{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,11]],"date-time":"2026-03-11T15:08:04Z","timestamp":1773241684682,"version":"3.50.1"},"reference-count":32,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2005,5,17]],"date-time":"2005-05-17T00:00:00Z","timestamp":1116288000000},"content-version":"vor","delay-in-days":10212,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratology"],"published-print":{"date-parts":[[1977,6]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Many studies have been performed on the in vivo teratogenicity of cyclophosphamide, and there is uncertainty whether the parent compound or P\u2010450 generated alkylating metabolite(s) is the proximal teratogen(s). We have examined the influence of cyclophosphamide and a metabolite, 4\u2010ketocyclophosphamide, on mouse limb development. Pregnant mice were injected with 10, 15 or 20 mg\/kg of cyclophosphamide on days 9 to 11 of gestation. Hindlimb buds were maximally sensitive to 20 mg\/kg of cyclophosphamide at 9 A. M. on day 11, and the predominant malformations formed were preaxial ectrodactyly and hemimelia. Hindlimb buds of the same gestational age exposed to cyclophosphamide in vitro responded identically to controls in morphology and uptake of <jats:sup>3<\/jats:sup>H\u2010thymidine and <jats:sup>35<\/jats:sup>SO<jats:sub>4<\/jats:sub>. Exposure to 4\u2010ketocyclophosphamide in culture, however, resulted in the formation of limbs with a \u201chemimelic\u201d appearance and distal limb reduction, and with reduced uptake of 3H\u2010thymidine and <jats:sup>35<\/jats:sup>SO<jats:sub>4<\/jats:sub>. These findings support the position that the P\u2010450 generated metabolite (s), and not the parent compound, is the proximal teratogen(s).<\/jats:p>","DOI":"10.1002\/tera.1420150311","type":"journal-article","created":{"date-parts":[[2005,6,11]],"date-time":"2005-06-11T14:14:04Z","timestamp":1118499244000},"page":"291-299","source":"Crossref","is-referenced-by-count":39,"title":["Influence of cyclophosphamide and 4\u2010ketocyclophosphamide on mouse limb development"],"prefix":"10.1002","volume":"15","author":[{"given":"Jeanne M.","family":"Manson","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carl C.","family":"Smith","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,5,17]]},"reference":[{"issue":"4","key":"e_1_2_1_2_1","first-page":"477","article-title":"Aspects of the teratology of cyclophosphamide","volume":"60","author":"Ashby R.","year":"1976","journal-title":"Cancer Treatment Reports"},{"key":"e_1_2_1_3_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(72)90137-6"},{"key":"e_1_2_1_4_1","first-page":"1021","article-title":"Uber die Aktivierung von Cyclophosphamide in vivo und in vitro","volume":"13","author":"Brock N.","year":"1963","journal-title":"Arzneimittel\u2010Forschung"},{"key":"e_1_2_1_5_1","doi-asserted-by":"publisher","DOI":"10.1002\/1097-0142(1967)20:5<900::AID-CNCR2820200552>3.0.CO;2-Y"},{"key":"e_1_2_1_6_1","first-page":"206","article-title":"Enzymatic basis of cyclophosphamide activation by hepatic microsomes of the rat","volume":"174","author":"Cohen J. 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