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)

Although no overall differences in survival have been observed between the many chemotherapy combinations in non-small-cell lung cancer, the clinical application of mRNA expression levels of amplified genes may disclose many genetic influences on cytotoxic drug sensitivity and enable clinicians to tailor chemotherapy according to each individual's gene profile. Specifically, the assessment of ribonucleotide reductase subunit M1 and thymidylate synthase mRNA expression levels might select patients who benefit from gemcitabine (Gemzar) or pemetrexed (Alimta) combinations. Until recently, clinical prognostic factors such as performance status, weight loss, and lactate dehydrogenase were the only parameters used to predict chemotherapy response and survival. However, accumulated data indicate that overexpression of genes involved in cancer glycolysis pathways plays an important role, and might be an independent mechanism of chemoresistance. The dysregulation of glycolytic genes is affected by growth signals involving the PI3K/Akt pathway and downstream genes such as hypoxia-inducible factor-1-alpha. One can thus envision that substantial improvements in therapeutic outcome could benefit from the integration of tailored ribonucleotide reductase-dependent chemotherapy, ribonucleotide reductase antisense therapy, and targeted therapy.
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PMID:The promise of pharmacogenomics: gemcitabine and pemetrexed. 1565 42

Modern platinum-based combination therapies containing gemcitabine, vinorelbine or taxanes produce response rates of 30-40%, median survival times of 8-10 months and 1-year survival rates of approximately 35% in patients with advanced non-small-cell lung cancer (NSCLC). Of the new drugs available, gemcitabine (Gemzar, Lilly, Bad Homburg, Germany) has been the most extensively researched in clinical trials and exhibits a consistent database. A total of 37 randomized phase III trials involving more than 15,000 patients have been published to evaluate gemcitabine as first-line therapy for treating locally advanced and/or metastatic NSCLC. One trial studied gemcitabine exclusively as a single agent and another four trials investigated the drug in monotherapy and combination therapy. Of the 36 combination treatment studies, 21 included gemcitabine plus cisplatin treatment arms, 6 investigated gemcitabine plus carboplatin, and another 12 evaluated platinum-free gemcitabine combinations with other third generation cytostatic agents (multiple nominations possible). In single-agent treatment, gemcitabine was similarly effective to older platinum-based combinations such as vindesine-cisplatin but was less toxic. Thrombocytopenia was the main dose-limiting toxicity but was rarely clinically relevant. A 3-week cycle with gemcitabine on days 1 and 8 was confirmed as being the most convenient of the gemcitabine-based combinations studied. No other modern platinum-based doublet with vinorelbine or taxanes was superior to gemcitabine plus cisplatin in terms of survival or time to progression in any of the eight phase III studies performed. These results are consistent with previous phase II data and with a recent meta-analysis of 11 phase III and 2 randomized phase II studies involving more than 4,500 patients (1,861 in gemcitabine-based treatment arms). This meta-analysis also demonstrated a statistically significant benefit regarding overall and progression-free survival for gemcitabine-platinum- based regimens compared with other platinum combinations. In summary, currently available data indicate that gemcitabine-platinum 2-agent combinations given in 3-week cycles may at present have the best benefit-risk ratio in the treatment of advanced NSCLC. In contrast, platinum based 3-agent schedules do not offer any survival benefit. In elderly patients with poor performance status single agent treatment with a modern cytotoxic agent should be considered. Furthermore, according to the experiences from phase III studies so far, platinum- free combinations open up the possibility of a more feasible and clinically practical, active and well tolerated treatment which is associated with a positive impact on patient quality of life.
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PMID:[Gemcitabine in the first line therapy of advanced and metastatic non-small-cell lung carcinoma (NSCLC): review of the results of phase III studies]. 1580 86

