Tags

Type your tag names separated by a space and hit enter

Camptothecin conjugated with DNA minor-groove binder netropsin: enhanced lactone stability, inhibition of human DNA topoisomerase I and antiproliferative activity.
Anticancer Res. 2003 May-Jun; 23(3B):2609-15.AR

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.

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.

Authors+Show Affiliations

EA 3306 Interactions Moléculaires et Cellulaires en Cancérologie, IFR no. 53 Biomolécules, UFR de Pharmacie, 51100 Reims, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

12894548

Citation

Sukhanova, Alyona, et al. "Camptothecin Conjugated With DNA Minor-groove Binder Netropsin: Enhanced Lactone Stability, Inhibition of Human DNA Topoisomerase I and Antiproliferative Activity." Anticancer Research, vol. 23, no. 3B, 2003, pp. 2609-15.
Sukhanova A, Grokhovsky S, Zhuze A, et al. Camptothecin conjugated with DNA minor-groove binder netropsin: enhanced lactone stability, inhibition of human DNA topoisomerase I and antiproliferative activity. Anticancer Res. 2003;23(3B):2609-15.
Sukhanova, A., Grokhovsky, S., Zhuze, A., Devy, J., Pluot, M., Oleinikov, V., & Nabiev, I. (2003). Camptothecin conjugated with DNA minor-groove binder netropsin: enhanced lactone stability, inhibition of human DNA topoisomerase I and antiproliferative activity. Anticancer Research, 23(3B), 2609-15.
Sukhanova A, et al. Camptothecin Conjugated With DNA Minor-groove Binder Netropsin: Enhanced Lactone Stability, Inhibition of Human DNA Topoisomerase I and Antiproliferative Activity. Anticancer Res. 2003 May-Jun;23(3B):2609-15. PubMed PMID: 12894548.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Camptothecin conjugated with DNA minor-groove binder netropsin: enhanced lactone stability, inhibition of human DNA topoisomerase I and antiproliferative activity. AU - Sukhanova,Alyona, AU - Grokhovsky,Sergei, AU - Zhuze,Alexei, AU - Devy,Jerome, AU - Pluot,Michel, AU - Oleinikov,Vladimir, AU - Nabiev,Igor, PY - 2003/8/5/pubmed PY - 2003/8/29/medline PY - 2003/8/5/entrez SP - 2609 EP - 15 JF - Anticancer research JO - Anticancer Res. VL - 23 IS - 3B N2 - 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. SN - 0250-7005 UR - https://www.unboundmedicine.com/medline/citation/12894548/Camptothecin_conjugated_with_DNA_minor_groove_binder_netropsin:_enhanced_lactone_stability_inhibition_of_human_DNA_topoisomerase_I_and_antiproliferative_activity_ DB - PRIME DP - Unbound Medicine ER -