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Teratogenic Effects of 5-Chlorodeoxyuridine on the Rat Fetus: Protection by Physiological Pyrimidines^*

( Embryology Section, Division of Experimental Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, New York)

Pregnant Wistar rats received single intraperitoneal injections of 5-chlorodeoxyuridine (ClUdR) on the 12th day of gestation. They were sacrificed on the 21st day and the fetuses examined for gross malformations. For study of skeletal malformations, specimens were fixed in 95 per cent ethanol, cleared and stained in alizarin red, and examined in 100 per cent glycerine. Single doses of 125, 250, 500, and 1000 mg/kg of ClUdR, which did not cause an excessive number of fetal resorptions, produced malformations such as clubbed appendages, poly- and ectrodactylous fore and rear paws, encephaly, cleft palate, and retarded kinky tail in 27, 78, 91, and 100 per cent of the survivors at each of these doses, respectively.

In experiments in which pregnant rats received 500 mg/kg of ClUdR and varying amounts of TdR simultaneously, doses of TdR below 125 mg/kg did not protect against the teratogenic action of ClUdR; but at 250 mg/kg or more of TdR complete protection occurred. In other experiments equal amounts (500 mg/kg) of the two compounds were given separately at time intervals ranging from 15 to 240 minutes. In the group of animals which received the ClUdR after TdR, complete protection occurred up to 30 minutes and partial protection thereafter. Resulting abnormalities were confined exclusively to the rear feet. When ClUdR was given prior to TdR, only 50 per cent of the surviving embryos were normal at 15 minutes (partial protection) and none at 90 minutes.

It is adduced that decline in protective activity of TdR is presumably proportional to the rate of incorporation of ClUdR into the replicating DNA in place of TdR and its rapid degradation in embryonic tissue.

^* This Research was supported in part by grants from the American Cancer Society, Inc. (T-40), the Albert and Mary Lasker Foundation, and grants from the National Institutes of Health (CA 03192-08 CY).

Received 7/ 2/64.