Restoring uptake and retention of daunorubicin and idarubicin in P170-related multidrug resistance cells by low concentration D-verapamil, cyclosporin-A and SDZ PSC 833.
BACKGROUND
Overexpression of the mdr-1 gene that codes for a 170 Kd transmembrane glycoprotein (P170) is a factor responsible for decreased cell sensitivity to anthracyclines and other drugs, and is related to treatment failure in acute leukemia and other tumors. Several agents, including verapamil and cyclosporine derivatives, can modify P170-related resistance in vitro and can be proposed as adjuvant treatment for leukemia and cancer.


METHODS
To investigate the optimal conditions for adjuvant treatment, D-verapamil (D-VRP), cyclosporin-A (CyA) and the cyclosporine derivative SDZ PSC 833 (PSC) were used alone and in combination at drug concentrations that can be achieved and maintained in vivo. The drugs were tested for their capacity to restore intracellular daunorubicin (DNR) and idarubicin (IDA) accumulation in high-resistance (CEM VLB 300) and intermediate-resistance (CEM VLB 100) cells to levels found in the non-resistant parental cell line (CCRF CEM).


RESULTS
In intermediate-resistance cells, IDA alone was more easily restored than DNR plus modifiers, and intracellular IDA concentration was returned to the level of non-resistant cells with low-dose D-VRP (1 microM), CyA (0.8 microM) and PSC (0.4 microM). In high-resistance cells no modifier or modifier combination was able to restore intracellular DNR concentration to the value of non-resistant cells. Intracellular IDA concentration was almost completely restored only with D-VRP (2-3 microM) and CyA (0.8-1.6 microM) in combination or with PSC alone (0.4 microM).


CONCLUSIONS
These data suggest that as far as P170-related resistance is concerned, IDA alone is as efficient as or even more efficient than DNR plus modifiers, and that residual resistance to IDA can be overcome with a combination of D-VRP and Cy-A at a clinically achievable concentration, or with a more powerful modifier like SDZ PSC 833.
Michieli
M
M
Department of Morphological and Clinical Research, University of Udine, Italy.
Damiani
D
D
Michelutti
A
A
Candoni
A
A
Masolini
P
P
Scaggiante
B
B
Quadrifoglio
F
F
Baccarani
M
M
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000502:physiology*; D001692:Biological Transport / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D003630:Daunorubicin / Q000378:metabolism*; D018432:Drug Resistance, Multiple; D006801:Humans; D015255:Idarubicin / Q000378:metabolism*; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000473:pathology*; D009363:Neoplasm Proteins / Q000502:physiology*; D014407:Tumor Cells, Cultured / Q000187:drug effects; D014700:Verapamil / Q000494:pharmacology*
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D009363:Neoplasm Proteins; D016572:Cyclosporine; D014700:Verapamil; C070272:valspodar; D015255:Idarubicin; D003630:Daunorubicin