Circadian Variation of 5-Fluorouracil and Cis-Platinum Toxicity in Mice

Circadian variations of organ specific and lethal toxicities were investigated in fem ale C3H mice following intraperitoneal injection(s) of 5-fluorouracil (5-FU) and/or cis-platinum (CDDP) with different doses at one of the four equidistant time points, viz., 3, 9, 15 and 21 HALO (Hours After Light On). Lethality, peripheral WBC count, spleen size, femoral bone marrow cell population and changes in body weight were analyzed. A single injection of 5-FU (300 mg/kg) showed 45% mortality with 3 HALO and 15% with 9 HALO treatment (p<0.05); that with CDDP (16 mg/kg) was 80% in 3 HALO and 10% in 9 HALO group (p<0.01). Peripheral WBC count on the 4th post-treatment day showed that drug induced leukopenia was less severe with 15 HALO dosing compared to the other HALO points (p<0.01). The reduction in spleen size following treatment was maximum in 3 HALO treated group with both drugs (p<0.01). The combination therapy of these two drugs also showed circadian variation of toxicity. The results suggest that the toxic effects of chemotherapy are dosing time dependent.