IN-VIVO EFFICACY OF NOVEL SYNTHETIC ENEDIYNES-1

We have investigated the biodistribution, toxicity, and antitumor acti vity of a new type of synthetic compound containing an enediyne functi onal group capable of benzenoid diradical generation. The design of th is cytotoxic molecule was based on the structures of naturally occurri ng enediyne antibiotics. Compared to the natural compounds, the synthe tic enediyne displayed cytotoxicities approaching the natural analogs. Using a tritiated analog, biodistribution studies revealed relatively high uptake levels in kidney, lung, heart, and spleen with moderate l evels in all other organs. Antitumor activity was apparent, with signi ficant tumor regression observed in athymic nude mice with established M21 melanomas. Significant tumor antiproliferative effects were obser ved against L-1210 mouse leukemia, A549 lung carcinomas and PC3 prosta te carcinomas in athymic nude mice, and against EMT-6 mouse mammary ad enocarcinomas in Balb/cByJ mice. These results suggest that synthetic enediynes may be useful therapeutic compounds since their design reduc es systemic toxicity compared to the natural products, without comprom ising antitumor activity. The relatively low sensitivity of many estab lished cell lines to synthetic enediynes suggests a discrepancy betwee n cell culture and in vivo tumor cytotoxicities. Adaptation of some ce ll lines for in vivo proliferation may affect their sensitivity to syn thetic enediynes.