Limb development in mouse embryos. III. Cellular events underlying the determination of altered skeletal patterns following treatment with 5′fluoro-2-deoxyuridine

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Abstract
A potent inhibitor of thymidylate synthetase, 5–Fluorodeoyxyuridine (FUdR), produced dose- and stage-dependent skeletal defects in embryos of mice injected during early development (10th-13th 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-dependent 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 “thymineless” cell death. Dose-dependent reduction of viable cell number led to a reduction in chondrogenic expression in vitro–more 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–and hence, higher sensitivity to antiproliferative agents such as FUdR.