Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0038362 (stomatitis)
 8,852 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

N-(Phosphonacetyl)-L-aspartic acid, an inhibitor of aspartate transcarbamylase, was administered to 25 patients with advanced cancer by 10-minute infusion daily x 5 consecutive days to determine the toxicity and to look for evidence of therapeutic effect. Planned dose escalations ranged from 100 to 1250 mg/m2 (daily dose). Nausea, vomiting, and diarrhea were the most frequent toxic effects, with three of six patients treated at a daily dose of 1250 mg/m2 having severe diarrhea. Other toxic effects were encountered rarely and were not dose-limiting; these included mild leukopenia, thrombocytopenia, rash, stomatitis, and increases in SGOT. One patient with a widely metastatic carcinoid of unknown origin had an objective response lasting 6 weeks.
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PMID:Phase I study of N-(phosphonacetyl)-L-aspartic acid (PALA). 52 23

This article reports a Phase I study of combined therapy with N-(phosphonacetyl)-L-aspartate (PALA) and L-alanosine in 26 patients with advanced cancer. Each agent exhibits antitumor effect by enzyme inhibition: PALA blocks pyrimidine biosynthesis by impeding aspartate transcarbamylase and L-alanosine depletes purine nucleotides by interfering with adenylosuccinate synthetase. These agents were selected for clinical investigation in light of synergistic cytotoxicity in vitro against human tumor cell lines and in vivo against P-388 murine leukemia resistant to cytosine arabinoside. Dose-limiting toxicities were stomatitis and diarrhea to a lesser extent. There was no substantial myelosuppression. The authors recommend either of two intravenous regimens for studies of therapeutic activity in selected patients with neoplastic diseases: a one-day treatment repeated of PALA, 5.0 g/m2 and L-alanosine, 3.0 g/m2, repeated every 3 weeks; or a monthly program of PALA, 500 mg/m2/d 1-5 and L-alanosine, 60 mg/m2/d 1-5.
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PMID:A Phase I study of the combination N-(phosphonacetyl)-L-aspartate (PALA, NSC-224131) and L-alanosine (NSC-153353) in patients with advanced cancer. 686 Oct 99

The biochemical modulators PALA, an inhibitor of aspartate transcarbamylase which depletes uridine nucleotide pools, and 6-methylmercaptopurine riboside (MMPR) which inhibits purine metabolism, selectively potentiate the antitumor activity of 5-fluorouracil (5-FU) in preclinical models. Based on a phase I trial of this combination, we performed a phase II trial in patients with advanced pancreatic cancer. PALA 250 mg/m2 was administered i.v. on day 1, followed 24h later by MMPR 150 mg/m2 as a bolus i.v. injection, and 5-FU 2300 mg/m2 by 24h infusion. Treatments were repeated weekly. Seventeen patients, all previously untreated with chemotherapy, were entered, of whom 14 are evaluable for response. Toxicity > or = grade 2 included nausea (6/17), vomiting (4/17), diarrhea (3/17), stomatitis (5/17), and neurotoxicity (2/17). Among 14 evaluable patients there were no partial responses, and two patients with stable disease. Pretreatment with PALA and MMPR is insufficient to enhance the activity of 5-FU in pancreatic cancer.
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PMID:Phase II trial of PALA and 6-methylmercaptopurine riboside (MMPR) in combination with 5-fluorouracil in advanced pancreatic cancer. 777 33

We conducted a combined biochemical modulation trial of N-(phosphonacetyl)-L-aspartate (PALA), dipyridamole (DP), and fluorouracil (5-FU) in patients with cancer. Eighty-eight patients with advanced cancer were entered into this Phase I trial. During the first part of the study, four doses of PALA (125, 250, 500, and 1000 mg/m2, administered on day 1) were evaluated to determine the PALA dose with maximal suppression of aspartate transcarbamylase (ATCase) activity that was clinically tolerable. Patients were randomized to receive DP (or no DP), 50 mg/m2, p.o. every 6 h on days 1-6, and all patients received 5-FU, 400 mg/m2, by bolus administration on days 2-5. Prior to and during therapy, WBCs were collected and assayed for ATCase activity. After the maximally tolerated PALA dose with 400 mg/m2 5-FU +/- 50 mg/m2 DP was defined, the 5-FU dose was escalated using the same administration schedule of 5-FU, PALA, and DP. The dose of 5-FU was escalated by 25% in each of the DP cohorts until dose-limiting toxicity was reached. ATCase activity was inhibited in a dose-dependent manner with PALA doses of 125, 250, 500, and 1000 mg/m2, resulting in 0, 13, 17, and 49% inhibition of ATCase activity. Only at the higher PALA doses (i.e., 500 and 1000 mg/m2) was ATCase activity suppressed during days 2-5, but the activity returned to pretreatment levels by day 15. Based on the clinical tolerance and significant suppression of ATCase activity, a PALA dose of 500 mg/m2 was selected for the 5-FU dose escalation phase. At a 5-FU dose of 625 mg/m2, dose-limiting toxicity (leukopenia, stomatitis, and diarrhea) occurred in both DP cohorts. We recommend that for this monthly treatment schedule, 500 mg/m2 PALA and 500 mg/m2 5-FU, with or without 50 mg/m2 DP, be used in subsequent Phase II trials.
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PMID:Phase I study of N-(phosphonacetyl)-L-aspartate with fluorouracil and with or without dipyridamole in patients with advanced cancer. 981 75