Pemetrexed (Alimta; Eli Lilly and Co, Indianapolis, IN) is a multitargeted antifolate that inhibits several folate-dependent enzymes that play roles in purine and pyrimidine synthesis. The principal toxicities of pemetrexed are neutropenia, diarrhea, nausea/vomiting, mucositis, and skin rash. These toxicities are more frequent in vitamin-deficient (folate and vitamin B 12 ) patients, and can be ameliorated by the co-administration of folate and vitamin B 12 . The use of prophylactic dexamethasone is also recommended to reduce the frequency of severe skin rash. Pemetrexed has significant single-agent activity in previously treated and untreated patients with non-small cell lung cancer (NSCLC). A recent phase III trial comparing pemetrexed with docetaxel in previously treated NSCLC patients showed equivalent efficacy with less bone marrow toxicity (eg, neutropenia) in the pemetrexed group. These results were pivotal in the approval of pemetrexed for the treatment of refractory NSCLC. Pemetrexed has been combined with the platinums (ie, cisplatin, carboplatin, and oxaliplatin) in NSCLC to yield clinical activity similar to that of other platinum-based doublets. A comparative phase III trial of cisplatin/pemetrexed against cisplatin/gemcitabine (Gemzar; Eli Lilly and Co) is under way. Pemetrexed has also been evaluated in combination with gemcitabine, and although the optimal dose and schedule of this combination has not been defined, clinical activity similar to other nonplatinum-based doublets has been observed. Preliminary evidence suggests that pemetrexed can be combined with thoracic radiation therapy, but more data are needed to evaluate the potential advantage(s) pemetrexed may have in this setting. Pemetrexed/platinum doublets also appear to possess activity in extensive stage small cell lung cancer. A phase II trial of single-agent pemetrexed is under way in both sensitive- and refractory-relapsed small cell lung cancer. Given the activity and excellent tolerability of pemetrexed, further studies in lung cancer are warranted.
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PMID:The evolving role of pemetrexed (Alimta) in lung cancer. 1581 33

With best supportive care alone, patients with metastatic non-small-cell lung cancer (NSCLC) have a median survival of 4 to 5 months and a 1-year survival rate of approximately 10%. Trials carried out in the 1980s and 1990s comparing chemotherapy to best supportive care reported variable efficacy results; however, a pivotal meta-analysis of these data indicated that cisplatin-based chemotherapy provided a survival benefit in advanced NSCLC. In the past decade newer agents such as gemcitabine (Gemzar), vinorelbine, paclitaxel, and docetaxel (Taxotere) have all demonstrated activity in NSCLC as single agents; consequently these agents have been combined with cisplatin or carboplatin. Randomized phase III trials comparing these "newer" platin-based doublets have failed to identify an optimal platinum-based doublet therapy regimen. Though it is clear that chemotherapy is an appropriate treatment for many patients with lung cancer, there a sense in which the use of traditional chemotherapeutic agents has reached a therapeutic plateau. Increased understanding of cancer biology has revealed numerous potential therapeutic strategies, including targeting the epidermal growth factor receptor, protein kinase C, rexinoid receptors, and the angiogenesis pathway. The Eastern Cooperative Oncology Group study E4599 comparing paclitaxel/carboplatin with/without bevacizumab is the first phase III randomized trial to show a survival advantage with the addition of a molecularly targeted agent to chemotherapy in the chemotherapy-naive patient population. Future studies will involve the evaluation of additional targeted agents plus chemotherapy as well as looking at combinations of these targeted agents alone or with chemotherapy.
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PMID:First-line treatment for advanced non-small-cell lung cancer. 1642 20

Erlotinib (Tarceva) is a human epidermal growth factor receptor type 1/epidermal growth factor receptor (HER1/EGFR) tyrosine kinase inhibitor initially approved by the US Food and Drug Administration for the treatment of patients with locally advanced or metastatic non-small-cell lung cancer after failure of at least one prior chemotherapy regimen. In this report, we present the pivotal study that led to the approval of erlotinib in combination with gemcitabine (Gemzar) in patients with locally advanced/metastatic chemonaive pancreatic cancer patients. The combination demonstrated a statistically significant increase in overall survival accompanied by an increase in toxicity. Physicians and patients now have a new option for the treatment of locally advanced/metastatic adenocarcinoma of the pancreas.
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PMID:Erlotinib/gemcitabine for first-line treatment of locally advanced or metastatic adenocarcinoma of the pancreas. 1824 17

