Phase I study of phosphonacetyl-L-aspartate, 5-fluorouracil, and leucovorin in patients with advanced cancer.
Cancer Chemother Pharmacol
; 35(3): 205-12, 1995.
Article
em En
| MEDLINE
| ID: mdl-7805178
ABSTRACT
Low-dose phosphonacetyl-L-aspartate (PALA) may potentiate both 5-fluorouracil (5-FU) incorporation into RNA and thymidylate synthase inhibition by 5-fluorodeoxyuridylate (5-FdUMP). The gastrointestinal toxicity of 5-FU is not increased by PALA administration. Exogenous leucovorin, on the other hand, which enhances thymidylate synthase inhibition, appears to increase the clinical toxicity of 5-FU in a dose-dependent manner. As a result, the clinical use of high-dose leucovorin requires a marked dose reduction of 5-FU. Extracellular leucovorin levels of 1 microM suffice to maximize the enhancement of thymidylate synthase inhibition in several models. We conducted a trial to add leucovorin to the PALA/5-FU regimen. We chose a leucovorin dose that was predicted to yield end-infusion total reduced folate concentrations of 1 microM. The major endpoint was to determine the maximum tolerated dose of 5-FU in this combination. The regimen consisted of 250 mg/m2 PALA given on day 1 and, 24 h later, escalating 5-FU doses ranging from 1,850 to 2,600 mg/m2 admixed with 50 mg/m2 leucovorin and given by 24-h infusion. Courses were repeated weekly. A total of 24 patients with a median performance status of 1 were entered at three dose levels. Diarrhea was dose-limiting; 6/13 patients had grade II or worse diarrhea at 2,600 mg/m2. Dose modification resulted in a mean dose intensity of 2,300 mg/m2 at both the 2,600- and 2,300-mg/m2 dose levels. The 2,300-mg/m2 dose is suitable for phase II testing of this regimen. Three patients (two with breast cancer and 1 with sarcoma) had a partial remission. We measured steady-state concentrations (Css) of 5-FU in 23 patients. The mean Css increased with dose from 0.738 to 1.03 micrograms/ml. Total body clearance did not vary with dose in this range. Patients with grade II or worse diarrhea had a higher mean Css (1.10 +/- 0.19) than those with grade O or I toxicity (0.835 +/- 0.25, P < 0.02). Total bioactive folates (bound and free) were measured using a biological assay. Pretreatment values ranged from 2 to 52 nM and were not predictive of toxicity. End-infusion (23-h) values were somewhat lower than predicted and ranged from 400 to 950 nM. The risk of diarrhea was positively correlated with end-infusion total folate values. In a logistic regression analysis, total folate values obtained at 23 h were a more powerful predictor of diarrhea than were 5-FU Css values.(ABSTRACT TRUNCATED AT 400 WORDS)
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Base de dados:
MEDLINE
Assunto principal:
Protocolos de Quimioterapia Combinada Antineoplásica
/
Neoplasias
Tipo de estudo:
Etiology_studies
/
Prognostic_studies
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Risk_factors_studies
Limite:
Adult
/
Aged
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Ano de publicação:
1995
Tipo de documento:
Article