CELL-SPECIFIC REGULATION OF APOPTOSIS BY DESIGNED ENEDIYNES

The naturally occurring enediyne antibiotics are a unique class of ant itumor drugs that combine reactive enediynes with additional structura l features conferring affinity for DNA. Dynemicin A, in which an enedi yne core is attached to an anthraquinone group capable of DNA intercal ation, readily cleaves double-stranded DNA. This activity is thought t o be the basis of its potent antitumor cytotoxicity. To investigate ce ll-specific mechanisms of cytotoxicity in the absence of DNA affinity, we have synthesized a variety of dynemicin-like enediynes that lack t he anthraquinone moiety. We have found that the cytotoxicity of these compounds is dependent on their chemical instability and their enantio meric form. Their selective toxicity results from a potent induction o f apoptosis primarily in human leukemic cells. A group of synthetic en ediynes were designed to be highly stable. These compounds were found to inhibit apoptotic cell death. This inhibition was observed in compe tition with the chemically unstable enediynes, including dynemicin and calicheamicin. The stable synthetic enediynes could also block the ap optotic morphology induced by unrelated cytotoxic agents such as cyclo heximide, actinomycin D, and ultraviolet radiation. The results sugges t that the cellular target(s) of synthetic enediynes may play a centra l role in regulating programmed cell death; a specific receptor-ligand interaction is proposed.