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Hageboutros A , Hudes GR , Brennan J , Green F , Hoffman J , LaCreta FP , Colofiore J , Martin DS , Ozols RF , Odwyer PJ
Phase I trial of fluorouracil modulation by N-phosphonacetyl-L- aspartate and 6-methylmercaptopurine ribonucleoside
Cancer Chemotherapy and Pharmacology. 1996 Jan;37(3) :229-234
AbstractInhibition 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(2) given on day 1, followed 24 h later by MMPR 150 mg/m(2), and escalating doses of 5-FU from 1625 to 2600 mg/m(2) 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(2). 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(2), MMPR 150 mg/m(2), and 5-FU 2300 mg/m(2) by continuous infusion over 24 h.
NotesTimes Cited: 2 English Article TJ731 CANCER CHEMOTHER PHARMACOL