Combined prenatal toxicity of 6-mercaptopurine riboside and hydroxyurea inmice

Hydroxyurea (HU) and 6-mercaptopurine riboside (6-MPr) are used as cytostat ic chemotherapeutics. Their teratogenic potential in experimental animals h as been well known for several decades. Generally, it is assumed that the t oxicity of both agents is due to an interference with enzymes of DNA synthe sis. In the case of 6-MPr, it was speculated that the teratogenicity in rod ents might be paralleled by or even correlated to an incorporation of 6-thi oguanine into the DNA of the embryos, in this study, the interaction betwee n these two compounds with regard to teratogenicity in NMRI mice was invest igated. Dose-response data of 6-MPr (s.c.-treatment) were published earlier . First, a dose-response study with HU alone (i.p.-treatment) was performed . From these data, the doses for the combination study were derived: HU 250 mg/kg (NOAEL dose) and 6-MPr 16 mg/kg (strongly teratogenic dose). In all experimental groups the substances were administered to the dams once on da y 11 of gestation. Combination effects were investigated applying various d osing regimens. In group I treatment was simultaneous, in group II HU was a dministered 2 h before 6-MPr, in group LU 2 h after 6-MPr. The differences in the overall frequency of gross structural abnormalities were moderate. H owever, when analysing the effects in more detail (single abnormalities), g roup III exhibited great differences: 1) 6-MPr co-treatment increased the f requency of HU effects (skull defects) and 2) HU co-treatment decreased the frequency of 6-MPr effects (limb defects) when compared to the findings of the dose-response studies. In addition, the influence of HU on the 6-MPr-i nduced DNA modification was determined by measuring the incorporation of 6- thioguanine into the DNA of day-ii embryos. As expected, the HU co-treatmen t corresponding to the group III dosing regimen of the teratogenicity exper iment decreased the incorporation rate by ca. 40%. This was in parallel to the decrease in the frequency of 6-MPr effects in the teratogenicity III gr oup. This finding may be considered as a further indication that in the cas e of 6-MPr, DNA modification is accompanying teratogenicity. Teratogenesis Carcinog. Mutagen. 19:223-232, 1999. (C) 1999 Wiley-Liss, Inc.