Targeting topoisomerase I cleavage to specific sequences of DNA by triple helix-forming oligonucleotide conjugates. A comparison between a rebeccamycin derivative and camptothecin

Topoisomerase I is an ubiquitous DNA cleaving enzyme and an important thera peutic target in cancer chemotherapy for the camptothecins as well as for i ndolocarbazole antibiotics such as rebeccamycin and its synthetic derivativ es, which stabilize the cleaved DNA-topoisomerase I complex. The covalent l inkage of a triple helix-forming oligonucleotide to camptothecin or to the indolocarbazole derivative R-6 directs DNA cleavage by topoisomerase I to s pecific sequences. Sequence-specific recognition of DNA is achieved by the triple helix-forming oligonucleotide, which binds to the major groove of do uble-helical DNA and positions the drug at a specific site. The efficacy of topoisomerase I-induced DNA cleavage mediated by the rebeccamycin-conjugat e and the camptothecin-conjugate was compared and related to the intrinsic potency of the isolated drugs. (C) 1999 Academie des sciences/Editions scie ntifiques et medicales Elsevier SAS.