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BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo.
Cancer Res. 2004 Jul 15; 64(14):4942-9.CR

Abstract

BN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered beta-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G(0)-G(1) synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC(50) values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927.

Authors+Show Affiliations

Institut Henri Beaufour, 5 avenue du Canada, F-91966 Les Ulis, France. daniele.demarquay@ipsen.comNo 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)

Journal Article

Language

eng

PubMed ID

15256467

Citation

Demarquay, Danièle, et al. "BN80927: a Novel Homocamptothecin That Inhibits Proliferation of Human Tumor Cells in Vitro and in Vivo." Cancer Research, vol. 64, no. 14, 2004, pp. 4942-9.
Demarquay D, Huchet M, Coulomb H, et al. BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo. Cancer Res. 2004;64(14):4942-9.
Demarquay, D., Huchet, M., Coulomb, H., Lesueur-Ginot, L., Lavergne, O., Camara, J., Kasprzyk, P. G., Prévost, G., & Bigg, D. C. (2004). BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo. Cancer Research, 64(14), 4942-9.
Demarquay D, et al. BN80927: a Novel Homocamptothecin That Inhibits Proliferation of Human Tumor Cells in Vitro and in Vivo. Cancer Res. 2004 Jul 15;64(14):4942-9. PubMed PMID: 15256467.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo. AU - Demarquay,Danièle, AU - Huchet,Marion, AU - Coulomb,Helène, AU - Lesueur-Ginot,Laurence, AU - Lavergne,Olivier, AU - Camara,José, AU - Kasprzyk,Philip G, AU - Prévost,Grégoire, AU - Bigg,Dennis C H, PY - 2004/7/17/pubmed PY - 2004/9/10/medline PY - 2004/7/17/entrez SP - 4942 EP - 9 JF - Cancer research JO - Cancer Res VL - 64 IS - 14 N2 - BN80927 belongs to a novel family of camptothecin analogs, the homocamptothecins, developed on the concept of topoisomerase I (Topo I) inhibition and characterized by a stable seven-membered beta-hydroxylactone ring. Preclinical data reported here show that BN80927 retains Topo I poisoning activity in cell-free assay (DNA relaxation) as well as in living cells, in which in vivo complexes of topoisomerase experiments and quantification of DNA-protein-complexes stabilization, have confirmed the higher potency of BN80927 as compared with the Topo I inhibitor SN38. In addition, BN80927 inhibits Topo II-mediated DNA relaxation in vitro but without cleavable-complex stabilization, thus indicating catalytic inhibition. Moreover, a Topo I-altered cell line (KBSTP2), resistant to SN38, remains sensitive to BN80927, suggesting that a part of the antiproliferative effects of BN80927 are mediated by a Topo I-independent pathway. This hypothesis is also supported by in vitro data showing an antiproliferative activity of BN80927 on a model of resistance related to the noncycling state of cells (G(0)-G(1) synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC(50) values consistently lower than those of SN38 in tumor cell lines as well as in their related drug-resistant lines. BN80927 shows high efficiency in vivo in tumor xenograft studies using human androgen-independent prostate tumors PC3 and DU145. Altogether, these data strongly support the clinical development of BN80927. SN - 0008-5472 UR - https://www.unboundmedicine.com/medline/citation/15256467/BN80927:_a_novel_homocamptothecin_that_inhibits_proliferation_of_human_tumor_cells_in_vitro_and_in_vivo_ L2 - http://cancerres.aacrjournals.org/cgi/pmidlookup?view=long&pmid=15256467 DB - PRIME DP - Unbound Medicine ER -