title: Stable circadian mechanisms of toxicity of two platinum analogs (cisplatin and carboplatin) despite repeated dosages in mice.
abstract: The toxicities and tissue uptake of cisplatin (CDDP) and carboplatin (CBDCA) vary largely according to the time of injection of a single dose. Repeated dosages may alter the mechanisms involved with such circadian-dependent toxicity. Weekly i.v. injections of CDDP (5 mg/kg) or CBDCA (50 mg/kg) were given over 2 months to 288 male B6D2F1 mice standardized by an alternation of 12 hr of light and 12 hr of darkness at any one of three circadian dosing times (0, 8 or 16 hr after light onset--HALO). Survival; body weight; complete blood cell counts; histologic lesions in kidney, liver, spleen, bone marrow and intestinal tract; platinum concentration in kidney, spleen and colon were determined every 2 weeks throughout treatment. Thrombocytopenia was 10-fold larger following CBDCA as compared with CDDP. Severe bone marrow necrosis was cumulative following CDDP, but reversible following CBDCA. Leukopenia and bone marrow lesions were, respectively, half as severe following the dosing of either drug at 16 HALO compared with 0 or 8 HALO. Cortical tubular necrosis was observed in CDDP-treated mice. It was cumulative and half as extensive after drug dosing at 16 HALO, as compared with 0 or 8 HALO (P less than or equal to .05). Total Pt accumulation in all three tissues was 3- to 4-fold higher following repeated dosages of CDDP as compared with CBDCA. Tissue Pt uptake was halved after CDDP or CBDCA dosing at 16 HALO as compared with 8 HALO (P less than or equal to .01). Dosing either Pt complex at the appropriate time is even more critical if administrations are to be repeated. Mechanisms appear to involve the circadian rhythm-dependent ability of target tissues to take up the drug.
authors.affiliation: SDI-Centre National de la Recherche Scientifique 6212 Chronobiologie-Chronopharmacologie-Cancer, Hôpital Paul-Brousse, Villejuif, France.
authors.forename: N A
authors.initials: NA
authors.lastname: Boughattas
authors.forename: F
authors.initials: F
authors.lastname: Lévi
authors.forename: C
authors.initials: C
authors.lastname: Fournier
authors.forename: B
authors.initials: B
authors.lastname: Hecquet
authors.forename: G
authors.initials: G
authors.lastname: Lemaigre
authors.forename: A
authors.initials: A
authors.lastname: Roulon
authors.forename: G
authors.initials: G
authors.lastname: Mathé
authors.forename: A
authors.initials: A
authors.lastname: Reinberg
mesh_terms: D000818:Animals; D001772:Blood Cell Count; D001831:Body Temperature / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D016190:Carboplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D002940:Circadian Rhythm; D002945:Cisplatin / Q000493:pharmacokinetics / Q000633:toxicity*; D005978:Glutathione / Q000502:physiology; D007668:Kidney / Q000187:drug effects; D008297:Male; D051379:Mice; D014018:Tissue Distribution
chemical_list: D016190:Carboplatin; D005978:Glutathione; D002945:Cisplatin