Potentiating effect of caffeine on embryotoxicity of cyclophosphamide treatment in vivo during the preimplantation period.

Since it is unknown if chemicals which are generally safe in pregnancy can potentiate the embryotoxicity of cytotoxic drugs before implantation, the combined effects of cyclophosphamide (CPA) and caffeine (CF) were studied in the mouse (day 2) with CPA at 20 mg/kg, which induces a 18% resorption rate, and CF at 100 mg/kg, which does not increase embryolethality. The embryotoxicity of CPA did not increase when CF was either given 6 h before or simultaneously with CPA on day 2. However, when CF was given 6 h after CPA, a potentiated increase of embryolethality was observed at term and of structural chromosomal aberrations in embryos even before implantation, while sister chromatid exchange (SCE) frequency was less increased than after single CPA treatment. The results demonstrate the importance of pharmacokinetics in pregnancy even before implantation. Furthermore, since SCE may not only indicate DNA damage but also repair, the reduced SCE rate and the increase in structural chromosome aberrations suggest that CF can inhibit the repair of CPA-induced DNA damage in preimplantation embryos. Finally, for the first time the data are providing evidence that CF at subthreshold doses can potentiate the embryotoxicity of an alkylating agent in vivo even before implantation.