Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.6.1.2 (alanine aminotransferase)
 26,722 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CB3717 is a quinazoline antifolate whose cytotoxic activity is mediated by inhibition of thymidylate synthase (TS). A phase I clinical trial commenced in September 1981 and 99 patients have received 296 treatments. Doses were dissolved in 0.15 mol/L NaHCO3 (pH 9.0) at a concentration of 4 mg/mL infused over one hour or in a total volume of 1 L infused over 12 hours. Doses were repeated every 3 weeks. The starting dose of 140 mg/m2 was escalated to 600 mg/m2. Renal toxicity, detected by a decrease in the 51Cr EDTA clearance, was dose-related and occurred in seven of ten patients receiving greater than 450 mg/m2. Reversible hepatic toxicity often associated with malaise occurred in 223 of 288 assessable courses (77%). Fifty-nine courses (20%) were associated with increases in alanine transaminase (ALT) levels to greater than 2.5 times the upper limit of the normal laboratory range. Increases in alkaline phosphatase levels also occurred, but were less marked. The severity and prevalence of these elevations were unaffected by the duration of the infusion. A self-limiting rash appeared in 12 patients and a radiation recall reaction was seen in two. Leukopenia developed in 17 patients (WBC less than 3 X 10(9)/L), and thrombocytopenia occurred in six patients (platelets less than 100 X 10(9)/L). The mean leucocyte nadir occurred on day 10 and was followed by recovery at 11 to 19 days. Neither the incidence nor the severity of any of these latter toxicities was dose related. The maximum tolerated dose was in the region of 600 mg/m2 with renal toxicity being dose limiting, although the inter-patient variation did not allow a precise definition. Seventy-six patients were evaluable for response. Responses occurred at doses greater than or equal to 200 mg/m2 and were ovary, one complete response (CR), one partial response (PR), seven minor responses (MR) in 30 cases; breast, two PRs and one MR in eight cases; adenocarcinoma of the lung, one MR in 5 cases; mesothelioma, one PR in five cases; and colon, two MRs in four cases. CB3717 has activity in heavily pretreated patients. The recommended phase II dose for good-risk patients is 400 mg/m2 using the one-hour infusion schedule of administration.
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PMID:A phase I evaluation of the quinazoline antifolate thymidylate synthase inhibitor, N10-propargyl-5,8-dideazafolic acid, CB3717. 373 49

In a chronic toxicity study in the rat, bidisomide administered as a dietary admixture produced a dose-related lowering of reticulocytes and leucocytes. Plasma alanine aminotransferase activity was increased at 300 mg/kg and decreased at 900 mg/kg. The potential mechanisms of these effects were investigated by comparing the responses in groups of male Sprague-Dawley rats receiving a control diet, or 300 or 1200 mg/kg/day bidisomide. Subsets of these groups were co-treated subcutaneously with folinic acid or with a vitamin B1, B6, B12 complex. Subsets of control and 300 mg/kg groups were maintained on a 20-25% feed restriction regimen for 3 months, to mimic the depression in body weight gain observed in animals receiving 1200 mg/kg. Body weight gains were significantly reduced at 1200 mg/kg and in all feed-restricted animals. Plasma and liver alanine aminotransferase (ALT) and plasma aspartate aminotransferase (AST) levels were also reduced at this dose level. At 300 mg/kg, plasma transaminases, glutamate dehydrogenase (GLDH) and sorbitol dehydrogenase (SDH) activities were increased. These changes were prevented in animals receiving folinic acid supplementation. Plasma glucose, triglycerides, and unsaturated and total iron binding capacities were decreased, while plasma iron levels tended to increase, mainly at the high dose. Vitamin supplementation prevented a decrease in reticulocyte counts at 300 mg/kg. Bidisomide increased urinary formimino-glutamic acid (FIGLU) excretion but did not affect methylmalonic acid (MMA) or taurine excretion. The effect on FIGLU at 1200 mg/kg was prevented by folinic acid co-treatment. Absolute liver weight was lowered at both dose levels and in feed-restricted animals. However, the relative liver weights were unaffected. Thymidine kinase and thymidylate synthase activity of the bone marrow cells were not altered by the bidisomide treatment. Except for the increase in plasma transaminase, GLDH and SDH levels at 300 mg/kg, changes in clinical chemistry parameters are considered to result mainly from nutritional restrictions. Changes in hematologic parameters appear to be related to the combination of decreased feed consumption (leukocytes) and decreased availability or utilization of folates (reticulocytes). This alteration, however, did not affect DNA synthesis in bone marrow. The prevention by folinic acid, but not by feed restriction, of the elevation of liver enzymes at 300 mg/kg is an intriguing, yet unexplained finding. There was no evidence that bidisomide affected B6 and B12 availability.
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PMID:Effect of folate supplementation on clinical chemistry and hematologic changes related to bidisomide administration in the rat. 858 20

