Enhancement of in vivo Antitumor Activity of a Novel Antimitotic 1‐Phenylpropenone Derivative, AM‐132, by Tumor Necrosis Factor‐cc or Interleukin‐6

Abstract

TK5048 and its derivatives, AM-132, AM-138, and AM-97, are recently developed antimitotic (AM) compounds. These 1-phenylpropenone derivatives induce cell cycle arrest at the G2/M phase of the cell cycle. TK5048 inhibited tubulin polymerization in human lung cancer PC-14 cells in a concentration-dependent 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 cell line resistant to a sulfonamide antimitotic agent, E7010, which binds to colchicine-binding sites on tubulin, was cross-resistant to the in vitro growth-inhibitory effect of AM compounds. Inhibition of tubulin polymerization is therefore one of the mechanisms of action of these AM compounds against 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-132 using three different treatment schedules. LLC tumors expressing tumor necrosis factor-α α α α (TNF-α α α α), granulocyte macrophage colony-stimulating factor (GM-CSF), or interleukin (IL)-6 were very sensitive to AM-132. In particular, LLC tumors expressing IL-6 were markedly reduced by AM-132 treatment, and showed coloring of the tumor surface and unusual hemorrhagic necrosis. These results suggest a combined effect of AM-132 and cytokines on the blood supply to tumors.Key words: Antimitotic -Tubulin -Cytokine -TNF-α -IL-6The antimitotic (AM) agents are among the most widely used drugs in chemotherapy. Both vinca alkaloids and taxanes have specific binding sites on β-tubulin.1, 2) In addition, the colchicine-binding site on β-tubulin is of increasing interest because several agents that act at this site have been developed, including the podophylotoxins. However, none of these compounds that bind to the colchicine-binding site has proved to be a potent antitumor agent in clinical use. Etoposide and its derivatives are major antitumor podophylotoxins, but their mechanism of action has been demonstrated to be the inhibition of DNA topoisomerase II.3) E7010, developed by Eisai Co., Ltd. (Tokyo), is a colchicine-binding type AM agent for which clinical phase I trials are now underway.4) AM compounds are 1-phenylpropenone derivatives that were developed by Kyowa Hakko Kogyo Co. (Tokyo) and these compounds show potent antitumor activity in vivo (unpublished data). Here we report the cytotoxicity profile against human cancer cells and the mechanisms of action of these agents.Tumors often secrete cytokines, and this can influence the performance status, survival, and tumor response of a patient.5-12) Small cell lung cancers frequently secrete several growth factors and cytokines, which can cause paraneoplastic syndromes.13-15) Some cytokines such as tumor necrosis factor (TNF)-α, and interleukin (IL)-2 have antitumor actions, but the effects are relatively weak and do not generally inf...