Phase I trial of fluorouracil modulation by N-phosphonacetyl-L-aspartate and 6-methylmercaptopurine ribonucleoside.

Autor: Hageboutros, Alxandre, Hudes, Gary, Brennan, James, Green, Fran, Hoffman, John, LaCreta, Frank, Colofiore, Joseph, Martin, Daniel, Ozols, Robert, O'Dwyer, Peter
Zdroj: Cancer Chemotherapy & Pharmacology; May1995, Vol. 37 Issue 3, p229-234, 6p
Abstrakt: Inhibition of pyrimidine and purine synthesis has been demonstrated to potentiate 5-fluorouracil (5-FU) activity in preclinical models. Low-dose phosphonacetyl- l-aspartate (PALA) potentiates the incorporation of 5-FU into RNA, without detectably increasing its toxicity. 6-Methylmercaptopurine riboside (MMPR) results in inhibition of purine biosynthesis with elevation of phosphoribosyl pyrophosphate (PRPP), which in turn is believed to increase the phosphorylation and intracellular retention of 5-FU. We conducted a phase I clinical trial to determine the maximum tolerated dose of 5-FU in combination with low-dose PALA and a biochemically-optimized dose of MMPR. The regimen consisted of PALA 250 mg/m given on day 1, followed 24 h later by MMPR 150 mg/m, and escalating doses of 5-FU from 1625 to 2600 mg/m by 24 h continuous infusion. This regimen was repeated weekly. A group of 29 patients with a diagnosis of malignant solid tumor were entered; their median performance status was 1. The dose-limiting toxicity was mucositis, while other gastrointestinal toxicity was minimal. Two patients also experienced ischemic chest pain during the 5-FU infusion. The maximum tolerated dose of 5-FU in this combination was 2600 mg/m. Several responses were observed including a complete remission in a previously treated breast cancer patient and two partial responses in breast and colon cancer. MMPR pharmacokinetics were obtained from urine analyses in 21 patients on this trial; there was no correlation between the pharmacokinetics of MMPR and the toxicity observed. This regimen was well tolerated and phase II trials are warranted using PALA 250 mg/m, MMPR 150 mg/m, and 5-FU 2300 mg/m by continuous infusion over 24 h. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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