Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.6.1.1 (aspartate aminotransferase)
21,665 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Using single-strand conformation polymorphism we have found two polymorphic sites, AAC to AAT at codon 511 (exon 12) and GCT to GCG at codon 708 (exon 15), in the MCC gene. These sites and an RsaI polymorphic site in APC allowed us to study 23 human small cell lung cancer (SCLC) and 7 non-small cell lung cancer samples for allele loss. Of the 23 SCLC samples, 21 (91%) were informative for one or more of these markers, and we found allele loss in more than 80% (17 of 21). In non-small cell lung cancer samples, 5 of 7 (71%) were informative, and reduction or loss of one allele was found in 2 of 5 (40%). Seven cases were informative for both genes, loss of heterozygosity occurred for both genes in five, one retained heterozygosity for both, and one SCLC had loss of heterozygosity for APC but not for MCC. We conclude that loss of heterozygosity occurs frequently for MCC and APC in lung cancer of all histological types and is very frequent in SCLC. This suggests the presence of tumor suppressor gene(s) in the MCC/APC region of 5q21 involved in human lung cancer.
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PMID:Polymorphic sites within the MCC and APC loci reveal very frequent loss of heterozygosity in human small cell lung cancer. 134 17

The Copenhagen Lung Cancer Study Group conducted a prospective randomized trial comparing three chemotherapy regimens: (A) vindesine (VDS) 4 mg/m2 IV weekly X 8, then every second week; (B) lomustine (CCNU) 70 mg/m2 orally, cyclophosphamide (CTX) 1000 mg/m2 IV every 4 weeks, methotrexate (MTX) 20 mg/m2 orally days 15 and 18 of each course; and (C) CCNU + CTX + MTX + VDS in the same schedule as above, but with lower doses of CCNU (50 mg/m2), CTX (750 mg/m2), and VDS (2 mg/m2). Two hundred fifty-nine patients were accrued with unresectable adenocarcinoma-type non-small cell lung cancer (NSCLC); 218 were evaluable for response. Overall response rates on the chemotherapy arms were: (A) 22%, (B) 23%, and (C) 27%. Median survival rates were: 29 weeks, (B) 29 weeks, and (C) 34 weeks. Peripheral neuropathy was the major toxicity in arm A, and myelosuppression in arms B and C. The independent influence of 27 pretreatment variables were analyzed by the Cox multivariate regression model, which revealed that six have prognostic impact: performance status, nonradical resection, liver metastases, serum LDH (lactate dehydrogenase), WBC (white blood count), and serum AST (aspartate aminotransferase). The data clearly demonstrate prognostic variables in this disease and emphasize the need for better chemotherapy.
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PMID:Chemotherapy for advanced adenocarcinoma of the lung: the Copenhagen study and review of the literature. 321 7

10-Ethyl-10-deazaaminopterin (10-EDAM) is an analogue of methotrexate with improved preclinical anticancer activity, more selective entry, and greater conversion to polyglutamate forms in neoplastic cells. In this Phase I trial, we have treated 62 adults with advanced solid tumors, giving 10-EDAM i.v. on either a weekly x 3 schedule (35 patients) or a weekly schedule (27 patients). The dosage levels ranged from 5 to 120 mg/m2. The toxicity observed with 10-EDAM was qualitatively similar to that of methotrexate. Oral mucositis was the dose-limiting toxicity; diarrhea, skin rash, leukopenia, thrombocytopenia, and mild elevations of serum glutamic-oxaloacetic transaminase, prothrombin, and partial thromboplastin times were also observed, but were not dose limiting. A weekly dosage of 80 mg/m2 with escalation or attenuation in accordance with patient tolerance, or 100 mg/m2 weekly for 3 weeks, followed by a 2-week "rest period" are recommended for Phase II assessment. 10-EDAM produced partial remissions in three patients with non-small cell lung cancer and one patient with breast cancer lasting 6, 40+, 26+, and 15 months, respectively. Pharmacokinetic studies carried out at the 5, 30, and 100 mg/m2 dosage levels demonstrated the drug to have a triphasic disappearance from plasma. Elimination was independent of dose over the range tested, with mean plasma half-lives of: alpha = 12.9 min, beta = 1.5 h, and gamma = 11.9 h. Cumulative urinary excretion of the drug ranged from 13 to 55% of the administered dose (mean = 33%); 88% of the urinary drug appeared within the first 4 h following drug administration. The pharmacokinetic behavior of the first and second weekly dosages were consistent within a given patient. The metabolites 7-hydroxy-10-EDAM, and 10-ethyl-10-deaza-2,4-diamino-pteroic acid were demonstrated in the plasma and urine of treated patients. In studies of tissue homogenates from two patients with skin metastases, more extensive retention of the drug and of its polyglutamates was observed in the breast cancer metastases than in the metastases from a kidney cancer or in normal skin.
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PMID:Phase I trial and clinical pharmacological evaluation of 10-ethyl-10-deazaaminopterin in adult patients with advanced cancer. 341 10