Gastric cancer is the fourth most common malignancy in the world, and mortality due to gastric cancer is second only to that from lung cancer. 'Transcriptome dissection' is a detailed analysis of the entire expressed transcripts from a cancer, for the purpose of understanding the precise molecular mechanism of pathogenesis. Serial analysis of gene expression (SAGE) is a suitable technique for performing transcriptome dissection. Gastric cancers of different stages and histology were analyzed on SAGE, and one of the largest gastric cancer SAGE libraries in the world was created (GEO accession number GSE 545). Through SAGE, many candidate genes have been identified as potential diagnostic and therapeutic targets for the treatment of gastric cancer. Regenerating islet-derived family, member 4 (Reg IV) participated in 5-fluorouracil (5-FU) resistance and peritoneal metastasis, and its expression was associated with an intestinal phenotype of gastric cancer and with endocrine differentiation. GW112 expression correlated with advanced tumor stage. Measurement of Reg IV and GW112 levels in sera indicated a sensitivity of 57% for detection of cancer. SPC18 participated in tumor growth and invasion through transforming tumor growth factor-alpha upregulation. Palate, lung, and nasal epithelium carcinoma-associated protein (PLUNC) was a useful marker for gastric hepatoid adenocarcinoma. Expression of SOX9, HOXA10, CDH17, and loss of claudin-18 expression were associated with an intestinal phenotype of gastric cancer. Information obtained from transcriptome dissection greatly contributes to diagnosis and treatment of gastric cancer.
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PMID:Transcriptome dissection of gastric cancer: identification of novel diagnostic and therapeutic targets from pathology specimens. 1926 Oct 89

Gemcitabine (Gemzar) is a nucleoside analogue used as a cytotoxic agent for the treatment of various carcinomas: pancreatic cancer, bladder cancer, breast cancer, and non-small-cell-lung cancer. Carboplatin, a DNA alkylating agent, is used alongside with gemcitabine in a regimen known as GemCarbo chemotherapy to treat several different types of cancer, most commonly lung cancer. We report an unusual case of hand-foot hyperpigmentation after the use of GemCarbo therapy on a man with stage IV non-small cell lung carcinoma. Physical examination revealed hyperpigmented lesions that were approximately 1-2 mm in diameter, of brown/purple discoloration localized to the palmar surface of his hands and the dorsum of his feet. A rapid plasma reagin blood test, used for the screening of syphilis was nonreactive. Discontinuation of both agents resulted in the dramatic disappearance of the lesions over the course of 2 weeks. In this report, we describe, to our knowledge, the first case of hand-foot hyperpigmentation that has been reported with the use of either of these 2 agents.
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PMID:Hand-foot hyperpigmentation skin lesions associated with combination gemcitabine-carboplatin (GemCarbo) therapy. 2046 Sep 84

The search for novel oncogenes is important because they could be the target of future specific anticancer therapies. In the present paper we report the identification of novel amplified genes in lung cancer by means of global gene expression analysis. To screen for amplicons, we aligned the gene expression data according to the position of transcripts in the human genome and searched for clusters of over-expressed genes. We found several clusters with gene over-expression, suggesting an underlying genomic amplification. FISH and microarray analysis for DNA copy number in two clusters, at chromosomes 11q12 and 13q34, confirmed the presence of amplifications spanning about 0.4 and 1 Mb for 11q12 and 13q34, respectively. Amplification at these regions each occurred at a frequency of 3%. Moreover, quantitative RT-PCR of each individual transcript within the amplicons allowed us to verify the increased in gene expression of several genes. The p120ctn and DP1 proteins, encoded by two candidate oncogenes, CTNND1 and TFDP1, at 11q12 and 13q amplicons, respectively, showed very strong immunostaining in lung tumours with gene amplification. We then focused on the 13q34 amplicon and in the TFDP1 candidate oncogene. To further determine the oncogenic properties of DP1, we searched for lung cancer cell lines carrying TFDP1 amplification. Depletion of TFDP1 expression by small interference RNA in a lung cancer cell line (HCC33) with TFDP1 amplification and protein over-expression reduced cell viability by 50%. In conclusion, we report the identification of two novel amplicons, at 13q34 and 11q12, each occurring at a frequency of 3% of non-small cell lung cancers. TFDP1, which encodes the E2F-associated transcription factor DP1 is a candidate oncogene at 13q34. The data discussed in this publication have been deposited in NCBIs Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) and are accessible through GEO Series Accession No. GSE21168.
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PMID:Gene amplification of the transcription factor DP1 and CTNND1 in human lung cancer. 2071 54

