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 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.
Arimondo
P B
PB
Laboratoire de biophysique, UMR 8646 CNRS-Muséum national d'histoire naturelle, Inserm U201, Paris, France.
Bailly
C
C
Boutorine
A
A
Sun
J S
JS
Garestier
T
T
Hélène
C
C
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents / Q000737:chemistry / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D001483:Base Sequence; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology*; D004264:DNA Topoisomerases, Type I / Q000378:metabolism*; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D009838:Oligodeoxyribonucleotides / Q000737:chemistry / Q000378:metabolism*; D013379:Substrate Specificity; D059004:Topoisomerase I Inhibitors
D000617:Aminoglycosides; D000900:Anti-Bacterial Agents; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D009838:Oligodeoxyribonucleotides; D059004:Topoisomerase I Inhibitors; C402784:indolocarbazole derivative R-6; D004264:DNA Topoisomerases, Type I; D002166:Camptothecin