{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,9,11]],"date-time":"2025-09-11T10:22:16Z","timestamp":1757586136224},"reference-count":33,"publisher":"Wiley","issue":"2","license":[{"start":{"date-parts":[[2005,5,19]],"date-time":"2005-05-19T00:00:00Z","timestamp":1116460800000},"content-version":"vor","delay-in-days":8814,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Teratology"],"published-print":{"date-parts":[[1981,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>A potent inhibitor of thymidylate synthetase, 5\u2013Fluorodeoyxyuridine (FUdR), produced dose\u2010 and stage\u2010dependent skeletal defects in embryos of mice injected during early development (10th\u201013th day). The dose of 25 mg\/kg was teratogenic producing few resorptions and little reduction in fetal weight. Hindlimbs were much more sensitive to the drug than were the forelimbs and showed dose\u2010dependent long bone reductions. Specific long bone reductions occurred after treatment on the 11th or 11.5 day and were accompanied by preaxial polydactyly; treatment on the 12th or 12.5 day produced high incidence of ectrodactyly but no long bone reductions. Limbs were insensitive on the 13th day of development and beyond. Limb buds in organ culture demonstrated a direct action of FUdR on undifferentiated mesenchymal cells, incurring what has been previously termed \u201cthymineless\u201d cell death. Dose\u2010dependent reduction of viable cell number led to a reduction in chondrogenic expression in vitro\u2013more so in the hindlimb than the forelimb. Similar occurrence of cell death was also noted after in utero exposure, and here, it was followed by a process of recovery. The recovery phase was characterized by the formation of a distal synchronized cell population derived from undamaged subridge cells leaving damaged cells at the proximal extent of the subridge zone. Limb segments maintained their temporal sequence of differentiation, and their regulatory capability was related to the time allotted for repopulation of the subridge zone. We propose that a faster growth during early development of the elements of the hindlimb versus analogous ones of the forelimb allows the former less time for regulation\u2013and hence, higher sensitivity to antiproliferative agents such as FUdR.<\/jats:p>","DOI":"10.1002\/tera.1420230209","type":"journal-article","created":{"date-parts":[[2005,6,11]],"date-time":"2005-06-11T14:37:52Z","timestamp":1118500672000},"page":"241-251","source":"Crossref","is-referenced-by-count":13,"title":["Limb development in mouse embryos. III. Cellular events underlying the determination of altered skeletal patterns following treatment with 5\u2032fluoro\u20102\u2013deoxyuridine"],"prefix":"10.1002","volume":"23","author":[{"given":"T. B.","family":"Knudsen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"D. M.","family":"Kochhar","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"311","published-online":{"date-parts":[[2005,5,19]]},"reference":[{"key":"e_1_2_1_2_1","first-page":"55","article-title":"Fluorodeoxyuridine\u2010induced malformations in mice","volume":"79","author":"Bro\u2010Rasmussen F.","year":"1971","journal-title":"Acta Path. Microbiol. Scand. Sec.\u2010A"},{"key":"e_1_2_1_3_1","first-page":"571","article-title":"The control of muscle and cartilage development in the chick limb: The role of differential vascularization","volume":"29","author":"Caplan A.","year":"1973","journal-title":"J. Embryol. Exp. Morphol."},{"key":"e_1_2_1_4_1","doi-asserted-by":"publisher","DOI":"10.1111\/j.1749-6632.1971.tb46984.x"},{"key":"e_1_2_1_5_1","first-page":"73","article-title":"Thymidylate synthetase\u2010a target enzyme in cancer chemotherapy","volume":"473","author":"Danenberg P. V.","year":"1977","journal-title":"Biochem. Biophys. Acta"},{"key":"e_1_2_1_6_1","first-page":"1","article-title":"The teratogenic effects of 5\u2013fluoro\u20102\u2013desoxyuridine (F.U.D.R.) on the Wistar rat fetus, with particular reference to cleft palate","volume":"126","author":"Ferguson M. W. J.","year":"1978","journal-title":"J. Anat."},{"key":"e_1_2_1_7_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420110102"},{"key":"e_1_2_1_8_1","doi-asserted-by":"crossref","first-page":"707","DOI":"10.1016\/S0015-0282(16)36784-X","article-title":"Biosynthesis of RNA and DNA in rabbit preimplantation blastocysts. Effects of 5\u2013halogenated deoxyuridine","volume":"19","author":"Fridhandler L.","year":"1968","journal-title":"Fertil. Steril."