5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine): toxicity reduction and increased antitumor activity in mice

Cancer Chemother Pharmacol (2006) 58: 136142

DOI 10.1007/s00280-005-0129-xCLINICAL TRIAL REPORTMuhammad Wasif Saif Reid von Borstel5-Fluorouracil dose escalation enabled with PN401 (triacetyluridine):

toxicity reduction and increased antitumor activity in miceReceived: 3 August 2005 / Accepted: 2 September 2005 / Published online: 27 September 2005

Springer-Verlag 2005Abstract Purpose: PN401, an oral prodrug of uridine

yields more bioavailable uridine than oral administration of uridine itself. PN401 may therefore be useful for

permitting dose escalation of 5-uorouracil (5-FU) with

consequent improvements in antitumor ecacy. Experimental design: Female BALB/c mice (Colon 26 adenocarcinoma) were treated with 5-FU with PN401 to

dene the MTD, and pharmacokinetic analyses were

done. A comparison of 5-FU/PN401 was made to 5-FU/

eniluracil (EU) and 5-FU/LV. The best timing of the

rst dose of PN401 relative to 5-FU was evaluated by

administering groups of mice PN401 beginning 2, 24, or

48 h after 5-FU dose. Results: The MTD of 5-FU was

100 mg/kg/week whereas the MTD of 5-FU + PN401

was 200 mg/kg/week. A complete response (CR) of 80%

and partial response (PR) of 20% was observed with

5-FU (200 mg/kg) + PN401, CR of 40% and PR of

60% with 5-FU (175 mg/kg) + PN401, PR of 10%

with 5-FU (150 mg/kg) + PN401 while no response

with 5-FU (100 mg/kg) + PN401. Analysis of 5-FU

pharmacokinetics displayed nonlinearity as a function of

administered dose in mice. In the comparison study, the

best response was achieved with PN401 when compared

to EU and LV. Mice that did not receive PN401 died by

day 12, while other groups were alive at day 31. The

proportion of mice surviving was highest in the group

which received PN401 at 2 h followed by 24 and 48 h.Conclusions: There is a threshold 5-FU dose after which

the ecacy is dramatically improvedin mice bearing

Colon 26 adenocarcinoma, that threshold is a dose of

>150 mg/kg/week, and the increased ecacy correlates

with about a fourfold increase in the AUC of 5-FU.

PN401 used to rescue mice from the lethal toxicity of

5-FU entails that PN401 can be used as an antidote even

when used up to 48 h after a 5-FU overdose.Key words 5-Fluorouracil PN401 Fluoropyrimidines Uridine DPDIntroductionFluorouracil (5-FU) is one of the most commonly used

chemotherapeutic agents and constitutes the...