mitochondrial perturbation; (2) The re-differentiation mechanism-jasmonates induce re-differentiation in human myeloid leukemia cells via mitogen-activated protein kinase (MAPK) activity; (3) The reactive oxygen species (ROS)-mediated mechanism-jasmonates induce apoptosis in lung carcinoma cells via the generation of hydrogen peroxide, and pro-apoptotic proteins of the Bcl-2 family. Several similarities between the effects of jasmonates on plant and cancer cells have been recorded, suggesting that additional analysis of jasmonate effects in plant cells may contribute to a deeper understanding of the anti-cancer actions of these compounds. Those similarities include: induction of cell death, suppression of proliferation and cell cycle arrest, MAPK induction, ROS generation, and enhancement of heat-shock proteins (HSP) expression. Finally, jasmonates can induce death in drug-resistant cells. The drug resistance was conferred by either p53 mutation or P-glycoprotein (P-gp) over-expression. In summary, the jasmonate family of novel anti-cancer agents presents new hope for the development of cancer therapeutics, which should attract further scientific and pharmaceutical interest.
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PMID:Jasmonates in cancer therapy. 1660 Apr 75

Imatinib mesylate (IM), is a selective and competitive inhibitor of tyrosine kinases, including BCR-ABL, ABL, KIT, and the platelet-derived growth factor receptors (PDGF-R). It binds to the ATP-binding site of the target kinase and prevents the transfer of phosphate from ATP to the tyrosine residues of various substrates. At oral doses of 200-600 mg, the majority of patients with chronic myeloid leukaemia, Philadelphia chromosome-positive acute lymphoblastic leukemia expressing the BCR-ABL fusion protein and gastrointestinal stromal tumours (GIST) achieve a bio-molecular and clinical response, frequently complete, associated with limited toxicity. Several other human cancers, as small-cell lung carcinoma, melanoma, seminoma, some sarcomas, and adenoid cystic carcinomas may over-express KIT or PDGF-R, and clinical trials to evaluate the role of IM in the treatment of such cancers are currently ongoing. We determined c-KIT with Dako CD 117 antibody in 5 cases of advanced ocular melanoma (OM) and we found positive immuno-reactivity for CD 117 in three patients. We treated all patients with palliative-use IM at the oral dose of 400 mgr daily. We obtained in expressing positive immuno-reactivity for CD 117 patients: a reduction of malignant ascites in one, a partial remission in the neck nodes in another, and progression of liver metastases in the third. Evidences of progression has been reported in the other two patients expressing negative immuno-reactivity for CD 117. We conclude that the effect of IM should be assessed only in OM with positive immuno-histochemical c-kit (CD 117) expression. IM might be a potential therapeutic strategy for these patients.
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PMID:Tyrosine kinase inhibitor imatinib mesylate as anticancer agent for advanced ocular melanoma expressing immunoistochemical C-KIT (CD 117): preliminary results of a compassionate use clinical trial. 1676

Endoglin is a transforming growth factor-beta(1) (TGF-beta(1)) accessory receptor which is highly expressed in tumor vessels. To study the role of endoglin in tumor growth and angiogenesis we induced a highly vascularized tumor in mice heterozygous for endoglin (Eng+/-) and in their control littermates (Eng+/+) by injecting 10(6) Lewis lung carcinoma (3LL) cells subcutaneously. Nine days after injection, the tumor was removed and weighed. Capillary density (CD31 immunohistochemistry), hemoglobin content and vascular cell adhesion molecule-1 (VCAM-1) expression were used to assess tumor vascularization. Tumor perfusion rate was measured by laser-Doppler technique. Expression of the hypoxia-inducible factor (HIF), endothelial nitric oxide synthase (eNOS) and vascular endothelial growth factor (VEGF) were determined by Western blot analysis. The aerobic metabolism and oxygen dependency were inferred from the measurement of ATP in tumoral tissue. Tumor weight, capillary density, hemoglobin and VCAM-1 were reduced by about 30% in Eng+/- compared to Eng+/+ littermates. The protein levels of eNOS and phosphorylated eNOS were significantly reduced in Eng+/- compared to Eng+/+ mice. HIF expression was slightly reduced whereas VEGF level was slightly increased in Eng+/- compared to Eng+/+. Tumor tissue levels of ATP and ADP were similar in both types of mice. These data demonstrate that endoglin plays a major role in tumor neoangiogenesis.
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PMID:Reduced tumor growth and angiogenesis in endoglin-haploinsufficient mice. 1710 12

Cyclin-dependent kinases (Cdk) and their associated pathways represent some of the most attractive targets for the development of anticancer therapeutics. Based on antitumor activity in animal models, a variety of Cdk inhibitors are undergoing clinical evaluation either as a single agent or in combination with other approved drugs. In our anticancer drug discovery program, a novel series of flavones have been synthesized for evaluation against the activity of Cdk4-D1. This enzyme catalyzes the phosphorylation of retinoblastoma protein, thus inhibiting its function. We have identified a series of potent Cdk4-D1 inhibitors with IC(50) below 250 nmol/L. In this report, we have described the properties of one of the best compound, P276-00 of the flavone's series. P276-00 shows 40-fold selectivity toward Cdk4-D1, compared with Cdk2-E. The specificity toward 14 other related and unrelated kinases was also determined. P276-00 was found to be more selective with IC(50)s <100 nmol/L for Cdk4-D1, Cdk1-B, and Cdk9-T1, as compared with other Cdks, and less selective for non-Cdk kinases. It showed potent antiproliferative effects against various human cancer cell lines, with an IC(50) ranging from 300 to 800 nmol/L and was further compared for its antiproliferative activity against cancer and normal fibroblast cell lines. P276-00 was found to be highly selective for cancer cells as compared with normal fibroblast cells. To delineate its mechanism of action, the effect of P276-00 on cell cycle proteins was studied in human breast cancer cell line (MCF-7) and human non-small cell lung carcinoma (H-460). A significant down-regulation of cyclin D1 and Cdk4 and a decrease in Cdk4-specific pRb Ser(780) phosphorylation was observed. P276-00 produced potent inhibition of Cdk4-D1 activity that was found to be competitive with ATP and not with retinoblastoma protein. The compound also induced apoptosis in human promyelocytic leukemia (HL-60) cells, as evidenced by the induction of caspase-3 and DNA ladder studies. These data suggest that P276-00 has the potential to be developed as an anti-Cdk chemotherapeutic agent.
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PMID:In vitro antitumor properties of a novel cyclin-dependent kinase inhibitor, P276-00. 1736 86


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