Implications of Circadian Dosing- Time in the Chrono tolerance and the Rhythmic Delivery of the 5- Fluorouracil (5-Fu) in Female Rats and its Relevance to Cancer Therapeutics

The present work aims to study whether the tolerance to 5-fluorouracil (5-FU) varies according to the circadian dosing timein female rats.The influence of dosing-time on tolerance to 5-FU was investigated in 120 adult female Wistar rats. All animals weresynchronized under a light-dark cycle (12:12). A potentially
lethal dose of 5-FU was first determined to be 350 ± 0.92mg/kg, it was administrated by intraperotonial route (i.p.). 5-FUwas injected to a total of 90 female rats divided in six circadianstages [1, 5, 9, 13, 17 and 21 Hours After Light Onset (HALO)]. Three toxicity end-points were analyzed such us survival rate,body weight and rectal temperature. Drug dosing at 21HALO resulted in 100% survival rate as compared to drug dosing at 5HALO (0%). The Cosinor analysis revealed a significant circadian rhythm in survival with an acrophase at 21.81HALO ±0.68 hours (p<0.0002). The most rectal temperature changeand body weight occurred when 5-FU was injected at 5 HALO resulted in -61.89% weight loss whereas drug dosing at 21HALO was a weight gain 11.39% (Ø=2 HALO ± 1.39 hours, p<0.0033).