Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study

Antonio C. Buzaid, Giuseppe Pizzorno, John C. Marsh, Thanjavur S. Ravikumar, John R. Murren, Mary Todd, Roger Strair, Wen Jen Poo, William N. Hait

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Abstract

Biochemical modulation can increase the efficacy of 5-fluorouracil (5-FU). Pizzorno et al. have previously shown that brequinar, a de novo pyrimidine synthesis inhibitor, enhances the antitumor effect of 5-FU in vivo [Cancer Res 52: 1660-1665, 1992]. On the basis of their data, we conducted a phase I study of brequinar in combination with 5-FU in patients with refractory solid tumors. The initial dose (100 mg/m2) of brequinar was raised in 100-mg/m2 increments in cohorts of three assessable patients. The initial dose of 5-FU was 500 mg/m2, but escalation was allowed in patients who showed no significant toxic reaction. Brequinar was administered over 1 h and 5-FU over 2 h starting 18-20 h after the initiation of infusion of brequinar. Treatments were repeated weekly. Responses were evaluated after 4 weeks (one course) and then every 8 weeks thereafter. Pharmacokinetics of brequinar and determination of plasma uridine levels were performed in at least three patients at each dose level. Of the 25 patients registered in the study, 21 were assessable for toxicity studies. The dose of brequinar was escalated up to 600 mg/m2. In addition, the dose of 5-FU was increased to 600 mg/m2 as a result of a lack of a significant toxic reaction in the first nine patients. No objective responses were observed. One patient developed grade 3 stomatitis, and one developed grade 3 esophagitis at the 400 and 600 mg/m2 dose of brequinar, respectively. Brequinar produced a dosedependent decrease in plasma uridine levels at doses up to 500 mg/m2. No additional decrease in plasma uridine occurred with higher doses of brequinar, thus suggesting a plateau effect. This observation prompted us to terminate the study before reaching the maximum tolerated dose of brequinar. Our data indicate that brequinar in doses≥400 mg/m2 results in significant biochemical modulation. The lack of toxicity seen at these doses of brequinar suggests that the initial dose of the effector agent 5-FU should be increased in future studies.

Original languageEnglish (US)
Pages (from-to)373-378
Number of pages6
JournalCancer chemotherapy and pharmacology
Volume36
Issue number5
DOIs
StatePublished - Sep 1 1995

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brequinar
Fluorouracil
Modulation
Uridine
Poisons
Plasmas
Toxicity

All Science Journal Classification (ASJC) codes

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

Cite this

Buzaid, A. C., Pizzorno, G., Marsh, J. C., Ravikumar, T. S., Murren, J. R., Todd, M., ... Hait, W. N. (1995). Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study. Cancer chemotherapy and pharmacology, 36(5), 373-378. https://doi.org/10.1007/BF00686185
Buzaid, Antonio C. ; Pizzorno, Giuseppe ; Marsh, John C. ; Ravikumar, Thanjavur S. ; Murren, John R. ; Todd, Mary ; Strair, Roger ; Poo, Wen Jen ; Hait, William N. / Biochemical modulation of 5-fluorouracil with brequinar : results of a phase I study. In: Cancer chemotherapy and pharmacology. 1995 ; Vol. 36, No. 5. pp. 373-378.
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Buzaid, AC, Pizzorno, G, Marsh, JC, Ravikumar, TS, Murren, JR, Todd, M, Strair, R, Poo, WJ & Hait, WN 1995, 'Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study', Cancer chemotherapy and pharmacology, vol. 36, no. 5, pp. 373-378. https://doi.org/10.1007/BF00686185

Biochemical modulation of 5-fluorouracil with brequinar : results of a phase I study. / Buzaid, Antonio C.; Pizzorno, Giuseppe; Marsh, John C.; Ravikumar, Thanjavur S.; Murren, John R.; Todd, Mary; Strair, Roger; Poo, Wen Jen; Hait, William N.

In: Cancer chemotherapy and pharmacology, Vol. 36, No. 5, 01.09.1995, p. 373-378.

Research output: Contribution to journalArticle

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T2 - results of a phase I study

AU - Buzaid, Antonio C.

AU - Pizzorno, Giuseppe

AU - Marsh, John C.

AU - Ravikumar, Thanjavur S.

AU - Murren, John R.

AU - Todd, Mary

AU - Strair, Roger

AU - Poo, Wen Jen

AU - Hait, William N.

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AB - Biochemical modulation can increase the efficacy of 5-fluorouracil (5-FU). Pizzorno et al. have previously shown that brequinar, a de novo pyrimidine synthesis inhibitor, enhances the antitumor effect of 5-FU in vivo [Cancer Res 52: 1660-1665, 1992]. On the basis of their data, we conducted a phase I study of brequinar in combination with 5-FU in patients with refractory solid tumors. The initial dose (100 mg/m2) of brequinar was raised in 100-mg/m2 increments in cohorts of three assessable patients. The initial dose of 5-FU was 500 mg/m2, but escalation was allowed in patients who showed no significant toxic reaction. Brequinar was administered over 1 h and 5-FU over 2 h starting 18-20 h after the initiation of infusion of brequinar. Treatments were repeated weekly. Responses were evaluated after 4 weeks (one course) and then every 8 weeks thereafter. Pharmacokinetics of brequinar and determination of plasma uridine levels were performed in at least three patients at each dose level. Of the 25 patients registered in the study, 21 were assessable for toxicity studies. The dose of brequinar was escalated up to 600 mg/m2. In addition, the dose of 5-FU was increased to 600 mg/m2 as a result of a lack of a significant toxic reaction in the first nine patients. No objective responses were observed. One patient developed grade 3 stomatitis, and one developed grade 3 esophagitis at the 400 and 600 mg/m2 dose of brequinar, respectively. Brequinar produced a dosedependent decrease in plasma uridine levels at doses up to 500 mg/m2. No additional decrease in plasma uridine occurred with higher doses of brequinar, thus suggesting a plateau effect. This observation prompted us to terminate the study before reaching the maximum tolerated dose of brequinar. Our data indicate that brequinar in doses≥400 mg/m2 results in significant biochemical modulation. The lack of toxicity seen at these doses of brequinar suggests that the initial dose of the effector agent 5-FU should be increased in future studies.

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Buzaid AC, Pizzorno G, Marsh JC, Ravikumar TS, Murren JR, Todd M et al. Biochemical modulation of 5-fluorouracil with brequinar: results of a phase I study. Cancer chemotherapy and pharmacology. 1995 Sep 1;36(5):373-378. https://doi.org/10.1007/BF00686185