Comparative study on reversal efficacy of SDZ PSC 833, cyclosporin A and verapamil on multidrug resistance in vitro and in vivo.
A non-immunosuppressive cyclosporin, SDZ PSC 833 (PSC833), shows a reversal effect on multidrug resistance (MDR) by functional modulation of MDR1 gene product, P-glycoprotein. The objective of the present study was to compare the reversal efficacy of three multidrug resistance modulators, PSC833, cyclosporin A (CsA) and verapamil (Vp). PSC833 has approximately 3-10-fold greater potency than CsA and Vp with respect to the restoring effect on reduced accumulation of doxorubicin (ADM) and vincristine (VCR) in ADM-resistant K562 myelogenous leukemia cells (K562/ADM) in vitro and also on the sensitivity of K562/ADM to ADM and VCR in in vitro growth inhibition. The in vivo efficacy of a combination of modifiers (PSC833 and CsA: 50 mg/kg, Vp 100 mg/kg administered p.o. 4 h before the administration of anticancer drugs) with anticancer drugs (ADM 2.5 mg/kg i.p., Q4D days 1, 5 and 9, VCR 0.05 mg/kg i.p., QD days 1-5) was tested in ADM-resistant P388-bearing mice. PSC833 significantly enhanced the increase in life span by more than 80%, whereas CsA and Vp enhanced by less than 50%. This reversal potency, which exceeded that of CsA and Vp, was confirmed by therapeutic experiments using colon adenocarcinoma 26-bearing mice. These results demonstrated that PSC833 has significant potency to reverse MDR in vitro and in vivo, suggesting that PSC833 is a good candidate for reversing multidrug resistance in clinical situations.
Watanabe
T
T
Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo.
Tsuge
H
H
Oh-Hara
T
T
Naito
M
M
Tsuruo
T
T
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics; D016572:Cyclosporine / Q000494:pharmacology*; D003524:Cyclosporins / Q000494:pharmacology*; D004317:Doxorubicin / Q000493:pharmacokinetics; D018432:Drug Resistance, Multiple; D006801:Humans; D007951:Leukemia, Myeloid / Q000188:drug therapy; D051379:Mice; D008807:Mice, Inbred BALB C; D008815:Mice, Inbred Strains; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism; D014700:Verapamil / Q000494:pharmacology*; D014750:Vincristine / Q000493:pharmacokinetics
D000970:Antineoplastic Agents; D003524:Cyclosporins; D014750:Vincristine; D004317:Doxorubicin; D016572:Cyclosporine; D014700:Verapamil; C070272:valspodar