title: Camptothecin conjugated with DNA minor-groove binder netropsin: enhanced lactone stability, inhibition of human DNA topoisomerase I and antiproliferative activity.
abstract: BACKGROUND
  The conjugates of camptothecin (CPT) with ligands possessing different DNA selectivity could be promising agents in cancer therapy affecting expression of specific genes by trapping DNA topoisomerase I (top I)-DNA complexes in a sequence-selective manner. Our recent data show that minor-groove binder netropsin (Nt) and its derivatives modulate the CPT-induced pattern of top I-mediated DNA cleavage. In an effort to develop a new molecule with good biological activity we have linked CPT with Nt and report here the first results of in vitro examination of the new compound.
  
  
  METHODS
  CPT-Nt conjugate linked with flexible spacer through position 7 of CPT chromophore was synthesized and analyzed for lactone stability, the ability to modulate a top I-mediated DNA cleavage and antiproliferative activity within a panel of six tumor cell lines.
  
  
  RESULTS
  CPT-Nt conjugate demonstrates enhanced lactone stability and concentration-dependent top I poisoning or suppression in vitro. The rate of conjugate hydrolysis in a water solution displays a 20-fold enhancement of stability compared with CPT. The cytotoxicity of the conjugate against acute promyelocytic leukaemia (HL60), chronic myelogenous leukaemia (K562), breast adenocarcinoma (MCF7), colorectal adenocarcinoma (HT29), lung carcinoma(A549) and ovarian adenocarcinoma (CaOV3) tumor cell lines was evaluated. The lowest IC50 value (0.08 microM) indicated its selective toxicity towards the ovarian adenocarcinoma cell line.
  
  
  CONCLUSIONS
  The enhanced stability of CPT-Nt conjugate and its selective toxicity against the CaOV3 cell line may indicate its utility as an antitumor agent against ovarian adenocarcinoma.
authors.affiliation: EA 3306 Interactions Moléculaires et Cellulaires en Cancérologie, IFR no. 53 Biomolécules, UFR de Pharmacie, 51100 Reims, France.
authors.forename: Alyona
authors.initials: A
authors.lastname: Sukhanova
authors.forename: Sergei
authors.initials: S
authors.lastname: Grokhovsky
authors.forename: Alexei
authors.initials: A
authors.lastname: Zhuze
authors.forename: Jerome
authors.initials: J
authors.lastname: Devy
authors.forename: Michel
authors.initials: M
authors.lastname: Pluot
authors.forename: Vladimir
authors.initials: V
authors.lastname: Oleinikov
authors.forename: Igor
authors.initials: I
authors.lastname: Nabiev
mesh_terms: D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology; D019073:HT29 Cells; D006801:Humans; D020014:K562 Cells; D007783:Lactones / Q000737:chemistry; D009429:Netropsin / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology; D059004:Topoisomerase I Inhibitors; D014407:Tumor Cells, Cultured
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D006131:Growth Inhibitors; D007783:Lactones; D059004:Topoisomerase I Inhibitors; D009429:Netropsin; D002166:Camptothecin