This paper reviews the toxicity profile of gemcitabine, a novel anticancer drug. Gemcitabine has been administered using two different treatment schedules: once weekly or twice weekly for 3 weeks followed by a week of rest (one cycle). It was well tolerated and alopecia was not a problem. Toxicity was greater in the twice-weekly schedule. Comparing the once-weekly with the twice-weekly schedule, WHO grade 3 or 4 thrombocytopenia was reported in 4.7 and 25.6% of patients, respectively. Other hematological toxicity was minimal. Transient WHO grade 3 or 4 elevations of ALT and AST occurred in 9.2 and 7.2% of patients, respectively, in the once-weekly schedule. For the twice-weekly schedule the corresponding percentages were 12.2 and 13.8%. Symptomatic toxicity was greater in patients who received twice-weekly gemcitabine. Nausea and vomiting was mild and generally well controlled without 5HT3 antagonists. However, there was a greater incidence of nausea and vomiting on the twice-weekly schedule. Flu-like symptoms were documented in 19.8% of patients receiving once-weekly and 63.3% of patients receiving twice-weekly gemcitabine. Peripheral edema, not related to cardiac, hepatic or renal failure, was seen more often in patients on twice-weekly treatment. As the efficacy of gemcitabine in non-small cell lung cancer was equivalent when using both regimens, the better tolerated and more easily administered once-weekly schedule is recommended.
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PMID:Gemcitabine: once-weekly schedule active and better tolerated than twice-weekly schedule. 879 11

Sixty patients with previously untreated non-small cell lung cancer of stages III and IV were treated with a 210 mg/m2 dose of paclitaxel by means of a 3-hour infusion. The objective response rate was 32% (95% confidence interval, 20-45%): 1 complete response and 18 partial responses. The median duration of response was 15 weeks, and the projected median survival duration of all patients was 30 weeks. Grade 3-4 neutropenia occurred in 73% of patients. Other grade 3-4 adverse events included anemia (5%), vomiting/nausea (8%), peripheral edema (2%), alopecia (7%), elevation of AST (2%), peripheral neuropathy (3%), allergic reaction (2%), arthralgia/myalgia (3%), and interstitial pneumonitis (3%). Paclitaxel administered at 210 mg/m2 by means of a 3-hour infusion every 3 weeks demonstrated a notable activity against previously untreated advanced non-small cell lung cancer, with a 32% major response rate. Major toxicity was neutropenia. Hypersensitivity, neurotoxicity, arthralgia/myalgia and cardiac toxicity were mild and easily managed.
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PMID:Phase II study of 3-hour infusion of paclitaxel in patients with previously untreated stage III and IV non-small cell lung cancer. West Japan Lung Cancer Group. 921 54

The efficacy and toxicity of combined paclitaxel and gemcitabine was evaluated in 54 chemotherapy-naive patients with metastatic non-small cell lung cancer (NSCLC). Gemcitabine i.v. 1000 mg/m(2)was administered on days 1 and 8 and paclitaxel 200 mg/m(2)as a continuous 3-hour infusion on day 1. Treatment was repeated every 21 days. Patients had a median age of 53 years. ECOG performance status was 0 or 1 in 48 patients. 41 patients (75.9%) had initial stage IV disease; histology was mainly adenocarcinoma (46.3%). 2 patients (4.3%) achieved a complete response and 15 (31.9%) achieved a partial response giving an overall response rate of 36.2% (95% CI: 22.4-49.9%); 19 patients (40.4%) had stable disease and 10 (21.3%) had progressive disease. The median survival time was 51 weeks (95% CI: 46.5-59.3), with a 1-year survival probability of 0.48 (95% CI: 0.34-0.63). Grade 3/4 neutropenia and febrile neutropenia occurred in 15.2% and 2.2% of courses, respectively. Grade 3/4 thrombocytopenia was rare (1.8% of courses). Peripheral neurotoxicity developed in 25 patients (47.2%), mostly grade 1/2. Arthalgia/myalgia was observed in 30 patients (56.6%), generally grade 1 or 2. Grade 3 abnormal levels of serum glutamate pyruvate transaminase (SGPT) and serum glutamate oxaloacetate transaminase (SGOT) occurred in 5 patients (9.4%) and 1 patient (1.9%), respectively. Combined paclitaxel and gemcitabine is an active and well-tolerated regimen for the treatment of advanced NSCLC, and warrants further investigation in comparative, randomized trials.
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PMID:Combined paclitaxel and gemcitabine as first-line treatment in metastatic non-small cell lung cancer: a multicentre phase II study. 1133 67

