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)

Gemcitabine (dFdC) and DMDC are new antimetabolites with good antitumor activities against various tumors which include human leukemic cell lines and a number of rodent and human solid tumors and human tumor. They are structurally related to cytarabine (Ara-C) which is known as one of the most effective drugs against adult acute leukemia, but many solid tumors are insensitive not been found to the drug. Gemcitabine acts as an inhibitor of ribonucleoside diphosphate reductase and inhibits DNA synthesis. Biochemically Gemcitabine is rapidly phosphorylated to dFdCTP which has a comparatively longer half-life than that of Ara-C, showing a therapeutic activity against tumors. In the phase I trials, the reported maximum-tolerated doses were 790 mg/m2 to 1370 mg/m2 at the schedule of 30 minutes i.v. infusion once a week for three weeks but higher dose levels (2,500 mg/m2 to 4,800 mg/m2) were reported in the schedule of prolongation of the infusion time. Reported toxicities were myelosuppression, fatigability, fever, appetite loss and skin rash. Toxicities were seemed to be mild. In USA, Europe and South Africa, phase II trials of Gemcitabine at the schedule of 30 minutes infusion once a week for three weeks followed by one week rest were performed against solid tumors (breast cancer, ovarian cancer, renal cancer, colorectal cancer, pancreas cancer, head and neck cancer, and lung cancer) and showed good responses to those tumors. DMDC was developed in Japan, and a phase I trial is currently on-going.
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PMID:[New antitumor antimetabolites--gemcitabine and DMDC]. 133 22

A total of 45 patients with locally advanced and/or metastatic non-small-cell lung cancer (NSCLC) were treated in a phase II trial with high-dose i.v. infusions of 24 g hydroxyurea over 24 h, with 50 mg/m2 i.v. cisplatin 8 h after the start of hydroxyurea infusion. Hydroxyurea, a cell-cycle-specific inhibitor of ribonucleotide reductase, inhibits DNA repair by depleting nucleotide pools. We gave hydroxyurea to achieve steady-state levels of greater than or equal to 1 mM and to potentiate therapy by inhibiting repair of DNA damage produced by cisplatin. Among 21 patients with squamous cell lung cancer, there were 1 complete response (CR), 2 partial responses (PR) and 3 minor responses (MR). Of 13 patients with adenocarcinoma of the lung, 2 had MRs; of 11 patients with large-cell anaplastic lung cancer, none responded. The dominant toxicity was nausea and vomiting, which was manageable and mainly related to cisplatin. The response rate in squamous cell lung cancer was similar to responses obtained with cisplatin alone. The relative ineffectiveness of high-dose 24-h infusions of hydroxyurea in inhibiting repair of DNA damage produced by cisplatin may be due to the low growth fraction of human NSCLC. The high-dose hydroxyurea approach may be more applicable in tumours with a high growth fraction.
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PMID:Cisplatin with high-dose infusions of hydroxyurea to inhibit DNA repair. A phase II study in non-small-cell lung cancer. 253 51

The pharmacology, pharmacokinetics, clinical efficacy, adverse effects, and dosage and administration of gemcitabine are reviewed. Gemcitabine is a deoxycytidine-analogue antimetabolite with activity against some solid tumors. Gemcitabine is phosphorylated intracellularly to difluorodeoxycytidine triphosphate, which terminates DNA-chain elongation and competitively inhibits DNA polymerase and ribonucleotide reductase. After i.v. administration, gemcitabine is rapidly distributed into total body water. The drug is deaminated in the plasma to inactive difluorodeoxyuridine; both gemcitabine and difluorodeoxyuridine are primarily renally eliminated. In clinical studies, gemcitabine reduced pain and improved function in patients with advanced pancreatic cancer. Gemcitabine has shown some activity against non-small-cell lung cancer, particularly when combined with cisplatin or ifosfamide. The agent has also shown modest activity against advanced ovarian and breast cancer. Adverse effects include dose-limiting myelosuppression, flu-like symptoms, nausea, vomiting, and rash. Gemcitabine has FDA-approved labeling for use in the treatment of locally advanced and metastatic pancreatic cancer. The recommended dosage for this indication is 1000 mg/m2 (as the hydrochloride salt) i.v. given over 30 minutes weekly for seven weeks, followed after one week of rest by 1000 mg/ m2 i.v. given over 30 minutes weekly for three weeks every four weeks. Gemcitabine palliates symptoms in patients with advanced or metastatic pancreatic cancer. More study is needed to determine gemcitabine's role in the treatment of non-small-cell lung cancer, ovarian cancer, and breast cancer.
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PMID:Gemcitabine: a cytidine analogue active against solid tumors. 911 4

