Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0854467 (myelosuppression)
 5,932 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fifty-two patients with advanced gastrointestinal (GI) malignancies who had not received previous chemotherapy or radiation therapy were randomized to be treated either with 24-hour infusion of weekly fluorouracil (5-FU) or the same plus N-(phosphonacetyl)-L-aspartic acid (PALA). Forty-seven patients were evaluable for the assessment of toxicity and antitumor activity. PALA was administered as an intravenous (IV) bolus over 15 minutes at a fixed dose, 250 mg/m2. The latter agent was administered 24 hours before the start of 5-FU infusion. 5-FU was initially administered at 750 mg/m2 and was incrementally increased to 3,400 mg/m2. In both arms of the randomized study, the courses were repeated every week. In both arms of the study, ataxia and myelosuppression were the dose-limiting toxic effects. At 5-FU dose of 3,400 mg/m2, one patient in each arm developed grade 3 hematologic toxicity. Other reversible side effects included grade 2 skin changes, nausea, and vomiting. During the administration of 2,600 mg/m2 of 5-FU over 24 hours, the steady state plasma 5-FU concentration was approximately 20 mumol/L. The maximum tolerated dose (MTD) for 5-FU for protracted treatment is 2,600 mg/m2 in either arm of the study. Therapeutic response was predominantly seen in the combination arm: there were two patients with complete response (CR) and 11 patients with partial response (PR) of 28 patients in the study. In the 5-FU alone arm there were four PR and 19 patients in the study.
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PMID:A randomized phase I and II study of short-term infusion of high-dose fluorouracil with or without N-(phosphonacetyl)-L-aspartic acid in patients with advanced pancreatic and colorectal cancers. 337 60

Sixty-three patients with Stage IV breast carcinoma refractory to standard combination chemotherapy agents such as 5-fluorouracil (5-FU) were entered into a study to determine the efficacy of a multiple dose schedule of N-(phosphonacetyl)-L-aspartic acid (PALA) and whether the addition of PALA improves the therapeutic efficacy of 5-FU. Patients were randomized to receive either PALA, 800 to 1000 mg/m2 per day for 5 days every 2 weeks; or PALA + 5-FU, 400 mg/m2 per day for 5 days, and 300 mg/m2 per day for 5 days every 28 days, respectively. The PALA alone arm of the study was closed after 20 patients had been treated and was replaced by 5-FU, 300 to 400 mg/m2 per day for 5 days every 21 days. Overall response rates were 5% for PALA alone, 28% for PALA + 5-FU, and 14% for 5-FU alone. All patients who responded to PALA + 5-FU or 5-FU alone had received prior therapy in which 5-FU was part of the combination chemotherapy program and were considered refractory to this drug. Toxicity affected the gastrointestinal tract but was tolerable in all three arms of the study. Myelosuppression was negligible for PALA and PALA + 5-FU and moderate for 5-FU. The authors concluded that PALA + 5-FU was superior to PALA alone in the therapy of these heavily pretreated patients. PALA alone had marginal efficacy. In view of its low hematologic toxicity, PALA + 5-FU may be combined with more myelosuppressive drugs. Additional studies are necessary to ascertain whether PALA + 5-FU is therapeutically superior to a full-dose schedule of 5-FU.
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PMID:A comparative study of PALA, PALA plus 5-FU, and 5-FU in advanced breast cancer. 402 72

Twenty-seven patients with colorectal adenocarcinoma, (12) non-small cell bronchogenic carcinoma, (11) gastric adenocarcinoma (3), and adenocarcinoma of unknown primary lesion (1) were treated with the combination of thymidine (TdR), 5-fluorouracil (FU), and N-phosphonacetyl-L-aspartic acid (PALA). PALA 1 g/m2 was given over 1 hour on day 1, followed on day 2 by 30 g of TdR given over 3 hours. FU, 150-300 mg/m2, was administered sequentially over 1 hour immediately following TdR infusion. There were no responses seen using this dose schedule. Gastrointestinal and central nervous system toxicities were dose-limiting. Myelosuppression was seen at all dose levels and was not dose related. Fever and infection occurred in 16% and 3% of the courses. The maximum tolerated dosages on this schedule were PALA, 1 g/m2; TdR, 30 g; and FU, 250 mg/m2. Pharmacologic studies done revealed the following half-lives: TdR, 1.6 hours; thymine, 5.0 hours; FU, 6.8 hours; and FUDR, 3.7 hours. The significant prolongation of the half-life of FU with this drug combination implies that the tumor tissues may be exposed longer to the anticancer action of FU.
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PMID:Sequential administration of thymidine, 5-fluorouracil, and PALA. A phase I-II study. 408 63

