Multiform Combination Effects of Smooth Muscle Relaxants with Antitumor Agents in Rat Ascites Hepatoma AH66 Cells
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概要
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At non-cytotoxic concentrations, actions of smooth muscle relaxants except for the action of isoproterenol (IPN) on the effect of vinblastine (VBL) and mitomycin C (MMC) in rat ascites hepatoma AH66 cells resistant to these antitumor agents clearly separated into two groups. I PN hardly influenced the effects of both VBL and MMC. Although verapamil, a calcium-antagonist, and W-7, a calmodulin inhibitor, enhanced the growth-inhibitory effect and uptake of VBL by inhibiting the VBL efflux, these drugs did not influence the effect and uptake of MMC. In contrast, forskolin, an adenylate cyclase activator, db-cAMP, a cAMP analog, and theophylline, a cyclic nucleotide phosphodiesterase inhibitor, potentiated the effect of MMC, but did not influence the effect of VBL. The combination effect of forskolin and db-cAMP might be elucidated from the increase of inward transport of MMC through the action of the intracellular cAMP elevated by these drugs. Theophylline, however, only slightly increased both intracellular cAMP level and MMC uptake into the cells, similar to the action of IPN. We thought that the combination effect of theophylline was effected through its other activity of repair inhibition against AH66 cells, which are resistant to MMC due to their high capacity to repair impaired DNA. Thus, the smooth muscle relaxants used in this study enhanced the growth-inhibitory effect of a distinct antitumor agent through their individual activity against tumor cells.
著者
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Wakusawa Shinya
Department Of Medical Technology Nagoya University School Of Health Sciences
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TAKAGI Kenzo
Second Department of Internal Medicine
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MATSUNAGA TAKAYUKI
Department of Pharmacology, Hokuriku University School of Pharmacy
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KOSHIURA RYOZO
Department of Pharmacology, Hokuriku University School of Pharmacy
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Miyamoto Kenichi
Department Of Chemistry For Materials Faculty Of Engineering And Graduate School Of Engineering Mie
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SATAKE Tatsuo
Second Department of Internal Medicine, Nagoya University School of Medicine
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HASEGAWA Takaaki
Department of Bacteriology, Nagoya University School of Medicine
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