Camptothecin conjugated with DNA minor-groove binder netropsin: enhanced lactone stability, inhibition of human DNA topoisomerase I and antiproliferative activity.

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.

Materials And 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.

Conclusion: 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.