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Cardiovascular anomalies produced by nimustine hydrochloride in the rat fetus
1Department of Pediatric Cardiology, Heart Institute of Japan, Tokyo.
Abstract:
The cardiovascular teratogenicity of nimustine hydrochloride (ACNU) was studied in rat fetuses. This drug is a nitrosourea derivative anticancer agent and produces alkylation of DNA. Pregnant Donryu rats were treated with single doses of 10, 11 or 13 mg/kg of the teratogen at various stages during gestation. Examination of the hearts was performed by microdissection after sacrificing the animals on the 20th day of gestation. The highest frequency of cardiovascular anomalies was found in the groups treated on the 8th day of gestation, but there was no difference in the rates induced by the three dosages of ACNU administered. The most common cardiovascular anomalies observed were ventricular septal defect (76.8%) and double outlet right ventricle (10.3%). A considerable number of affected fetuses (37/263) showed complex cardiac anomalies with atrioventricular (AV) malalignment and other AV valve anomalies. These anomalies include: double inlet left ventricle, straddling AV valve, atresia or stenosis of the AV valve, and dysplastic AV valve. ACNU appears to be a useful teratogenic agent for inducing complexes of cardiac anomalies which include AV malalignment.
Insights
Nimustine hydrochloride (ACNU), a DNA-alkylating anticancer drug, causes cardiovascular defects in rat fetuses. The study found ACNU effectively induces complex cardiac anomalies, including atrioventricular malalignment.
Area of Science:
- Developmental toxicology
- Cardiovascular embryology
- Pharmacology
Background:
- Nimustine hydrochloride (ACNU) is a nitrosourea derivative anticancer agent known for DNA alkylation.
- Understanding the teratogenic potential of anticancer drugs is crucial for managing treatment during pregnancy.
Purpose of the Study:
- To investigate the cardiovascular teratogenicity of nimustine hydrochloride (ACNU) in rat fetuses.
- To determine the types and frequencies of cardiac anomalies induced by ACNU exposure during gestation.
Main Methods:
- Pregnant Donryu rats were administered single doses of ACNU (10, 11, or 13 mg/kg) at different gestational stages.
- Fetal hearts were examined by microdissection on day 20 of gestation.
- Cardiovascular anomalies were documented and categorized.
Main Results:
- The highest incidence of cardiovascular anomalies occurred when ACNU was administered on day 8 of gestation.
- Ventricular septal defect (76.8%) and double outlet right ventricle (10.3%) were the most frequent anomalies.
- Complex cardiac anomalies, including atrioventricular malalignment and valve abnormalities, were observed in a significant number of fetuses (37/263).
Conclusions:
- Nimustine hydrochloride (ACNU) is a potent teratogen capable of inducing a spectrum of cardiovascular anomalies in rat fetuses.
- ACNU is effective in generating complex cardiac malformations, particularly those involving atrioventricular alignment.
- The findings highlight the risks associated with ACNU exposure during critical periods of cardiac development.