Studies on Reversing Effect of Multidrug Resistance by Dipyridamole. II. Inhibition of Epirubicin Efflux from Resistant Cells by Dipyridamole and Its Pharmacological Effect

HAYASHI Atsushi, FURUSAWA Shinobu, TAKAYANAGI Motoaki, TAKAYANAGI Yoshio, SASAKI Ken-ichi

doi:10.1248/yakushi1947.116.3_228

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ジピリダモールの多剤耐性克服作用に関する研究(第2報)ジピリダモールによる耐性細胞からのエピルビシンのエフラックス阻害とその薬理学的効果に関する検討
ジピリダモールノタザイタイセイコクフクサヨウニカンスルケンキュウ

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We have previously reported that dipyridamole increases the cytotoxicity of epirubicin and alters the cell cycle in doxorubicin-resistant (P388/DOX) cells, increasing the accumulation of G₂/M phase by blocking the cell cycle. In cultured cells, dipyridamole increased dose-dependently the intracellular accumulation of epirubicin in the resistant cells. Simultaneous exposure of the resistant cells to epirubicin and 100μM dipyridamole resulted in a 4.2-fold increase in proportion to the control level of epirubicin after 60 min. Dipyridamole inhibited the enhanced efflux of epirubicin in doxorubicin-resistant cells. However, dipyridamole had no effect on both the influx and efflux of epirubicin in doxorubicin-sensitive cells. In mice, lethal and bone marrow toxicity induced by epirubicin were potentiated by administration of high-dose of dipyridamole. In addition, in vivo results also demonstrated that dipyridamole in combination with epirubicin produced a significant reversal of the in vivo antitumor activity of epirubicin in mice bearing P388/DOX cells. These data imply the enhancement effects of dipyridamole on the efficacy and toxicity of epirubicin.

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YAKUGAKU ZASSHI

YAKUGAKU ZASSHI 116 (3), 228-237, 1996

The Pharmaceutical Society of Japan

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