Circadian rhythm in toxic effects of cystemustine in mice: relevance for chronomodulated delivery.
Cystemustine is a new nitrosourea with high anti-tumor activity and a short plasma half-life in mice. The influence of circadian dosing time upon its toxicities was first investigated in a total of 368 synchronized male B6D2F1 mice. Late survival rate varied from 4% in mice receiving a single dose of cystemustine (conventional lethal dose 50%) at 7 hours after light onset (HALO) up to 88% in mice treated at 15 or at 19 HALO. Target organ toxicities (bone marrow, circulating blood cells, spleen, colon and duodenum) were studied following a single slightly lower dose of cystemustine. Leukopenia was the major hematologic effect encountered. Leukocyte count nadir occurred 7 days after injection and was lowest following cystemustine at 7 HALO as compared to 13 or 19 HALO. Recovery was faster after cystemustine at 19 HALO as compared to other dosing times. Bone-marrow necrotic lesions were more pronounced 1 day after cystemustine at 7 HALO than after cystemustine at 19 HALO. Thus, a large-amplitude circadian rhythm characterized the toxicity of this nitrosourea in mice. The lowest cystemustine toxicity was found near the middle of the active span of the rest-activity circadian cycle of mice.
Martineau-Pivoteau
N
N
Laboratoire Rythmes biologiques et Chronothérapeutique (Université Paris XI), I.C.I.G., Hôpital Paul Brousse, Villejuif, France.
Levi
F
F
Rolhion
C
C
Kwiatkowski
F
F
Lemaigre
G
G
Filipski
E
E
Chollet
P
P
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000633:toxicity; D019454:Chronotherapy; D008297:Male; D051379:Mice; D009607:Nitrosourea Compounds / Q000008:administration & dosage* / Q000633:toxicity
D000970:Antineoplastic Agents; D009607:Nitrosourea Compounds; C051263:N'-(2-chloroethyl)-N-(2-(methylsulfonyl)ethyl)-N'-nitrosourea