[Telomeres and telomerase, new targets for anticancer chemotherapy].
Telomeres are composed of single-strand DNA rich in guanine which can adopt particular structures such as T-loop or G-quadruples, a four-strand DAN structure formed by guanine repeats. Telomeric single-strand DNA is the substrate of telomerase, an enzyme necessary for telomeric replication which is suppressed in most cancer cells and which participates in tumor genesis. The formation of a telomeric G-quadruplex blocks telomerase activity and offers an original strategy for new anti-cancer agents. Using an original approach combining rational screening and synthesis, several series of compounds have been identified which specifically bind to the telomeric quadruplex. These derivatives, called "G-quadruplex DNA ligands", are able to block telomeric replication in cancer cells and provoke replicative senescence and/or apoptosis after a few cell cycles. Our team is working on characterizing the cellular and molecular mechanisms of action of these ligands. Using mutant cell models resistant to these ligands or expressing a protein cuff covering the telomere in tumor lines, we have demonstrated that the telomere is the principal intracellular target of action of these compounds and the implicit existence of the G-quadruplex structure. In collaboration with academic and industrial partners, optimization of these ligands to develop pharmacologically active products should enable in vivo validation of a new therapeutic concept.
Laboratoire d'Onco-Pharmacologie, JE 2428, UFR de pharmacie, Université de Reims Champagne-Ardenne, 51, rue Cognacq-Jay, F 51096 Reims. jf.riou@univ-reims.fr
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Trentesaux
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D004273:DNA, Neoplasm / Q000187:drug effects / Q000235:genetics; D004354:Drug Screening Assays, Antitumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006801:Humans; D008024:Ligands; D009369:Neoplasms / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D019098:Telomerase / Q000037:antagonists & inhibitors*; D016615:Telomere / Q000187:drug effects / Q000648:ultrastructure*
D000970:Antineoplastic Agents; D004273:DNA, Neoplasm; D004791:Enzyme Inhibitors; D008024:Ligands; D019098:Telomerase