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The Effects of Hydroxyurea and Related Compounds on the Rat Fetus¹

Division of Clinical Chemotherapy, Sloan-Kettering Institute for Cancer Research, New York, New York

Hydroxyurea given in single i.p. doses to the pregnant rat from the 9th through the 12th day of gestation produced malformations in fetuses at 21 days at doses approximately - 1/10 of those lethal to the adult rat. These malformations included severe and characteristic injury to the fetal brain (exencephaly and encephalocele), palate and lip (cleft), appendages (clubbed and retarded), paws (ectro- and polydactyl), and tail (short and kinked). The highest incidence of head abnormalities occurred in fetuses treated on the 9th and the 12th day; only minor tail deformities were observed on the 10th day. The effects of hydroxyurea over the 4-day period appear to be cumulative and vary with the total dose and not with the multiple doses used at each injection day, the total number of injections given, or the specific days included in the injection schedule. There was similarity in the range of abnormalities between fetuses from the single and multiple dose treatment experiments, but the individual abnormalities in specimens from the 24-hr multiple dose treatment experiments were more severe.

Hydroxyurethan and acetohydroxamic acid were also teratogenic to the rat fetus from the 9th through the 12th day of gestation and produced a range of abnormalities similar to hydroxyurea at biologically comparable doses. Fetuses were about 7 times more sensitive to the lethal effects of acetohydroxamic acid and hydroxyurea than the maternal host; hydroxyurethan was equally lethal in both.

Hydroxylamine and urethan did not produce fetal abnormalities even at doses causing some maternal deaths.

The similarity in the spectra of abnormalities produced by hydroxyurea, hydroxyurethan, and acetohydroxamic acid at biologically comparable doses suggest that these compounds may have a common mechanism of action.

¹ This research was supported in part by grants from the American Cancer Society, Inc. (T-40), the Albert and Mary Lasker Foundation, and the NIH (CA 03192-08 CY).

Received 3/18/65. Revised 1/ 5/66.