PHASE-I TRIAL OF FLUOROURACIL MODULATION BY N-PHOSPHONACETYL-L-ASPARTATE AND 6-METHYLMERCAPTOPURINE RIBONUCLEOSIDE

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 o f 5-FU into RNA, without detectably increasing its toxicity. 6-Methylm ercaptopurine riboside (MMPR) results in inhibition of purine biosynth esis with elevation of phosphoribosyl pyrophosphate (PRPP), which in t urn is believed to increase the phosphorylation and intracellular rete ntion 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 2 50 mg/m(2) given on day 1, followed 24 h later by MMPR 150 mg/m(2), an d escalating doses of 5-FU from 1625 to 2600 mg/m(2) by 24 h continuou s infusion. This regimen was repeated weekly. A group of 29 patients w ith a diagnosis of malignant solid tumor were entered; their median pe rformance status was 1. The dose-limiting toxicity was mucositis, whil e other gastrointestinal toxicity was minimal. Two patients also exper ienced ischemic chest pain during the 5-FU infusion. The maximum toler ated dose of 5-FU in this combination was 2600 mg/m(2). Several respon ses were observed including a complete remission in a previously treat ed 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 pharmaco kinetics of MMPR and the toxicity observed. This regimen was well tole rated and phase II trials are warranted using PALA 250 mg/m(2), MMPR 1 50 mg/m(2), and 5-FU 2300 mg/m(2) by continuous infusion over 24 h.