Circadian rhythm in toxicities and tissue uptake of 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) in mice

Mechanisms involved in the circadian rhythm in murine tolerance for the new platinum analogue, 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) (1-OHP) were sought in 404 male C57BL/6 x DBA/2 F1 mice standardized by 12 h light-12 h dark. A potentially lethal dose of 1-OHP (17 mg/kg i.v.) resulted...

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Bibliographic Details
Published in:Cancer research (Chicago, Ill.) Ill.), 1989-06, Vol.49 (12), p.3362
Main Authors: Boughattas, N A, Lévi, F, Fournier, C, Lemaigre, G, Roulon, A, Hecquet, B, Mathé, G, Reinberg, A
Format: Article
Language:English
Subjects:
Animals
Body Temperature - drug effects
Body Weight - drug effects
Bone Marrow - drug effects
Bone Marrow - pathology
Circadian Rhythm
Erythrocytes - metabolism
Intestinal Mucosa - drug effects
Intestinal Mucosa - pathology
Jejunum - drug effects
Jejunum - pathology
Male
Mice
Mice, Inbred Strains
Organoplatinum Compounds - pharmacokinetics
Organoplatinum Compounds - toxicity
Spleen - metabolism
Tissue Distribution
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Summary:Mechanisms involved in the circadian rhythm in murine tolerance for the new platinum analogue, 1,2-diamminocyclohexane(trans-1)oxalatoplatinum(II) (1-OHP) were sought in 404 male C57BL/6 x DBA/2 F1 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) (chi 2 21.3; P less than 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, less than 0.001). Jejunal lesions were less severe after 1-OHP dosing at 16 HALO as compared to 8 HALO (P less than 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.
ISSN:0008-5472