We performed a phase I study combining gemcitabine and interferon (IFN)- 2b in patients with advanced solid tumors to determine the maximum tolerated dose (MTD) and recommended doses for phase II trials. Five dose levels of gemcitabine (mg/m )/IFN- (x10 IU) were planned: 500/5, 1000/5, 1000/7, 1000/10 and 1200/10. Gemcitabine was given once weekly and IFN 3 x weekly for 3 consecutive weeks followed by 1 week of rest (28-day cycles). Between February 1997 and June 1999, 21 patients with advanced pancreatic ( =3), ovarian ( =1), renal ( =10) and non-small cell lung cancer (NSCLC; =7) were enrolled. The MTD was reached at gemcitabine 1000 mg/m and IFN- 7 x 10 IU, with two of three patients having dose-limiting toxicity (thrombocytopenia). The predominant hematologic toxicities (grade 3/4) were neutropenia and thrombocytopenia (13 and five patients, respectively). Three patients had moderate neutropenic fever and one had grade 4 AST/ALT; none required hospitalization. Of the 18 evaluable patients, responses included one partial response (NSCLC) and 10 stable diseases (eight renal cancer). We conclude that the recommended phase II study regimen is gemcitabine 1000 mg/m and IFN- 5 x 10 IU, every 28 days. The results, particularly those in metastatic renal carcinoma, are encouraging and worthy of further evaluation in phase II trials.
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PMID:Gemcitabine and interferon-alpha 2b in solid tumors: a phase I study in patients with advanced or metastatic non-small cell lung, ovarian, pancreatic or renal cancer. 1239 52

Transforming growth factor-beta receptor-dependent signals are critical for cell growth and differentiation and are often disrupted during tumorigenesis. The entire coding region of TGFbetaRI and flanking intron sequences from 53 primary non-small cell lung cancer (NSCLC) tissues were examined for alterations using SSCP and direct sequencing. No somatic point mutations other than two silent mutations and a polymorphism were found in the TGFbetaRI gene. The two silent mutations located at codon 344 (AAT to AAC) and codon 406 (TTA to CTA), respectively, and the polymorphism was at the 24th base of intron 7 (G to A). To investigate whether the presence of this polymorphism is associated with NSCLC, we determined its allele distribution in all the 53 carcinomas and 89 normal controls. Interestingly, we found that the subjects with homozygous genotype A/A displayed more than 3-fold increased risk of developing NSCLC than the common wild genotype G/G. As the first report, the present study showed that TGFbetaRI gene is not a frequent site of spontaneous mutational inactivation while the detected polymorphism is frequent in the pathogenesis of NSCLC.
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PMID:Mutational analysis of the transforming growth factor beta receptor type I gene in primary non-small cell lung cancer. 1278 26

Lung cancer remains a leading cause of disease globally, with smoking being the largest single cause. Phase I enzymes, including cytochrome P(450), family 1, subfamily A, polypeptide 1 (CYP1A1), are involved in the activation of carcinogens, such as polycyclic aromatic hydrocarbons, to reactive intermediates that are capable of binding covalently to DNA to form DNA adducts, potentially initiating the carcinogenic process. The aim of the present study was to investigate the association of CYP1A1 gene polymorphisms and haplotypes with lung cancer risk. A case-control study was carried out on 1,040 nonsmall cell lung cancer (NSCLC) cases and 784 controls to investigate three CYP1A1 variants, CYP1A1*2A (rs4646903; thymidine to cytosine substitution at nucleotide 3801 (3801T>C)), CYP1A1*2C (rs1048943; 2455A>G; substitution of isoleucine 462 with valine (exon 7)) and CYP1A1*4 (rs1799814; 2453C>A; substitution of threonine 461 with asparagine (exon 7)) using PCR restriction fragment length polymorphism methods. The CYP1A1*2A and CYP1A1*2C variants were significantly over-represented in NSCLC cases compared with controls, whereas the CYP1A1*4 variant was under-represented. CYP1A1 haplotypes (in allele order CYP1A1*4, CYP1A1*2C, CYP1A1*2A) CGC and CGT were associated with an increased risk of lung cancer, whereas AAT was associated with decreased lung cancer risk in this population. The present study has identified risk haplotypes for CYP1A1 in NSCLC and confirmed that CYP1A1 polymorphisms are a minor risk factor for NSCLC.
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PMID:Genetic association study of CYP1A1 polymorphisms identifies risk haplotypes in nonsmall cell lung cancer. 1960 85

We report a case of a female in her 80s who was diagnosed with recurrent lung adenocarcinoma after primary surgery. She was treated with a systemic chemotherapy regimen consisting of carboplatin plus paclitaxel until the disease showed progression. On detection of epidermal growth factor receptor(EGFR)mutations, we administered gefitinib, an EGFR tyrosine kinase inhibitor, at a dosage of 250 mg daily. After 6 months of gefitinib therapy, laboratory findings revealed elevated serum aspartate aminotransferase(AST)and alanine aminotransferase(ALT)levels(grade 2), indicative of hepatotoxicity. Gefitinib was discontinued and erlotinib was initiated at a dosage of 50 mg daily. She continued the therapy for 3 years, during which her disease stabilized without any further complications or hepatotoxicity. Thus, low-dose erlotinib may be effective and well tolerated by patients with non-small cell lung cancer harboring EGFR mutations who are intolerant to gefitinib.
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PMID:[Efficacy of low-dose erlotinib against gefitinib-induced hepatotoxicity in a patient with lung adenocarcinoma harboring EGFR mutations]. 2330 23


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