[Studies on reversing effect of multidrug resistance by dipyridamole. II. Inhibition of epirubicin efflux from resistant cells by dipyridamole and its pharmacological effect].
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 100 microM 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.
Hayashi
A
A
Department of Pharmacology and Toxicology, Tohoku College of Pharmacy, Sendai, Japan.
Furusawa
S
S
Takayanagi
M
M
Takasyanagi
Y
Y
Sasaki
K
K
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology*; D004176:Dipyridamole / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D018432:Drug Resistance, Multiple; D004357:Drug Synergism; D015251:Epirubicin / Q000493:pharmacokinetics* / Q000494:pharmacology*; D005260:Female; D007941:Leukemia P388 / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008815:Mice, Inbred Strains; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D015251:Epirubicin; D004176:Dipyridamole