Reversal of typical multidrug resistance by cyclosporin and its non-immunosuppressive analogue SDZ PSC 833 in Chinese hamster ovary cells expressing the mdr1 phenotype.
The new non-immunosuppressive cyclosporin derivative SDZ PSC 833 (PSC) is a potent agent used to overcome typical multidrug resistance (MDR) associated with overexpression of the mdr1 gene encoding for a P-170 glycoprotein. In the present study, the efficacy of PSC as compared with cyclosporin was determined in Chinese hamster ovary cell lines exhibiting different levels of resistance to colchicine (0, 0.1, 0.2 and 10 micrograms/ml, respectively). Low concentrations of PSC (8.2 nM) increased the cytotoxicity of colchicine in cell lines expressing low levels of drug resistance. The concentration resulting in 50% cell survival (LC50 value) found for colchicine alone or in combination with PSC in the CHO-A3 cell line that was resistant to 100 ng colchicine/ml decreased from greater than 500 to 200 ng/ml at 8.2 nM PSC and to less than 100 ng/ml at 82 and 820 nM PSC. In the CHO-A3 cell line that was resistant to 200 ng colchicine/ml, the LC50 values decreased from greater than 500 ng/ml for colchicine alone to 500 ng/ml for colchicine used in combination with 8.2 nM PSC and to less than 100 ng/ml for colchicine combined with 82 or 820 nM PSC. At a concentration of 82 nM PSC, the maximal effect in MDR reversal was observed in the cell lines exhibiting moderate resistance. In the highly resistant cell line, PSC (820 nM) also reversed colchicine resistance. In drug-accumulation experiments, we obtained a 4-fold increase in intracellular doxorubicin accumulation using 820 nM PSC. A comparison of PSC with cyclosporin revealed that a cyclosporin concentration 20-fold that of PSC was required to obtain the same sensitising effect. On the basis of these data, it may be concluded that PSC is a most promising chemosensitiser.
te Boekhorst
P A
PA
Department of Haematology, Erasmus University Rotterdam, The Netherlands.
van Kapel
J
J
Schoester
M
M
Sonneveld
P
P
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004351:Drug Resistance / Q000235:genetics; D015870:Gene Expression; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000032:analysis / Q000235:genetics; D010641:Phenotype
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D016572:Cyclosporine; C070272:valspodar