AG331 (N6-[4-(morpholinosulfonyl)benzyl]-N6-methyl-2, 6-diaminobenz-[c,d]-indole glucuronate) is a lipophilic thymidylate synthase inhibitor with activity in solid tumor models. On the basis of preclinical data supporting regimens of frequent drug administration, we performed a Phase I trial of AG331 as a 5-day continuous infusion repeated every 3 weeks. Twenty-nine patients were entered at doses ranging from 25 to 1000 mg/m2/day. The major side effects were mild to moderate fatigue, nausea, vomiting, diarrhea, and fever. At doses >/=400 mg/m2, acute reversible elevation of bilirubin, aspartate aminotransferase, alanine aminotransferase, and gamma-glutamyltranspeptidase was observed. All patients who received >/=600 mg/m2/day experienced elevated alanine aminotransferase. Elevated liver function tests were evident by day 3 of the infusion and had resolved by day 8 in the majority. This toxicity was dose limiting at 1000 mg/m2/day, at which dose two of two patients developed grade 4 reversible hyperbilirubinemia in addition to the enzyme elevations. Serum and urine samples were analyzed by a novel high-pressure liquid chromatography method for the determination of the pharmacokinetics of AG331. Over the 50-1000 mg/m2/day dose range, mean total clearance ranged from 11.6 to 30.0 liters/h/m2, and volume of distribution at steady state ranged from 279.5 to 758.7 liters/m2. These parameters were dose independent over the dose range tested. The harmonic mean terminal half-life of AG331 was 20.2 h. Less than 5% of an AG331 dose is eliminated unchanged in the urine. Both the administered dose and exposure to the drug were related to the changes in bilirubin and aminotransferase blood levels. Evidence for inhibition of thymidylate synthase was obtained at doses ranging from 100 to 1000 mg/m2 in seven patients; plasma deoxyuridine concentrations at end-infusion were 1.8-3.8-fold higher than pretreatment values. Because of the nature of toxicity on this schedule, more extensive Phase II evaluation is not recommended, although an AG331 dose of 800 mg/m2/day for 5 days is tolerable. Exploration of less frequent dose administration is under way.
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PMID:Phase I trial of the thymidylate synthase inhibitor AG331 as a 5-day continuous infusion. 981 17

A multicenter cooperative phase I study of ZD-1694 (raltitrexed), a novel, folate-based thymidylate synthase (TS) inhibitor, was conducted with single and repeated doses in 30 patients with various malignant tumors. ZD-1694 was intravenously infused over 15 minutes. In the single-dose study, the initial dose was fixed at 1.0 mg/m2 (1n), and the dose was escalated stepwise up to 3.5 mg/m2 (3.5 n). Based on the results of the single-dose study, in the repeated-dose study, doses of 2.5 n and 3 n were infused every three weeks (3 weeks/one course). In principle, patients received 2 courses or more. Of the 29 eligible patients, 16 were in the single-dose study and 13 in the repeated-dose study. Adverse reactions were evaluated in all eligible patients. In the single-dose study, neutropenia, nausea/vomiting, diarrhea, and transaminase (GOT, GPT) increases, of grade 3 or higher, occurred at high doses of 3 n and 3.5 n. These were regarded as dose-limiting toxicities (DLT). DLT of grade 3 or higher were observed in 1 of 4 patients given 3 n and 2 of 4 patients given 3.5 n. These results suggested that the maximum tolerated dose (MTD) of ZD-1694 was 3.5 n (3.5 mg/m2). In the repeated-dose study, DLT of grade 3 or higher was observed in no more than one third of each dose group, 2 of the 6 patients given 2.5 n and 2 of the 7 patients given 3 n. These results suggested that 3 n (3.0 mg/m2), a dose nearer to MTD, was the recommended dose for the phase II study. Although transaminase increases were observed in all patients, in 12 of them the increase was grade 2 or lower and reversible. A pharmacokinetic investigation showed the mean elimination half life of ZD-1694 plasma concentration was 91.5 hours in the single-dose group and 119.1 hours in the repeated dose group. It was suggested that ZD-1694 is metabolized to polyglutamates after uptake and retained in the cells for a long duration. However, no accumulation was seen in plasma concentration of ZD-1694 following repeated doses at 3-weekly intervals. One PR was observed in a patient with colorectal cancer receiving 2.5 n in the repeated-dose study. Based on these results, the recommended dosage and administration for the phase II study of ZD-1694 was 3 n (3.0 mg/m2) intravenously infused over 15 minutes every 3 weeks.
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PMID:[Phase I study of raltitrexed (ZD-1694)]. 983 10

2-Amino-3,4-dihydro-6-methyl-4-oxo-5-(4-pyridylthio)-quinazoline dihydrochloride (nolatrexed dihydrochloride, Thymitaq, AG337), a specific inhibitor of thymidylate synthase, was developed using protein structure-based drug design. Intravenously administered nolatrexed is active clinically. As oral bioavailability is high (70-100%), nolatrexed was administered orally, 6 hourly for 10 days, at 3-week intervals, and dose escalated from 80 to 572 mg m(-2) day(-1) in 23 patients. Common toxicity criteria (CTC) grade 3 toxicities included nausea, vomiting, stomatitis and liver function test (LFT) abnormalities. Thrombocytopenia (grade 1 or 2) occurred at doses > or = 318 mg m(-2) day(-1) and neutropenia (grade 2) at 429 and 572 mg m(-2) day(-1). An erythematous maculopapular rash occurred at dosages > or = 318 mg m(-2) day(-1) (7 out of 19 patients). LFT abnormalities occurred in two out of six patients (grade 3 or 4 bilirubin and grade 3 alanine transaminase) at 572 mg m(-2) day(-1). Nolatrexed plasma concentrations 1 h after dosing were 6-16 microg ml(-1), and trough 3-8 microg ml(-1), at 572 mg m(-2) day(-1). Inhibition of thymidylate synthase was demonstrated by elevation of plasma deoxyuridine. Six-hourly oral nolatrexed for 10 days was associated with antiproliferative effects, but nausea and vomiting was dose limiting at 572 mg m(-2) day(-1). Nine patients were treated at 429 mg m(-2) day(-1); three out of nine experienced grade 3 nausea, but 17 out of 22 treatment courses were completed (with the co-administration of prophylactic antiemetics) and this dose level could be considered for phase II testing.
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PMID:A phase I study of the lipophilic thymidylate synthase inhibitor Thymitaq (nolatrexed dihydrochloride) given by 10-day oral administration. 1007 Aug 90