D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicity.
N-(pyridin-4-yl)-[1-(4-chlorbenzyl)-indol-3-yl]-glyoxyl-amid (D-24851) is a novel synthetic compound that was identified in a cell-based screening assay to discover cytotoxic drugs. D-24851 destabilizes microtubules and blocks cell cycle transition specifically at G2-M phase. The binding site of D-24851 does not overlap with the tubulin binding sites of known microtubule-destabilizing agents like vincristine or colchicine. In vitro, D-24851 has potent cytotoxic activity toward a panel of established human tumor cell lines including SKOV3 ovarian cancer, U87 glioblastoma, and ASPC-1 pancreatic cancer cells. In vivo, oral D-24851 treatment induced complete tumor regressions (cures) in rats bearing Yoshida AH13 sarcomas. Of importance is that the administration of curative doses of D-24851 to the animals revealed no systemic toxicity in terms of body weight loss and neurotoxicity in contrast to the administration of paclitaxel or vincristine. Interestingly, multidrug-resistant cell lines generated by vincristine-driven selection or transfection with the Mr 170,000 P-glycoprotein encoding cDNA were rendered resistant toward paclitaxel, vincristine, or doxorubicin but not towards D-24851 when compared with the parental cells. Because of its synthetic nature, its oral applicability, its potent in vitro and in vivo antitumoral activity, its efficacy against multidrug-resistant tumors, and the lack of neurotoxicity, D-24851 may have significant potential for the treatment of various malignancies.
Bacher
G
G
ASTA Medica AG, Department of Cancer Research, Frankfurt am Main, Germany.
Nickel
B
B
Emig
P
P
Vanhoefer
U
U
Seeber
S
S
Shandra
A
A
Klenner
T
T
Beckers
T
T
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000081:Acetamides / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D001665:Binding Sites; D001667:Binding, Competitive; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003078:Colchicine / Q000378:metabolism; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm; D005260:Female; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology* / Q000633:toxicity; D008870:Microtubules / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D009422:Nervous System Diseases / Q000139:chemically induced; D009431:Neural Conduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012517:Sarcoma, Yoshida / Q000188:drug therapy; D014404:Tubulin / Q000378:metabolism; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014750:Vincristine / Q000378:metabolism
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D018528:ATP-Binding Cassette Transporters; D000081:Acetamides; D000970:Antineoplastic Agents; D003078:Colchicine; D007211:Indoles; D027425:ATP-Binding Cassette, Sub-Family C Proteins; D014404:Tubulin; D014750:Vincristine; C419187:indibulin