Enhancement of in vivo antitumor activity of a novel antimitotic 1-phenylpropenone derivative, AM-132, by tumor necrosis factor-alpha or interleukin-6

TK5048 and its derivatives, AM-132, AM-138, and AM-97, are recently develop ed antimitotic (AM) compounds. These 1-phenylpropenone derivatives induce c ell cycle arrest at the G2/M phase of the cell cycle. TK5048 inhibited tubu lin polymerization in human lung cancer PC-14 cells in a concentration-depe ndent manner. In a polymerization assay using bovine brain tubulin, AM-132 and AM-138 were quite strong, AM-97 was moderately strong, and TK5048 was a relatively weak inhibitor of tubulin polymerization. A murine leukemia cel l line resistant to a sulfonamide antimitotic agent, E7010, which binds to colchicine-binding sites on tubulin, was cross-resistant to the in vitro gr owth-inhibitory effect of AM compounds. Inhibition of tubulin polymerizatio n is therefore one of the mechanisms of action of these AM compounds agains t tumor cells. To profile the antitumor effect of AM compounds, the in vivo antitumor effect of AM-132 was evaluated against cytokine-secreting Lewis lung carcinoma (LLC). Tumor-bearing mice were treated with intravenous AM-1 32 using three different treatment schedules. LLC tumors expressing tumor n ecrosis factor-a (TNF-cc), granulocyte macrophage colony-stimulating factor (GM-CSF), or interleukin (IL)-6 were very sensitive to AM-132. In particul ar, LLC tumors expressing IL-6 were markedly reduced by AM-132 treatment, a nd showed coloring of the tumor surface and unusual hemorrhagic necrosis. T hese results suggest a combined effect of AM-132 and cytokines on the blood supply to tumors.