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Circadian rhythm in toxic effects of cystemustine in mice: Relevance for chronomodulated delivery
Author(s) -
MartineauPivoteau Nathalie,
Levi Francis,
Rolhion Christine,
Kwiatkowski Fabrice,
Lemaigre Guy,
Filipski Elisabeth,
Chollet Philippe
Publication year - 1996
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/(sici)1097-0215(19961127)68:5<669::aid-ijc18>3.0.co;2-x
Subject(s) - circadian rhythm , toxicity , bone marrow , leukopenia , endocrinology , medicine , biology , pharmacology
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 1ight 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 I 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. © 1996 Wiley‐Liss, Inc.