Relationship of temporal patterns of cell death and development to malformations in the rat limb. Possible mechanisms of teratogenesis with inhibitors of DNA synthesis

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Abstract
Cytosine arabinoside palmitate (ara‐CP) is a sustained‐action form of the DNA‐synthesis‐inhibitor cytosine arabinoside (ara‐C). When given at day 12 of rat gestation ara‐CP caused moderate but prolonged depression of DNA synthesis, killed embryonic cells after 2–3 days, and led to severe limb and other defects and extreme growth retardation. The results were compared with those obtained in earlier studies with hydroxyurea and with ara‐C, both of which also caused depression of DNA synthesis, cell death, and limb defects, but at different times in relation to treatment. There was a relation between the time of maximal cell death in the limbs after treatment and the specific limb malformations seen at day 20. The relation of cell death to teratogenesis seen with these chemical agents is similar to that previously reported for X irradiation.