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Developmental toxicity of pentostatin (2'-deoxycoformycin) in rats and rabbits
1Department of Pathology and Experimental Toxicology, Parke-Davis Pharmaceutical Research Division, Warner-Lambert Company, Ann Arbor, Michigan 48105.
Insights
Pentostatin, an adenosine deaminase (ADA) inhibitor, caused developmental toxicity and teratogenicity in rats at maternally toxic doses. Rabbits experienced maternal toxicity and reproductive issues, but no significant fetal malformations were observed.
Area of Science:
- Toxicology
- Developmental Biology
- Pharmacology
Background:
- Adenosine deaminase (ADA) inhibitors, such as pentostatin, are used in treating certain cancers.
- Understanding the developmental toxicity of such potent drugs is crucial for risk assessment during pregnancy.
Purpose of the Study:
- To investigate the developmental toxicity and teratogenicity of pentostatin in pregnant rats and rabbits.
- To evaluate the effects of pentostatin on maternal and fetal parameters during organogenesis.
Main Methods:
- Pregnant rats and rabbits were administered daily intravenous doses of pentostatin during organogenesis.
- Maternal and fetal parameters, including malformations and variations, were assessed at term.
Main Results:
- In rats, pentostatin caused maternal toxicity, increased postimplantation loss, and fetal malformations (vertebral) and variations at the highest dose.
- In rabbits, pentostatin induced severe maternal toxicity and reproductive issues (abortion, premature delivery) but did not significantly affect fetal development or cause malformations.
Conclusions:
- Pentostatin exhibits developmental toxicity and teratogenicity in rats at maternally toxic doses.
- While pentostatin causes significant maternal and reproductive toxicity in rabbits, it does not appear to induce fetal malformations in this species.
Abstract:
The developmental toxicity of the potent adenosine deaminase (ADA) inhibitor, pentostatin (2'-deoxycoformycin), was investigated in pregnant rats and rabbits administered daily iv doses during organogenesis. Rats received 0, 0.01, 0.10, or 0.75 mg/kg on gestation days 6-15 and rabbits received 0, 0.005, 0.01, or 0.02 mg/kg on gestation days 6-18 and maternal and fetal parameters were evaluated on gestation day 21 (rats) or 30 (rabbits). Live fetuses were examined for external, visceral, and skeletal malformations and variations. In rats, maternal body weight gain and food consumption were significantly suppressed at doses of 0.10 and 0.75 mg/kg during the treatment period but returned to control levels during posttreatment. Increased postimplantation loss and decreased numbers of live fetuses, litter size, and fetal body weight were observed at 0.75 mg/kg. A statistically significant increase in the incidence of vertebral malformations occurred at 0.75 mg/kg. The incidence of certain skeletal variations (extra presacral vertebrae, extra ribs, hypoplastic vertebrae) was also increased at 0.75 mg/kg. Ossification of cervical centra was reduced at 0.75 mg/kg compared with controls. In rabbits, marked maternal toxicity (death, body weight loss, and decreased food consumption) and reproductive toxicity (abortion and premature delivery) occurred in all pentostatin-treated groups. However, there were no significant effects on number of live fetuses, pre- or postimplantation loss, litter size, or fetal body weights in the animals with live litters. There was also no apparent increase in the incidence of malformations or variations in the live fetuses of pentostatin-treated rabbits. Thus, these studies demonstrate developmental toxicity of pentostatin in rats and rabbits, and teratogenicity in rats, at maternally toxic doses.