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Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties.
Cancer Res. 1999 Jun 15; 59(12):2939-43.CR

Abstract

Homocamptothecin (hCPT) is a semisynthetic analogue of camptothecin (CPT) with a seven-membered beta-hydroxylactone resulting from the insertion of a methylene spacer between the alcohol moiety and the carboxyl function of the naturally occurring six-membered alpha-hydroxylactone of CPT. This E-ring modification provides a less reactive lactone with enhanced stability and decreased protein binding in human plasma. Biological testing against CPT revealed that, instead of being detrimental, the modified lactone of hCPT has a positive impact on topoisomerase I (Topo I) poisoning properties. In vitro tests showed hCPT to fully conserve the ability to stabilize Topo I-DNA cleavage complexes and to stimulate a higher level of DNA cleavage than CPT. A similar trend toward improvement was also observed in antiproliferative assays with human tumor cell lines (including cells overexpressing P-glycoprotein). In two distinct in vivo models, using L1210 murine leukemia or human colon carcinoma HT29, hCPT was found to be more efficacious than CPT. The slow, but irreversible, hydrolysis of hCPT, instead of the fast equilibrium of CPT, may account for its good in vivo activity. Overall, these results provide evidence that a highly reactive lactone is not a requisite for the Topo I-mediated antitumor activity of CPT analogues, and that hCPT is an interesting pharmacological tool with improved solution behavior as well as a promising new template for the preparation of more efficacious Topo I poisons.

Authors+Show Affiliations

Institut Henri Beaufour, Les Ulis, France.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

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

Language

eng

PubMed ID

10383158

Citation

Lesueur-Ginot, L, et al. "Homocamptothecin, an E-ring Modified Camptothecin With Enhanced Lactone Stability, Retains Topoisomerase I-targeted Activity and Antitumor Properties." Cancer Research, vol. 59, no. 12, 1999, pp. 2939-43.
Lesueur-Ginot L, Demarquay D, Kiss R, et al. Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res. 1999;59(12):2939-43.
Lesueur-Ginot, L., Demarquay, D., Kiss, R., Kasprzyk, P. G., Dassonneville, L., Bailly, C., Camara, J., Lavergne, O., & Bigg, D. C. (1999). Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Research, 59(12), 2939-43.
Lesueur-Ginot L, et al. Homocamptothecin, an E-ring Modified Camptothecin With Enhanced Lactone Stability, Retains Topoisomerase I-targeted Activity and Antitumor Properties. Cancer Res. 1999 Jun 15;59(12):2939-43. PubMed PMID: 10383158.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. AU - Lesueur-Ginot,L, AU - Demarquay,D, AU - Kiss,R, AU - Kasprzyk,P G, AU - Dassonneville,L, AU - Bailly,C, AU - Camara,J, AU - Lavergne,O, AU - Bigg,D C, PY - 1999/6/26/pubmed PY - 1999/6/26/medline PY - 1999/6/26/entrez SP - 2939 EP - 43 JF - Cancer research JO - Cancer Res. VL - 59 IS - 12 N2 - Homocamptothecin (hCPT) is a semisynthetic analogue of camptothecin (CPT) with a seven-membered beta-hydroxylactone resulting from the insertion of a methylene spacer between the alcohol moiety and the carboxyl function of the naturally occurring six-membered alpha-hydroxylactone of CPT. This E-ring modification provides a less reactive lactone with enhanced stability and decreased protein binding in human plasma. Biological testing against CPT revealed that, instead of being detrimental, the modified lactone of hCPT has a positive impact on topoisomerase I (Topo I) poisoning properties. In vitro tests showed hCPT to fully conserve the ability to stabilize Topo I-DNA cleavage complexes and to stimulate a higher level of DNA cleavage than CPT. A similar trend toward improvement was also observed in antiproliferative assays with human tumor cell lines (including cells overexpressing P-glycoprotein). In two distinct in vivo models, using L1210 murine leukemia or human colon carcinoma HT29, hCPT was found to be more efficacious than CPT. The slow, but irreversible, hydrolysis of hCPT, instead of the fast equilibrium of CPT, may account for its good in vivo activity. Overall, these results provide evidence that a highly reactive lactone is not a requisite for the Topo I-mediated antitumor activity of CPT analogues, and that hCPT is an interesting pharmacological tool with improved solution behavior as well as a promising new template for the preparation of more efficacious Topo I poisons. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/10383158/Homocamptothecin_an_E_ring_modified_camptothecin_with_enhanced_lactone_stability_retains_topoisomerase_I_targeted_activity_and_antitumor_properties_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=10383158 DB - PRIME DP - Unbound Medicine ER -