The lung is a very common site for primary cancer and metastatic disease. Advances in tumor biology have provided insight into the sequence of genetic alterations leading to tumor and metastasis formation in the lung. In this review we address two genetic alterations, the dominant ras oncogene and the p53 tumor suppressor gene, which are commonly found in lung cancer and pulmonary metastases. We discuss their specific roles in tumor development, invasion, metastasis formation, and their potential prognostic utility. In addition, we will discuss the concept of a novel modulator gene, ribonucleotide reductase, and review its role in the control of metastasis formation.
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PMID:Molecular genetic analysis of primary lung cancer and cancer metastatic to the lung. 1036 61

A wealth of data indicates that certain genetic abnormalities can target specific cytotoxic drugs and intervene at an early step as a mechanism of resistance in the treatment of non-small-cell lung cancer. Therefore prescribing certain combinations of cytotoxic anticancer agents to a vast majority of these patients is futile. Genetic abnormalities have been found to be useful surrogate markers for response, particularly in colorectal cancer: thymidylate synthase mRNA and ERCC1 mRNA levels. In addition, beta-tubulin mutations may also confer paclitaxel resistance in patients. An important target to be explored for gemcitabine resistance is the assessment of a particular region in chromosome 11p15.5 wherein lies the ribonucleotide reductase gene that could affect gemcitabine metabolism. Shedding light on this genetic framework, several proposed customized chemotherapy studies could help validate the relevance of these markers.
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PMID:Novel approaches in the treatment of non-small-cell lung cancer. 1130 50

The main mechanism of action of the anticancer drug gemcitabine is assumed to be incorporation of its triphosphate (dFdCTP) into DNA, resulting in inhibition of DNA polymerization, inhibition of DNA synthesis and repair. Another mechanism is inhibition of ribonucleotide reductase leading to imbalance in the deoxyribonucleotide (dNTP) pools. One assay to measure dNTP pools is based on oligonucleotide elongation mediated by DNA polymerase. Since the latter may be affected by dFdCTP, we studied the effect of 0.1-600 pmol dFdCTP on this assay; 10 pmol and more dFdCTP significantly increased the average dpm of the blank (absence of other dNTP) and that of the calibration line of dATP (1.4-1.6-fold); 0.1 pmol and more increased that of the standard dGTP curve significantly (1.1-1.8-fold); 10-75 pmol decreased that of dCTP while 75 and 100 pmol significantly increased that of dCTP (1.3-fold); 50 pmol significantly increased that of dTTP (1.3-1.5-fold). For dATP, dGTP and dTTP, a saturation was reached at 100 pmol dFdCTP, but not yet for dCTP. To minimize these effects, we added an excess of 200 pmol dFdCTP to all samples and calibration lines when measuring dNTP levels of gemcitabine treated samples. In this way the effects of gemcitabine on dNTP levels were studied in human A2780 ovarian, HT29 colon, K562 myelogenous leukemia, H322 non-small cell lung cancer cell lines and the murine lung cancer cell line Lewis Lung. In all cell lines, intrinsic dTTP pools (3-77 pmol/106 cells) were the highest, followed by dATP (1.5-31), dCTP (0.7-27) and (nd-14) dGTP. Exposure to 1 and 10 microM gemcitabine for 4-h concentration dependently decreased dATP 3-10-fold and dGTP to undetectable levels, but dCTP at most 3-fold, while dTTP increased. In conclusion, dFdCTP affects dNTP measurements with the DNA polymerase elongation assay, but its effect could be controlled by addition of similar amounts of dFdCTP to each assay.
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PMID:Interference of gemcitabine triphosphate with the measurements of deoxynucleotides using an optimized DNA polymerase elongation assay. 1140 37

Detection of genomic differences predictive of drug response or resistance in individual patients may allow therapy to be customized to the characteristics of particular tumors. Preliminary findings are that non-small cell lung cancer patients overexpressing ERCC1 mRNA have lower response to cisplatin chemotherapy, while those overexpressing ribonucleotide reductase mRNA have limited benefit from gemcitabine. In addition, overexpression of beta-tubulin III and stathmin can influence the sensitivity to microtubule interacting drugs, like vinorelbine and paclitaxel. The introduction of biological agents which target highly specific intracellular pathways offers the promise of enhancing the efficacy of cytotoxic chemotherapy. Among many promising biological agents is the monoclonal antibody C225, which blocks the EGFR receptor. The addition of C225 appears to induce responses in a proportion of colon cancer patients refractory to 5-FU or irinotecan, supporting pre-clinical evidence of synergistic activity. It also appears from xenograft data that C225 enhances the sensitivity of tumors to radiation and docetaxel or the combination.
Lung Cancer 2002 Dec
PMID:Molecular markers and targeted therapy with novel agents: prospects in the treatment of non-small cell lung cancer. 1248 Jan 94

