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Activation of camptothecin derivatives by conjugation to triple helix-forming oligonucleotides.
- Source :
-
Biochemistry [Biochemistry] 2005 Mar 22; Vol. 44 (11), pp. 4171-80. - Publication Year :
- 2005
-
Abstract
- Topoisomerase I (topo I) is a ubiquitous DNA-cleaving enzyme and an important therapeutic target in cancer chemotherapy. Camptothecins (CPTs) reversibly trap topo I in covalent complex with DNA but exhibit limited sequence preference. The utilization of conjugates such as triplex-forming oligonucleotides (TFOs) to target a medicinal agent (like CPT) to a specific genetic sequence and orientation within the DNA has been accomplished successfully. In this study, different attachment points of the TFO to CPT (including positions 7, 9, 10, and 12) were investigated and our findings confirmed and extended previous conclusions. Interestingly, the conjugates induced specific DNA cleavage by topo I at the triplex site even when poorly active or inactive CPT derivatives were used. This suggests that the positioning of the drug in the cleavage complex by the sequence-specific DNA ligand is able to stabilize the ternary complex, even when important interactions between topo I and CPT are disrupted. Finally, certain TFO-CPT conjugates were able to induce sequence-specific DNA cleavage with the topo I mutants R364H and N722S that are resistant to camptothecin. The TFO-CPT conjugates are thus valuable tools to study the interactions involved in the formation of the ternary complex and also to enlarge the family of compounds that poison topo I. The fact that an inactive CPT analogue can act as a topo I poison when appropriately coupled to a TFO provides a new perspective at the level of drug design.
- Subjects :
- Amino Acid Substitution genetics
Base Sequence
DNA Damage
DNA Topoisomerases, Type I chemistry
DNA Topoisomerases, Type I genetics
DNA Topoisomerases, Type I toxicity
Enzyme Activation
Enzyme Stability genetics
Humans
Molecular Sequence Data
Nucleic Acid Heteroduplexes metabolism
Oligonucleotides metabolism
Point Mutation
Structure-Activity Relationship
Camptothecin analogs & derivatives
Camptothecin chemical synthesis
Camptothecin metabolism
Nucleic Acid Conformation
Nucleic Acid Heteroduplexes chemical synthesis
Oligonucleotides chemical synthesis
Subjects
Details
- Language :
- English
- ISSN :
- 0006-2960
- Volume :
- 44
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Biochemistry
- Publication Type :
- Academic Journal
- Accession number :
- 15766244
- Full Text :
- https://doi.org/10.1021/bi048031k