Effect of allopurinol on the toxicity of high-dose 5-fluorouracil administered by intermittent bolus injection
✍ Scribed by Stephen B. Howell; Craig E. Pfeifle; Wally E. Wung
- Publisher
- John Wiley and Sons
- Year
- 1983
- Tongue
- English
- Weight
- 555 KB
- Volume
- 51
- Category
- Article
- ISSN
- 0008-543X
No coin nor oath required. For personal study only.
✦ Synopsis
The effect of allopurinol pretreatment on the toxicity of 5-tluorouracil(5-FU) was examined in a clinical trial. Twenty-three patients were given bolus infusions of 5-FU every two weeks in doses that produced mild toxicity (0.8-1 .9 g/m'). O n alternate courses patients were pretreated with allopurinol either 300 mg two hours prior to and 10 hours after 5-FU. or 300 mg every 8 hours for 4 doses starting 24 hours before 5-FU. Seventeen and 20 pairs of courses were evaluable froni the 2-and 24-hour pretreatment groups, respectively. Allopurinol did not produce a significant degree of protection against 5-FU-induced myelosuppression or mucositis on either dose schedule. Neurotoxicity nianifesting as both cerebellar and encephalopathic signs and symptoms was the most important toxicity encountered and was doselimiting for 5-FU on this schedule. Mean oxipurinol serum concentrations at the time of 5-FU administration were 24 uM and 104 uM for the 2-and 24-hour allopuriiiol pretreatment schedules respectively. Allopurinol increased the 1' Yz of 5-FU by a mean of 67% in three of the four patients studied. Pretreatment with allopurinol did not reduce the toxicity of 5-FU administered as an intravenous bolus.
Cuncrr 51:220-225, 1983.
N ORDER to damage cells, 5-fluorouracil (5-FU) must I be converted intracellularly to either 5-tluorodeoxyuridine monophosphate (FdUMP) or 5-fluorouridine triphosphate (FUTP). The former is a potent inhibitor of thymidylate synthetase,'.' while the latter is incorporated into RNA where it interferes with RNA stability and function.'.' Three routes of activation of 5-FU to its nucleotide forms have been identified (Fig. 1): ( 1 ) 5-FU can be convened directly to FUMP by the enzyme orotidine phosphoribosyl-transferase (OPRTdse) in a reaction that also requires 5-phosphoribosyltransferase (PRPP); (2) 5-FU can react sequentially with uridine phosphorylase and then uridine kinase to form FUMP; or (3) 5-FU can react with deoxyribose-l-phosphate and be converted to FdUR directly by thymidine phosphorylase. This latter pathway is probably of little significance in man because of the scarcity of deoxyribose-1 -phosphate.