Examination of meningocele induced by the antitumor agent DE-310 in rat fetuses.
The antitumor drug, DE-310, is the slow release form of the camptothecin derivative DX-8951. We investigated a toxicological profile of meningoceles in SD rat fetuses, whose mothers received intravenous DE-310 at several doses, and the time course changes of histology. DE-310 induced a meningocele in the posterior fontanelle of live fetuses by the four-time administration of 0.3 mg/(kgday) or more during the organogenetic period, or by a single administration of 1.0 mg/kg, particularly, between days 7 and 13 of gestation with an incidence of 100%. The meningocele was caused by the principal ingredient DX-8951. The earliest histological change was focal congestion between the skin and cerebrum, followed by the formation of a space covered by thinned epidermis with necrosed basal cells, hemorrhage in the surrounding connective tissues, cerebrum and ventricles, cavitation of the cerebrum, and incomplete formation of the skull bones and subarachnoid space. DE-310 was characterized as preferentially inducing meningocele (meningoencephalocele in severe cases) in rat fetuses.
Kato
Michiyuki
M
Drug Safety Research Laboratory, Daiichi Pharmaceutical Co. Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134-8630, Japan. katomd36@daiichipharm.co.jp
Matsuhashi
Kunio
K
Shimomura
Kazuhiro
K
Shimada
Makoto
M
Hagiwara
Miyoko
M
Fujikawa
Katsuko
K
Furuhama
Kazuhisa
K
D000014:Abnormalities, Drug-Induced / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000633:toxicity*; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000633:toxicity; D002531:Cerebellum / Q000002:abnormalities*; D004677:Encephalocele / Q000139:chemically induced / Q000473:pathology*; D005260:Female; D005333:Fetus / Q000187:drug effects*; D005865:Gestational Age; D008431:Maternal-Fetal Exchange; D008588:Meningocele / Q000139:chemically induced / Q000473:pathology*; D009436:Neural Tube Defects / Q000139:chemically induced; D010012:Osteogenesis / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012886:Skull / Q000002:abnormalities*
D000970:Antineoplastic Agents; C452060:DE-310 cpd; D002166:Camptothecin