D-24851, a novel synthetic microtubule inhibitor, exerts curative antitumoral activity in vivo, shows efficacy toward multidrug-resistant tumor cells, and lacks neurotoxicity.

Abstract

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.

• Authors: G Bacher, B Nickel, P Emig, U Vanhoefer, S Seeber, A Shandra, T Klenner, T Beckers
• Journal: Cancer research (Cancer Res) Vol. 61 Issue 1 Pg. 392-9 (Jan 01 2001) ISSN: 0008-5472 [Print] United States
• PMID: 11196193 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ATP Binding Cassette Transporter, Subfamily B, Member 1
• ATP-Binding Cassette Transporters
• Acetamides
• Antineoplastic Agents
• Indoles
• Multidrug Resistance-Associated Proteins
• Tubulin
• Vincristine
• indibulin
• Colchicine

Topics

• ATP Binding Cassette Transporter, Subfamily B, Member 1 (metabolism)
• ATP-Binding Cassette Transporters (metabolism)
• Acetamides (metabolism, pharmacology, toxicity)
• Animals
• Antineoplastic Agents (metabolism, pharmacology, toxicity)
• Binding Sites
• Binding, Competitive
• Cell Cycle (drug effects)
• Cell Division (drug effects)
• Colchicine (metabolism)
• Drug Resistance, Multiple
• Drug Resistance, Neoplasm
• Female
• Humans
• Indoles (metabolism, pharmacology, toxicity)
• Microtubules (drug effects)
• Motor Activity (drug effects)
• Multidrug Resistance-Associated Proteins
• Nervous System Diseases (chemically induced)
• Neural Conduction (drug effects)
• Rats
• Rats, Sprague-Dawley
• Rats, Wistar
• Sarcoma, Yoshida (drug therapy)
• Tubulin (metabolism)
• Tumor Cells, Cultured (drug effects)
• Vincristine (metabolism)