A phase I study of continuous infusion 5-fluorouracil plus calcium leucovorin in combination with N-(phosphonacetyl)-L-aspartate in metastatic gastrointestinal adenocarcinoma

Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In th...

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Published in:Cancer research (Chicago, Ill.) Ill.), 1993-10, Vol.53 (20), p.4828-4836
Main Authors: GREM, J. L, MCATEE, N, SORENSEN, J. M, CHEN, A. P, GOLDSTEIN, L, JORDAN, E, SETSER, A, GOLDSPIEL, B, DECARVALHO, M, ALLEGRA, C. J, STEINBERG, S. M, HAMILTON, J. M, MURPHY, R. F, DRAKE, J, CHISENA, T, BALIS, F, CYSYK, R, ARBRUCK, S. G
Format: Article
Language:English
Subjects:
Adenocarcinoma - drug therapy
Adenocarcinoma - pathology
Adult
Aged
Antineoplastic agents
Antineoplastic Agents - administration & dosage
Antineoplastic Agents - toxicity
Antineoplastic Combined Chemotherapy Protocols - therapeutic use
Antineoplastic Combined Chemotherapy Protocols - toxicity
Aspartate Carbamoyltransferase - antagonists & inhibitors
Aspartate Carbamoyltransferase - blood
Aspartic Acid - administration & dosage
Aspartic Acid - analogs & derivatives
Aspartic Acid - toxicity
Biological and medical sciences
Chemotherapy
Female
Fluorouracil - administration & dosage
Fluorouracil - pharmacokinetics
Fluorouracil - toxicity
Gastrointestinal Neoplasms - drug therapy
Gastrointestinal Neoplasms - pathology
Humans
Infusions, Intravenous
Leucovorin - administration & dosage
Male
Medical sciences
Middle Aged
Monocytes - drug effects
Monocytes - enzymology
Neoplasm Metastasis
Pharmacology. Drug treatments
Phosphonoacetic Acid - administration & dosage
Phosphonoacetic Acid - analogs & derivatives
Phosphonoacetic Acid - toxicity
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Summary:Preclinical studies suggest that the biochemical effects of N-(phosphonacetyl)-L-aspartate (PALA), an inhibitor of aspartate carbamoyltransferase (ACTase), may increase the metabolic activation of 5-fluorouracil (5-FU) and enhance its cytotoxicity through both RNA- and DNA-directed mechanisms. In this Phase I trial, 22 evaluable patients with adenocarcinoma of the gastrointestinal tract were entered at escalating doses of 5-FU starting at 1150 mg/m2/day given as a concurrent 72-h i.v. infusion with a fixed dose of leucovorin (LCV), 500 mg/m2/day. The dose of 5-FU was escalated within patients according to individual tolerance, and then PALA at 250 mg/m2 was added 24 h prior to the initiation of the 5-FU/LCV infusion of the subsequent cycle. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 3 of 5 patients treated with 2300 mg/m2/day 5-FU; therefore, the recommended dose of 5-FU with concurrent LCV is 2000 mg/m2/day. Twenty-seven additional patients were then treated with escalating doses of PALA ranging from 375 to 2848 mg/m2, i.v., followed 24 h later by 2000 mg/m2/day 5-FU with high-dose LCV. Dose-limiting mucositis and myelosuppression occurred during the initial cycle in 2 of 3 patients entered at 2848 mg/m2 PALA. Dose-limiting mucositis and skin rash ultimately required both PALA and 5-FU dose reductions in 4 of 6 patients treated with 1899 mg/m2 PALA. Toxicity was similar, however, in patients receiving PALA at doses ranging from 375 to 1266 mg/m2. The mean steady-state plasma concentration of 5-FU at 2000 mg/m2/day was 6.5 +/- 0.9 microM; patients with 5-FU levels > 9 microM had a significantly higher incidence of serious gastrointestinal and hematological toxicity. Compared to each patient's own baseline, a significant trend for decreasing ACTase activity with increasing PALA dose was evident using cytosol isolated from peripheral blood mononuclear cells 24 h after PALA treatment (P2 = 0.01). PALA < or = 844 mg/m2 failed to appreciably inhibit ACTase activity at 24 h in most patients; furthermore, a decrease in ACTase activity by > 50% from baseline was seen in only 29% of cycles. More consistent inhibition of ACTase activity was seen with PALA > or = 1266 mg/m2. Even with the highest PALA doses, however, ACTase activity returned to baseline by 96 h in most patients.
ISSN:0008-5472
1538-7445