Activation of Camptothecin Derivatives by Conjugation to Triple Helix-Forming Oligonucleotides

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• 作者：Paola B. Arimondo ; Gary S. Laco ; Craig J. Thomas ; Ludovic Halby ; Didier Pez ; Philippe Schmitt ; Alexandre Boutorine ; Thé ; rè ; se Garestier ; Yves Pommier ; Sidney M. Hecht ; Jian-Sheng Sun ; and
• 刊名：Biochemistry
• 出版年：2005
• 出版时间：March 22, 2005
• 年：2005
• 卷：44
• 期：11
• 页码：4171 - 4180
• 全文大小：402K
• 年卷期：v.44,no.11(March 22, 2005)
• ISSN：1520-4995

文摘

Topoisomerase I (topo I) is a ubiquitous DNA-cleaving enzyme and an important therapeutictarget in cancer chemotherapy. Camptothecins (CPTs) reversibly trap topo I in covalent complex withDNA but exhibit limited sequence preference. The utilization of conjugates such as triplex-formingoligonucleotides (TFOs) to target a medicinal agent (like CPT) to a specific genetic sequence and orientationwithin the DNA has been accomplished successfully. In this study, different attachment points of theTFO to CPT (including positions 7, 9, 10, and 12) were investigated and our findings confirmed andextended previous conclusions. Interestingly, the conjugates induced specific DNA cleavage by topo I atthe triplex site even when poorly active or inactive CPT derivatives were used. This suggests that thepositioning of the drug in the cleavage complex by the sequence-specific DNA ligand is able to stabilizethe 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 mutantsR364H and N722S that are resistant to camptothecin. The TFO-CPT conjugates are thus valuable toolsto study the interactions involved in the formation of the ternary complex and also to enlarge the familyof compounds that poison topo I. The fact that an inactive CPT analogue can act as a topo I poison whenappropriately coupled to a TFO provides a new perspective at the level of drug design.