Interference of transcriptional activation by the antineoplastic drug ecteinascidin-743

Ecteinascidin-743 (ET-743) is a tetrahydroisoquinoline alkaloid isolated fr om the tunicate Ecteinascidia turbinata currently under phase II clinical t rials for its potent anticancer activity. ET-743 binds DNA in the minor gro ove and forms covalent adducts with some sequence specificity. It selective ly inhibits in vitro binding of the CCAAT box factor NF-Y, In this study, w e assayed ET-743 function in vivo on the HSP70 promoter. On heat induction, the drug blocks transcription rapidly at pharmacological concentrations an d in a CCAAT-dependent manner, whereas the activity of the CCAAT-less simia n virus 40 promoter is not affected. The effect is exerted at the mRNA leve l. The distamycin-like alkylating tallimustine is inactive in these assays. Binding of NF-Y and of the heat-shock factor is normal in ET-743-treated c ells. Run-on analysis of several endogenous genes further proves that the d rug has rapid, profound, and selective negative effects on transcription. T hus, this marine-derived compound is a promoter-specific, transcription-int erfering agent.