Thirty-seven patients with inoperable malignancies were given 75 courses of N-(phosphonaceteyl)-L-aspartic acid (PALA). Twenty-seven of these patients received PALA as a continuous iv infusion over 24 hours at dose levels ranging from 500 to 10,500 mg/m2 of estimated body surface area. In addition, ten patients were given PALA by continuous iv infusion over 120 hours at total doses ranging from 4000 t0 8700 mg/m2. The dose-limiting toxic effects occurred in the skin (erythema, vesiculation, and bullae) and gastrointestinal mucosa (oral pain, cheilosis, oral mucosal ulceration, diarrhea, and hematochezia). Toxic reactions seemed more pronounced in patients with third-space fluid compartments. Myelosuppression was severe only in patients with pre-existing marrow dysfunction from neoplastic infiltration. No renal, hepatic, cardiac, or neurologic toxicity was seen. No cumulative toxic effects were evident in 14 patients who received repeated courses of PALA at 21-day intervals. For patients without third-space fluid, 8700 mg/m2/24 hours or 6500 mg/m2/120 hours were well-tolerated doses. One patient with chondrosarcoma had a partial response lasting 5 months.
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PMID:Initial clinical study with N-(phosphonacetyl)-L-aspartic acid (PALA) in patients with advanced cancer. 644 87

5-Fluorouracil (FUra) is a clinically useful antineoplastic agent. Preclinical studies suggest that the therapeutic effects of FUra can be enhanced by pretreatment with N-(phosphonacetyl)-L-aspartic acid (PALA), an inhibitor of aspartate transcarbamylase. The objective of treatment with PALA is to increase the activation of FUra by inhibiting the normal pathway of de novo pyrimidine biosynthesis. Theoretically, the optimal dose of PALA should produce effective blockade of this pathway without increasing toxic effects of FUra. Using pyrazofurin-induced orotic aciduria and orotidinuria as a measure of this pathway, it as determined that PALA (250 mg/sq m) is effective in inhibiting total-body pyrimidine synthesis. Sixty-eight adult patients with cancer were treated with combinations of PALA and FUra. High doses of PALA (1 to 2 g/sq m) prevented the use of full dosage of FUra; however, PALA (250 mg/sq m) can be administered 24 hr before FUra (750 mg/sq m) once weekly for at least 3 weeks. The toxicity observed using that combination of doses was mild to moderate myelosuppression, mucositis, diarrhea, nausea, and vomiting. Further clinical studies are warranted.
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PMID:Phase I and clinical pharmacological evaluation of biochemical modulation of 5-fluorouracil with N-(phosphonacetyl)-L-aspartic acid. 683 57

N-(Phosphonacetyl)-L-aspartic acid (PALA) was administered at a dose of 1.5 g/m2/day x 5 days in a phase II evaluation of 21 patients with metastatic adenocarcinoma of the colon or rectum. Courses were repeated every 3 weeks. No responses were seen, but 11 patients had disease stabilization. PALA toxicity was marked, causing discontinuation of therapy in two patients. Major toxicity was cutaneous (90%), mucosal (35%), and gastrointestinal (diarrhea, at times bloody) (50%). There was no evidence of myelosuppression or CNS toxicity. PALA appears inactive in patients with metastatic colorectal carcinoma in the dose and schedule used in this study.
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PMID:Phase II evaluation of N-(phosphonacetyl)-L-aspartic acid (PALA) in metastatic adenocarcinoma of the colon or rectum. 740 67