Increasing evidence suggests that PRMT5, a protein arginine methyltransferase, is involved in tumorigenesis. However, no systematic research has demonstrated the cell-transforming activity of PRMT5. We investigated the involvement of PRMT5 in tumor formation. First, we showed that PRMT5 was associated with many human cancers, through statistical analysis of microarray data in the NCBI GEO database. Overexpression of ectopic PRMT5 per se or its specific shRNA enhanced or reduced cell growth under conditions of normal or low concentrations of serum, low cell density, and poor cell attachment. A stable clone that expressed exogenous PRMT5 formed tumors in nude mice, which demonstrated that PRMT5 is a potential oncoprotein. PRMT5 accelerated cell cycle progression through G1 phase and modulated regulators of G1; for example, it upregulated cyclin-dependent kinase (CDK) 4, CDK6, and cyclins D1, D2 and E1, and inactivated retinoblastoma protein (Rb). Moreover, PRMT5 activated phosphoinositide 3-kinase (PI3K)/AKT and suppressed c-Jun N-terminal kinase (JNK)/c-Jun signaling cascades. However, only inhibition of PI3K activity, and not overexpression of JNK, blocked PRMT5-induced cell proliferation. Further analysis of PRMT5 expression in 64 samples of human lung cancer tissues by microarray and western blot analysis revealed a tight association of PRMT5 with lung cancer. Knockdown of PRMT5 retarded cell growth of lung cancer cell lines A549 and H1299. In conclusion, to the best of our knowledge, we have characterized the cell-transforming activity of PRMT5 and delineated its underlying mechanisms for the first time.
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PMID:Protein arginine methyltransferase 5 is a potential oncoprotein that upregulates G1 cyclins/cyclin-dependent kinases and the phosphoinositide 3-kinase/AKT signaling cascade. 2272 90

Many reports have inferred that macrophages can interact with tumor cells in the tumor microenvironment (TME) in a vicious cycle of tumor development; however, the changes in gene expression in tumor cells under the effects of macrophages are still largely unknown. The present study was carried out to illustrate the changes in the gene expression profile in lung cancer cells under the effects of macrophage-conditioned medium. Gene expression profile data were derived from the GEO database GSE9315. The GSM234968 sample was derived from a highly invasive human pulmonary adenocarcinoma cell line, CL1-5, and was treated with conditioned medium (supernatant of a culture solution of human monocyte THP-1). The GSM234967 sample that was not treated with the conditioned medium was used as a control. GO and KEGG enrichment analyses were carried out using DAVID software, and visualization networks were constructed using Cytoscape software. The results showed that 40 differentially expressed genes were annotated. Five differentially expressed transcription factors were identified, EIF2B4, EIF2B5, JUNB, GNG11 and HMGB2, which were all related to 'stress' and 'responses'. The gene cluster of JUNB was mainly enriched in cancer-related pathways, 'Wnt signaling pathway' and 'MAPK signaling pathway'. Finally, 10 small molecules, thioridazine, resveratrol, astemizole, ciclopirox, calmidazolium, etoposide, anisomycin, pyrvinium, azacyclonol and terfenadine, which may act on transcription factors, were identified using the CMap database. In conclusion, we identified transcription factors playing key roles in tumor cells under the effects of macrophages in order to provide new clues for blocking this vicious cycle of tumor development.
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PMID:Screening for transcription factors and their regulatory small molecules involved in regulating the functions of CL1-5 cancer cells under the effects of macrophage-conditioned medium. 2436 84


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