A controlled trial of the effect of 4-hydroxypyrazolopyrimidine (allopurinol) on the toxicity of a single bolus dose of 5-fluorouracil.

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Abstract
In a controlled study, the modification of the toxicity of a single bolus dose of 5-fluorouracil (5-FU) by allopurinol was evaluated. Patients first received a single dose of 5-FU and were monitored for toxicity. If a measurable nadir in WBC (white blood cell) or platelet count occurred, then the same dose of 5-FU was repeated with concurrent allopurinol, given for 4 consecutive days at an initial dose of 300 mg twice daily, starting the day before the administration of 5-FU. With this schedule, each evaluable patient received courses of 5-FU with and without allopurinol that could be compared for toxicity. Twenty patients received initial 5-FU doses of 1200 mg/m2 or 1500 mg/m2 and later had the same dose repeated with allopurinol. Nineteen of these patients had a higher WBC count with allopurinol than without it. In several patients who received a further course of 5-FU with 900-mg/day allopurinol, the WBC count was higher than with 600-mg/day allopurinol. The myelosuppression produced by 5-FU was characterized by a decrease in granulocyte levels that was much greater than the decrease in lymphocyte levels, and the result of allopurinol treatment was to attenuate this effort on granulocytes. In a 2nd part of the trial, the goal was to establish the maximum tolerated dose of 5-FU given with concurrent allopurinol. All patients entered were given 5-FU, usually 1200 mg/m2, with allopurinol, usually 600 mg/day for 4 days. Escalations of 1 or the other drugs were made on subsequent treatments. The data for 22 patients showed that 1800 mg/m2 of 5-FU was well tolerated if given with 600-1200 mg of allopurinol/day, and that the WBC count nadirs were no more severe than those of 1200-mg/m2 5-FU without allopurinol. Neurotoxicity became limiting in some patients treated at these higher doses. Thus, allopurinol given in the proper dose and schedule can diminish the granulocytopenia produced by bolus doses of 5-FU, thereby allowing a 50% increase in the maximal tolerated dose of 5-FU.

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