This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Boughattas, N. A. Articles by Reinberg, A. Search for Related Content PubMed PubMed Citation Articles by Boughattas, N. A. Articles by Reinberg, A.

Circadian Rhythm in Toxicities and Tissue Uptake of 1,2-Diamminocyclohexane(trans-1)oxalatoplatinum(II) in Mice¹

U. A. CNRS 581 "Chronobiologie-Chronopharmacologie" Fondation A. de Rothschild, 29 rue Manin, 75019 Paris [N. A. B., F. L., A. R.]; Pharmacologie 2, SMSIT & ICIG (CNRS UA 04-1163 and Association Claude-Bernard), H^opital Paul-Brousse, 94800 Villejuif [N. A. B., F. L., A. R., G. M.]; Laboratoire de Pharmacodynamie, Centre Oscar Lambret, 59000 Lille [C. F., B. H.]; and Service d'Anatomie et de Cytologie Pathologique, Hôpital Antoine Béclère, 92000 Clamart [G. L.], France

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) (x² 21.3; 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.

¹ Supported in part by Ministèrieur de la Recherche et de l'Enseignement Supérieur, Paris, and by Roger-Bellon Laboratories, Neuilly, France.

² To whom requests for reprints should be addressed, at Pharmacologie 2, I. C. I. G., Hôpital Paul-Brousse, 14, av. Paul-Vaillant-Couturier, 94804 Villejuif Cédex, France.

Received 11/14/88. Revised 3/13/89. Accepted 3/21/89.

This article has been cited by other articles:

				T. A. Martino, N. Tata, G. A. Bjarnason, M. Straume, and M. J. Sole Diurnal protein expression in blood revealed by high throughput mass spectrometry proteomics and implications for translational medicine and body time of day Am J Physiol Regulatory Integrative Comp Physiol, September 1, 2007; 293(3): R1430 - R1437. [Abstract] [Full Text] [PDF]

				E. Filipski, V. M. King, M.-C. Etienne, X. Li, B. Claustrat, T. G. Granda, G. Milano, M. H. Hastings, and F. Levi Persistent twenty-four hour changes in liver and bone marrow despite suprachiasmatic nuclei ablation in mice Am J Physiol Regulatory Integrative Comp Physiol, October 1, 2004; 287(4): R844 - R851. [Abstract] [Full Text] [PDF]

				L. Canaple, T. Kakizawa, and V. Laudet The Days and Nights of Cancer Cells Cancer Res., November 15, 2003; 63(22): 7545 - 7552. [Abstract] [Full Text] [PDF]

				T. Price, C. Karapetis, V. Chevalier, H. Cure, P. Chollet, and F. Levi Chronomodulated Chemotherapy in Advanced Colorectal Carcinoma J. Clin. Oncol., September 15, 2002; 20(18): 3937 - 3939. [Full Text] [PDF]

				S. Giacchetti, B. Perpoint, R. Zidani, N. Le Bail, R. Faggiuolo, C. Focan, P. Chollet, J. F. Llory, Y. Letourneau, B. Coudert, et al. Phase III Multicenter Randomized Trial of Oxaliplatin Added to Chronomodulated Fluorouracil-Leucovorin as First-Line Treatment of Metastatic Colorectal Cancer J. Clin. Oncol., January 5, 2000; 18(1): 136 - 136. [Abstract] [Full Text] [PDF]

				S. Ohdo, T. Makinosumi, T. Ishizaki, E. Yukawa, S. Higuchi, S. Nakano, and N. Ogawa Cell Cycle-Dependent Chronotoxicity of Irinotecan Hydrochloride in Mice J. Pharmacol. Exp. Ther., December 1, 1997; 283(3): 1383 - 1388. [Abstract] [Full Text]