Orcadian Rhythm in Toxicities and Tissue Uptake of 1,2-Diammino-cyclohexane(trans-1)oxalatoplatinum(II) in Mice

Mechanisms involved in the circadian rhythm in murine tolerance for the new platinum analogue, 1,2-diamminrcyclohexane(trans-1)oxalatoplatinum(II) (1-OHP) were sought in 404 male C57BL/6 x DBA/2 F, mice standardized by 12 h light-12 h dark. A potentially lethal dose of 1-OHP (17 mg/kg i.v.) resulted in 76% long-term survival at 15 h after light onset (HALO) (activity span) as compared to 24% after treatment at 7 HALO (rest span) (x2 213; P < 0.001). A total of 204 mice received the same dose of 1-OHP at one of three circadian stages (0, 8, or 16 HALO). No renal toxicity was encountered. Bone marrow and jejunal villi constituted the chief targets of 1-OHP toxicity at this dosage and schedule. Hematological tolerance as gauged by leukocyte counts was optimal when the drug was given at 16 HALO (P from analysis of variance, <0.001). Jejunal lesions were less severe after 1-OHP dosing at 16 HALO as compared to 8 HALO (P < 0.001). Total platinum concentrations were determined in 18 tissues 24 h after 1-OHP dosing. The highest levels of platinum were found in the spleen on day 1 as well as on day 5 following 1-OHP treatment. Despite the fact that the highest platinum concentrations in tissues usually corresponded to drug dosing at 8 HALO, no correlation was documented between such variables and tissue toxicity. Tissue pharmacokinetics of 1-OHP contribute only in part if at all to the circadian rhythm in hematological and jejunal toxicity of this drug. © 1989, American Association for Cancer Research. All rights reserved.