BN80927: a novel homocamptothecin that inhibits proliferation of human tumor cells in vitro and in vivo.
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.
Demarquay
Danièle
D
Institut Henri Beaufour, 5 avenue du Canada, F-91966 Les Ulis, France. daniele.demarquay@ipsen.com
Huchet
Marion
M
Coulomb
Helène
H
Lesueur-Ginot
Laurence
L
Lavergne
Olivier
O
Camara
José
J
Kasprzyk
Philip G
PG
Prévost
Grégoire
G
Bigg
Dennis C H
DC
D000230:Adenocarcinoma / Q000097:blood / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002166:Camptothecin / Q000031:analogs & derivatives* / Q000097:blood / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D004264:DNA Topoisomerases, Type I / Q000378:metabolism; D004250:DNA Topoisomerases, Type II / Q000378:metabolism; D004278:DNA, Superhelical / Q000187:drug effects / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D004355:Drug Stability; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D020014:K562 Cells; D008297:Male; D051379:Mice; D008819:Mice, Nude; D009376:Neoplasms, Hormone-Dependent / Q000188:drug therapy / Q000473:pathology; D011471:Prostatic Neoplasms / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; C121907:BN 80927; D004278:DNA, Superhelical; D004791:Enzyme Inhibitors; D059004:Topoisomerase I Inhibitors; D059005:Topoisomerase II Inhibitors; D004264:DNA Topoisomerases, Type I; D004250:DNA Topoisomerases, Type II; D002166:Camptothecin