},{"key":"e_1_2_1_9_1","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)76419-9"},{"key":"e_1_2_1_10_1","first-page":"137A","article-title":"A formaldehyde\u2010glutaraldehyde fixative of high osmolarity for use in electron microscopy","volume":"27","author":"Karnovsky M. J.","year":"1965","journal-title":"J. Cell Biol."},{"key":"e_1_2_1_11_1","doi-asserted-by":"publisher","DOI":"10.1002\/path.1711050103"},{"key":"e_1_2_1_12_1","first-page":"87","volume-title":"Vertebrate Limb and Somite Morphogenesis","author":"Kieny M.","year":"1977"},{"key":"e_1_2_1_13_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420070310"},{"key":"e_1_2_1_14_1","first-page":"721","article-title":"Susceptible stages and abnormal morphogensis in the developing mouse limb, analyzed in organ culture after transplacental exposure to vitamin\u2010A (retinoic acid)","volume":"31","author":"Kochhar D. M.","year":"1974","journal-title":"J. Embryol. Exp. Morphol."},{"key":"e_1_2_1_15_1","first-page":"250","volume-title":"New Approaches to the Evaluation of Abnormal Embryonic Development","author":"Kochhar D. M.","year":"1975"},{"key":"e_1_2_1_16_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(77)90310-4"},{"key":"e_1_2_1_17_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420180111"},{"key":"e_1_2_1_18_1","doi-asserted-by":"publisher","DOI":"10.1016\/0041-008X(80)90252-5"},{"key":"e_1_2_1_19_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420170304"},{"key":"e_1_2_1_20_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420050111"},{"key":"e_1_2_1_21_1","first-page":"14","article-title":"Fluorinated pyrimidines. XXVI. Mammalian thymidylate synthetase: Its mechanism of action and inhibition by fluorinated nucleotides","volume":"1","author":"Reyes P.","year":"1965","journal-title":"Mol. Pharmacol."},{"key":"e_1_2_1_22_1","doi-asserted-by":"publisher","DOI":"10.2165\/00003088-197702060-00004"},{"key":"e_1_2_1_23_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420080211"},{"key":"e_1_2_1_24_1","doi-asserted-by":"publisher","DOI":"10.1002\/jez.1401080304"},{"key":"e_1_2_1_25_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420020204"},{"key":"e_1_2_1_26_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(71)90129-1"},{"key":"e_1_2_1_27_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(75)90245-6"},{"key":"e_1_2_1_28_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(71)90095-9"},{"key":"e_1_2_1_29_1","first-page":"105","volume-title":"Vertebrate Limb and Somite Morphogenesis","author":"Searls R. L.","year":"1977"},{"key":"e_1_2_1_30_1","doi-asserted-by":"publisher","DOI":"10.1002\/tera.1420040112"},{"key":"e_1_2_1_31_1","doi-asserted-by":"publisher","DOI":"10.1016\/0012-1606(73)90170-X"},{"key":"e_1_2_1_32_1","first-page":"24","article-title":"Cell density and cell division in the early morphogenesis of the chick wing","volume":"239","author":"Summerbell D.","year":"1972","journal-title":"Nature"},{"key":"e_1_2_1_33_1","volume-title":"The House Mouse","author":"Theiler K.","year":"1972"},{"key":"e_1_2_1_34_1","first-page":"175","article-title":"The effect of cell killing by X\u2010irradiation on pattern formation in the chick limb","volume":"50","author":"Wolpert L.","year":"1979","journal-title":"J. Embryol. Exp. Morphol."}],"container-title":["Teratology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Ftera.1420230209","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/tera.1420230209","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,11,12]],"date-time":"2023-11-12T09:21:59Z","timestamp":1699780919000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/tera.1420230209"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1981,4]]},"references-count":33,"journal-issue":{"issue":"2","published-print":{"date-parts":[[1981,4]]}},"alternative-id":["10.1002\/tera.1420230209"],"URL":"https:\/\/doi.org\/10.1002\/tera.1420230209","archive":["Portico"],"relation":{},"ISSN":["0040-3709","1096-9926"],"issn-type":[{"value":"0040-3709","type":"print"},{"value":"1096-9926","type":"electronic"}],"subject":[],"published":{"date-parts":[[1981,4]]}}}