The embryotoxicity of adriamycin in rat embryos in vitro

Adriamycin (ADR) is a widely used and highly valued antineoplastic agent but chronic treatment is limited by cardiotoxicity. To investigate its embryotoxic potential, cultured rat embryos were exposed to ADR at concentrations ranging from 0.4 to 1.2 microM. Within this range, ADR elicited decreases in growth parameters (somite numbers, embryonic length, and protein and DNA content), malformations involving the prosencephalic region, and embryolethality at the higher concentrations. Embryotoxicity was significantly increased (p less than 0.05) when cultures included cofactors for cytochrome P-450-dependent biotransformation and a hepatic microsomal preparation (S-9) prepared from animals pretreated with 3-methylcholanthrene or a mixture of polychlorinated biphenyls (Aroclor 1254). When S-9 from control animals or from rats pretreated with phenobarbital was used, significant increases in ADR-elicited embryotoxicity were not observed. Substitution of NADH for NADPH as a cofactor reduced the incidence of malformations from 100 to 60% at ADR concentrations of 0.5 microM. Increasing O2 concentrations partially counteracted the embryotoxic effects of ADR. Several other agents [including various antioxidants, compounds bearing free sulfhydryl groups, coenzyme Q10, and superoxide dismutase (with or without catalase)] that prevent or reduce the cardiotoxicity of ADR without impairing its antineoplastic properties, failed to modify the embryotoxicity significantly. This suggested that the embryopathic and antineoplastic properties of ADR may share a common mechanism which is distinct from that responsible for cardiotoxicity.