© 1991 by Oxford University Press
Journal of the National Cancer Institute, Vol. 83, No. 17, 1235-1240,
September 4, 1991
© 1991 Oxford University Press
Phase I Trial Of Fluorouracil Modulation by N-Phosphonacety-L-aspartate and 6-Methylmercaptopurine Riboside: Optimization of 6-Methylmercaptopurine Riboside Dose and Schedule Through Biochemical Analysis of Sequential Tumor Biopsy Specimens
1Fox Chase Cancer Center Philadelphia, Pa.
2Catholic Medical Center Woodhaven, N.Y.
*Correspondence to: Peter J. O'Dwyer, M.D., Developmental Chemotherapy, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111.
Preclinical and Clinical studies demonstrate that the selective antitumor activity of fluroruracil (5-FU) is enhanced by agents which perturb certain interacellular 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 phosphoribosyl pyrophosphate (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 in travenously 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/brief-reportm2 dose level was favored. Tumor levels of PRPP decreased be-tween 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 24hour infusion of 5-FU. [J Natl Cancer Inst 83:1235–1240, 1991]
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