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SDZ PSC 833, A non‐immunosuppressive cyclosporine: Its potency in overcoming P‐glycoprotein‐mediated multidrug resistance of murine leukemia
Author(s) -
Keller Roland P.,
Altermatt Hans J.,
Nooter Kees,
Poschmann Guenter,
Laissue Jean A.,
Bollinger Pietro,
Hiestand Peter C.
Publication year - 1992
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.2910500418
Subject(s) - in vivo , pharmacology , potency , multiple drug resistance , p glycoprotein , toxicity , leukemia , medicine , verapamil , in vitro , drug resistance , biology , immunology , biochemistry , microbiology and biotechnology , calcium
Abstract Cyclosporin A (CsA, Sandimmune) is known to reverse P‐glycoprotein(P‐gp 170)‐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.