Cisplatin is widely used as an
antitumor drug. To reduce its toxic side effects in patients,
cisplatin has been bound with
procaine in a
cisplatin-procaine complex (DPR). The lethal and teratogenic effects of
cisplatin alone and of complexed
cisplatin were determined in the chick embryo in ovo in order to compare their influence on rapidly proliferating embryonic tissues. The embryotoxic (lethal + teratogenic) effect was examined after a single intra-amniotic injection of one of six different doses, ranging from 0.03 to 30.0 microg, on embryonic days (ED) 3, 4 or 5. The minimal embryotoxic dose was lower for
cisplatin alone (0.03-0.3 microg) than for
cisplatin in the
DPR complex (0.3-3.0 microg), suggesting that
cisplatin alone is more embryotoxic than complexed
cisplatin. Both substances caused malformations in the surviving embryos evaluated on ED 9. These malformations included
microphthalmia,
microcephaly, hypoplasia of the upper and lower jaw, cleft beak, and haemocephaly. Moreover, heart septum defects and limb reduction
deformities were found after exposure to the
DPR complex. The embryotoxicity of complexed
cisplatin exhibited a stage-response effect. It was highest on day 3 and gradually decreased until ED 5. Such an apparent stage-response effect was not observed for
cisplatin alone. The embryotoxicity of
procaine hydrochloride - a component of the complex - was also tested.
Procaine hydrochloride alone did not produce any embryotoxic effect, not even after a single injection of the maximal tested dose (100.0 microg per embryo). We also examined the protective effect of
procaine hydrochloride, whose separate administration at ED 4 was followed by the injection of 0.3 microg
cisplatin. We did not observe any protective effect of
procaine hydrochloride if injected separately.