Gemcitabine (2'-2'-difluorodeoxycytidine) is a recently developed pyrimidine antagonist that is structurally related to cytarabine (ara-C). When phosphorylated intracellularly, gemcitabine inhibits ribonucleotide reductase and arrests cell cycling in the S phase. Paclitaxel is a potent promoter and stabilizer of microtubule spindle formation and an inhibitor of cell cycling. In this report, we discuss 2 patients with advanced-stage non-small-cell lung cancer (NSCLC) treated with a combination of gemcitabine/paclitaxel who developed pulmonary symptoms of dyspnea and cough. Chest radiographs and computed tomography revealed diffuse pulmonary infiltrates. Bronchoscopic evaluation revealed diffuse alveolar damage with associated type II pneumocyte hyperplasia without evidence of infection or metastatic carcinoma, suggesting the development of a drug-induced pulmonary toxicity. Both cases improved with the discontinuation of gemcitabine/paclitaxel and with supportive care including steroids in one of the patients. We also review the published case reports of pneumonitis believed to be secondary to the taxanes or gemcitabine when used as single agents and a solitary case report describing pneumonitis in the setting of both a taxane and gemcitabine. Because the combination of gemcitabine/paclitaxel has demonstrated activity in NSCLC, the use of this combination is likely to increase. Clinicians caring for lung cancer patients receiving this combination should be aware of this potential pulmonary toxicity.
Clin Lung Cancer 2002 Jul
PMID:Hypersensitivity pneumonitis in advanced non-small-cell lung cancer patients receiving gemcitabine and paclitaxel: report of two cases and a review of the literature. 1465 77

Antisense oligonucleotides (ASONs) are one of the new classes of molecularly targeted agents that have transitioned from the laboratory into clinical trials. Rational drug design has resulted in agents directed against a number of important cellular targets, including the mRNA of bcl-2, protein kinase (PK) C-alpha, PKA-I, H-ras, c-raf, R1 and R2 subunit of ribonucleotide reductase, and transforming growth factor beta2. These drugs are well tolerated with favorable toxicity profiles, and preliminary studies have demonstrated that they can be feasibly combined with chemotherapy. Plasma half-life is short, generally necessitating continuous prolonged intravenous infusion. Shorter administration schedules are being investigated. Efficacy has been demonstrated in early-phase studies in non-small-cell lung cancer (NSCLC), non-Hodgkin's lymphoma, ovarian cancer, melanoma, and prostate cancer. Molecular correlative studies with peripheral blood mononuclear cells and tumor tissue have demonstrated suppression of target proteins, suggesting that these drugs are indeed reaching the target. Here we discuss the current status of development of ASONs, focusing on LY900003 (formerly ISIS 3521), an agent directed against PKC-alpha currently under study in NSCLC. Phase III studies will determine the ultimate role these agents will play in the treatment of cancer. Future areas of study include combination with radiation and other molecularly targeted agents, alternative dosing schedules, liposomal administration, and the development of new antisense agents directed against additional molecular targets.
Clin Lung Cancer 2003 Jan
PMID:Antisense oligonucleotides in the treatment of non-small-cell lung cancer. 1472 Mar 40

Translation initiation in eukaryotes is a rate-limiting step in protein synthesis. It is a complicated process that involves many eukaryotic initiation factors (eIFs). Altering the expression level or the function of eIFs may influence the synthesis of some proteins and consequently cause abnormal cell growth and malignant transformation. P170, the largest putative subunit of eIF3, has been found elevated in human breast, cervical, esophageal, and lung cancers, suggesting that p170 may have a potential role in malignant transformation and/or cell growth control. Our recent studies suggested that p170 is likely a translational regulator and it may mediate the effect of mimosine on the translation of a subset mRNAs. Mimosine, a plant nonprotein amino acid, inhibits mammalian DNA synthesis, an essential event of cell growth. The rate-limiting step in DNA synthesis is the conversion of the ribonucleotides to their corresponding deoxyribonucleotides catalysed by ribonucleotide reductase of which the activity is regulated by the level of its M2 subunit. It has been reported that inhibiting the activity of M2 also inhibits cell growth. To understand the relationship between protein and DNA synthesis and between p170 and cell growth control, we investigated in this study whether p170 regulates the synthesis of M2 and, thus, cell growth. We found that altering the expression level of p170 changes the synthesis rate of both M2 and DNA. Decreasing p170 expression in human lung cancer cell line H1299 and breast cancer cell line MCF7 significantly reversed their malignant growth phenotype. However, the overall [35S]methionine incorporation following dramatic decrease in p170 expression was only approximately 25% less than the control cells. These observations, together with our previous findings, suggest that p170 may regulate the translation of a subset mRNAs and its elevated expression level may be important for cancer cell growth and for maintaining their malignant phenotype.
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PMID:Role of eIF3 p170 in controlling synthesis of ribonucleotide reductase M2 and cell growth. 1509 76


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