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Mechanism of Action of E7010, an Orally Active Sulfonamide Antitumor Agent: Inhibition of Mitosis by Binding to the Colchicine Site of Tubulin

Tsukuba Research Laboratories, Eisai Co. Ltd., 1-3 Tokodai 5-chome, Tsukuba-shi, Ibaraki 300-26, Japan

E7010 (N-[2-[(4-hydroxyphenyl)amino]-3pyridinyl]-4-methoxybenzenesulfonamide), an orally active sulfonamide antitumor agent that is currently in a Phase I clinical trial, showed rather consistent growth-inhibitory activities against a panel of 26 human tumor cell lines (IC₅₀ = 0.06–0.8 µg/ml), in contrast to vincristine (VCR; IC₅₀ = 0.0002–0.04 µg/ml), 5-fluorouracil (IC₅₀ = 0.2–30 µg/ml), Adriamycin (IC₅₀ = 0.002–0.7 µg/ml), mitomycin C (IC₅₀ = 0.007–3 µg/ml), 1-ß-D-arabinofuranoxylcytosine (IC₅₀ = 0.005 to >30 µg/ml), camptothecin (IC₅₀ = 0.002–0.4 µg/ml), and cisplatin (IC₅₀ = 0.5–20 µg/ml). It caused a dose-dependent increase in the percentage of mitotic cells in parallel with a decrease in cell proliferation, like VCR. It also showed a dose-dependent inhibition of tubulin polymerization, which correlated well with the cell growth-inhibitory activity. ¹⁴C-labeled E7010 bound to purified tubulin, and this binding was inhibited by colchicine but not by VCR. However, its binding properties were different from those of colchicine, as well as those of VCR. E7010 was active against two kinds of VCR-resistant P388 cell lines, one of which showed multidrug resistance due to the overexpression of P-glycoprotein (resistant to Taxol), and the other did not show multidrug resistance (sensitive to Taxol). Furthermore, four E7010-resistant P388 cell lines showed no cross-resistance to VCR, a different pattern of resistance to podophyllotoxin, and collateral sensitivity to Taxol. Therefore, E7010 is a novel tubulin-binding agent that has a wider antitumor spectrum than VCR and has different properties from those of VCR or Taxol.

¹ To whom requests for reprints should be addressed. Phone: 81-298-47-5749; Fax: 81-298-47-2037.

Received 3/ 4/97. Accepted 6/ 2/97.

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