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

C R Acad Sci III. 1999 Sep;322(9):785-90. doi: 10.1016/s0764-4469(00)80037-2.

Abstract

Topoisomerase I is an ubiquitous DNA cleaving enzyme and an important therapeutic target in cancer chemotherapy for the camptothecins as well as for indolocarbazole antibiotics such as rebeccamycin and its synthetic derivatives, which stabilize the cleaved DNA-topoisomerase I complex. The covalent linkage of a triple helixforming oligonucleotide to camptothecin or to the indolocarbazole derivative R-6 directs DNA cleavage by topoisomerase I to specific sequences. Sequence-specific recognition of DNA is achieved by the triple helix-forming oligonucleotide, which binds to the major groove of double-helical DNA and positions the drug at a specific site. The efficacy of topoisomerase I-induced DNA cleavage mediated by the rebeccamycin-conjugate and the camptothecin-conjugate was compared and related to the intrinsic potency of the isolated drugs.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aminoglycosides*
  • Anti-Bacterial Agents / chemistry
  • Anti-Bacterial Agents / pharmacology*
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / pharmacology*
  • Base Sequence
  • Camptothecin / chemistry
  • Camptothecin / pharmacology*
  • DNA Topoisomerases, Type I / metabolism*
  • Drug Design
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Molecular Sequence Data
  • Nucleic Acid Conformation*
  • Oligodeoxyribonucleotides / chemistry
  • Oligodeoxyribonucleotides / metabolism*
  • Substrate Specificity
  • Topoisomerase I Inhibitors

Substances

  • Aminoglycosides
  • Anti-Bacterial Agents
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Oligodeoxyribonucleotides
  • Topoisomerase I Inhibitors
  • indolocarbazole derivative R-6
  • DNA Topoisomerases, Type I
  • Camptothecin