SDZ PSC 833, a non-immunosuppressive cyclosporine: its potency in overcoming P-glycoprotein-mediated multidrug resistance of murine leukemia.
Cyclosporin A (CsA, Sandimmune) is known to reverse P-glycoprotein (P-gp170)-mediated multidrug resistance as efficiently as other prototype compounds of resistance modifiers. The immunosuppressive activity and nephrotoxicity of CsA, however, may limit its clinical use. PSC-833, a new cyclosporine, exerts a similar resistance-modifying activity but lacks toxicity or immunosuppressive activity. We have tested its potency in vitro and in vivo on the L1210 leukemia cell line transfected with a full-length cDNA copy of the human mdr I gene, which showed a stable 30-fold resistance towards adriamycin as compared to the parental cell line. In vitro growth of the transfected cell was unchanged. In vivo growth was less aggressive; the survival time of inoculated mice was prolonged. In vitro, PSC-833 was at least as potent as CsA or verapamil in reversing multidrug resistance. In vivo, the drug-resistant L1210 leukemia was completely unresponsive to i.v. monotherapy with adriamycin at its maximum tolerated dose (MTD). PSC-833 enhanced the activity and toxicity of adriamycin. The MTD of adriamycin was about 3 times lower than when given alone. On this basis, the MTD of i.v. adriamycin in combination with oral PSC-833 successfully overcame refractoriness to treatment. Survival times of the mice were considerably prolonged and even some cures of leukemic mice occurred.
Keller
R P
RP
Sandoz Pharma Ltd, Preclinical Research, Basel, Switzerland.
Altermatt
H J
HJ
Nooter
K
K
Poschmann
G
G
Laissue
J A
JA
Bollinger
P
P
Hiestand
P C
PC
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000818:Animals; D002455:Cell Division; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000494:pharmacology; D004351:Drug Resistance; D007109:Immunity / Q000187:drug effects; D066298:In Vitro Techniques; D007939:Leukemia L1210 / Q000188:drug therapy*; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D010456:Peptides, Cyclic / Q000494:pharmacology; D016019:Survival Analysis
D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D003524:Cyclosporins; D008562:Membrane Glycoproteins; D010456:Peptides, Cyclic; D004317:Doxorubicin; C070272:valspodar