Martineau-Pivoteau N, Levi F, Rolhion C, Kwiatkowski F, Lemaigre G, Filipski E, Chollet P
Laboratoire Rythmes biologiques et Chronothérapeutique (Université Paris XI), I.C.I.G., Hôpital Paul Brousse, Villejuif, France.
Int J Cancer. 1996 Nov 27;68(5):669-74. doi: 10.1002/(SICI)1097-0215(19961127)68:5<669::AID-IJC18>3.0.CO;2-X.
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.
