BACKGROUND Dose intensification of 5-fluorouracil (5-FU) is complicated by increased toxicity. 5-FU is a fluorine-substituted pyrimidine analog of uracil. In preclinical studies, administration of oral uridine (Ur) has been shown to allow for dose intensification of 5-FU with enhancement of its antitumor activity. Therefore, a Phase I trial was designed aimed at dose intensification of 5-FU as a component of a modified 5-FU-doxorubicin-methotrexate (FAMTX) regimen using oral Ur rescue. METHODS Methotrexate (MTX) was administered to all patients at a fixed dose of 1.5 g/m2. MTX was followed 24 hours later by escalating doses of 5-FU starting at 800 mg/m2 with leucovorin rescue. Cycles of 5-FU and MTX were repeated every 15 days. Every other cycle, patients received doxorubicin. "Adria cycles") at a dose of 30 mg/m2. Oral Ur was administered at a dose of 8 gm/m2 every 6 hours for 12 doses. In the first phase of the study, patients received Ur only if they developed Grade 3 or 4 hematologic toxicity. In the second phase, all patients received Ur 24 hours after 5-FU on all cycles. RESULTS Without Ur rescue, the maximum tolerated dose (MTD) of 5-FU was 900 mg/m2 on the Adria cycles and 1.1 gm/m2 on the non-Adria cycles. With Ur, the MTD of 5-FU increased to 1.2 gm/m2 on the Adria cycles and to 1.6 gm/m2 on the non-Adria cycles. CONCLUSIONS In this modified FAMTX regimen, oral Ur administration allowed for dose-intensification of 5-FU, with a 33% increase in the MTD of 5-FU on the Adria cycles and a 45% increase in the MTD of 5-FU dose on the non-Adria cycles.