RT Journal Article
SR Electronic
T1 BN80927
JF Cancer Research
JO Cancer Res
FD American Association for Cancer Research
SP 4942
OP 4949
DO 10.1158/0008-5472.CAN-03-3872
VO 64
IS 14
A1 Demarquay, Danièle
A1 Huchet, Marion
A1 Coulomb, Helène
A1 Lesueur-Ginot, Laurence
A1 Lavergne, Olivier
A1 Camara, José
A1 Kasprzyk, Philip G.
A1 Prévost, Grégoire
A1 Bigg, Dennis C. H.
YR 2004
UL http://cancerres.aacrjournals.org/content/64/14/4942.abstract
AB 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 β-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 (G0-G1 synchronized). In cell growth assays, BN80927 is a very potent antiproliferative agent as shown by IC50 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. ©2004 American Association for Cancer Research.