Preclinical and clinical studies demonstrate that the selective antitumor activity of
fluorouracil (5-FU) is enhanced by agents which perturb certain intracellular
nucleotide pools. We previously demonstrated that the combination of
N-phosphonacetyl-L-aspartate (
PALA), which depletes
pyrimidine nucleotide pools, and
5-FU yielded a 43% response rate among 37 assessable patients with
colorectal carcinoma. In preclinical
tumor models,
6-methylmercaptopurine riboside (MMPR), an inhibitor of
purine synthesis, elevates phosphoribosylpyrophosphate (PRPP) pools and promotes the anabolism of
5-FU to fluorinated
nucleotides. In vivo, the addition of MMPR enhances the therapeutic efficacy of PALA-5-FU. In a phase I trial, we sought to determine the optimal dose and schedule of MMPR in combination with
PALA (250 mg/m2 on day 1) and
5-FU (1300 mg/m2 by 24-hour infusion on day 2). MMPR (75-225 mg/m2) was given intravenously on day 1 to 27 patients with solid
tumors (15 colorectal, seven breast, five other). Toxic effects were mild to moderate and included
leukopenia,
mucositis,
nausea, or
rash. Two of seven patients given MMPR at 225 mg/m2 had grade 3
diarrhea. PRPP was measured using a [14C]
orotic acid 14CO2 release assay in
tumor biopsy specimens obtained before and 12 hours and 24 hours after MMPR doses were given to 20 patients. The addition of MMPR elevated PRPP pools in human solid
tumors. At 12 hours
after treatment, two (50%) of four patients showed a twofold or greater elevation of PRPP at the MMPR dose level of 75 mg/m2; a similar elevation was observed in five (71%) of seven patients given 150 mg/m2 MMPR and in three (43%) of seven patients given 225 mg/m2 MMPR. At 24 hours
after treatment, results for the respective dose levels of MMPR were two (33%) of six patients, one (20%) of five patients, and four (57%) of seven patients. Administration of the two highest MMPR dose levels appeared to result in a greater increase in
tumor PRPP levels. However, toxicity was greater at the 225 mg/m2 dose level; therefore, the 150 mg/m2 dose level was favored.
Tumor levels of PRPP decreased between 12 hours and 24 hours in nine (56%) of 16 patients. This time course indicates that MMPR should be administered at the beginning of the 24-hour infusion of
5-FU.