Time dependency of hematopoietic growth factor coupled to chronotoxicity of carboplatin
A large amplitude circadian rhythm in murine tolerance for the anticancer agent, carboplatin (cyclobutane dicarboxylatoplatinum II, CBDCA) was demonstrated. Two studies were performed in a total of 266 male B6D2F1 mice standardized by LD 12:12. In the first experiment CBDCA (80 mg/kg/day) was administered intravenously (iv) daily for three consecutive days at all six circadian stages (3, 7, 11, 15, 19, or 23 hr after light onset, HALO). CBDCA dosing at 15 HALO resulted in 58% long-term survivors as compared to 0% after treatment at 3 or 23 HALO (chi 2 = 28; p less than 0.001). In the second experiment, CBDCA (72 or 80 mg/kg/day X 3 days, iv) was administered at any of three circadian stages (0, 8, or 16 HALO). Mice were killed, blood was collected, and seven tissues were obtained 5 and 10 days after the first dose, in order to determine serum urea and creatinine concentrations, leukocyte and red blood cell counts, and to evaluate histologic lesions. No renal toxicity was encountered. Bone marrow and colon mucosa were the major target tissues of CBDCA in these dosages and schedules. CBDCA dosing at 16 HALO was least toxic to the bone marrow as assessed by peripheral leukocyte count and histologic score (p from ANOVA less than 0.05). Histologically assessed lesions of the colon mucosa were less severe after CBDCA dosing at 16 HALO as compared to those at 8 HALO, and significantly so for the lowest dosage tested (p approximately 0.05). Uptake of CBDCA 24 hr after the third dose ranged from 23 micrograms/g of dry tissue in the colon to 7 micrograms/g in the duodenum. Mean tissue concentrations increased between Day 4 and Day 10 for the liver and spleen, and remained similar for the kidney. No consistent circadian dependence was found with regard to Day 4 mean Pt uptake in different tissues, whereas the lowest Day 10 Pt concentrations corresponded to CBDCA dosing at 16 HALO for all tissues investigated. Toxicity did not appear to be directly related to the total platinum concentration in these tissues.