Cyclosporin A and verapamil have different effects on energy metabolism in multidrug-resistant tumour cells.
Cyclosporin A (Sandimmune) rapidly induced an increase in daunorubicin accumulation in multidrug-resistant human ovarian carcinoma cells (2780AD) and was more potent than verapamil. Steady-state 3H-cyclosporin A accumulation at 37 degrees C in 2780AD cells was 60-70% of that in the sensitive A2780 cells. A rapid increase of ATP consumption and lactate production was induced in 2780AD cells by verapamil, but not by cyclosporin A. These results suggest that the interactions of cyclosporin A and verapamil with P-glycoprotein, which leads to inhibition of drug transport, have a different mechanistic basis.
Broxterman
H J
HJ
Department of Medical Oncology, Free University Hospital, Amsterdam, The Netherlands.
Pinedo
H M
HM
Schuurhuis
G J
GJ
Lankelma
J
J
D000249:Adenosine Monophosphate / Q000032:analysis; D000255:Adenosine Triphosphate / Q000032:analysis; D002460:Cell Line; D003524:Cyclosporins / Q000494:pharmacology*; D003630:Daunorubicin / Q000493:pharmacokinetics; D004351:Drug Resistance / Q000502:physiology*; D004734:Energy Metabolism / Q000187:drug effects*; D005260:Female; D006801:Humans; D007773:Lactates / Q000096:biosynthesis; D019344:Lactic Acid; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism*; D014700:Verapamil / Q000494:pharmacology*
D003524:Cyclosporins; D007773:Lactates; D019344:Lactic Acid; D000249:Adenosine Monophosphate; D000255:Adenosine Triphosphate; D014700:Verapamil; D003630:Daunorubicin