COMPARATIVE-STUDY ON REVERSAL EFFICACY OF SDZ PSC-833, CYCLOSPORINE-A AND VERAPAMIL ON MULTIDRUG-RESISTANCE IN-VITRO AND IN-VIVO

被引:107
作者
WATANABE, T
TSUGE, H
OHHARA, T
NAITO, M
TSURUO, T
机构
[1] UNIV TOKYO,INST MOLEC & CELLULAR BIOSCI,BUNKYO KU,TOKYO 113,JAPAN
[2] JAPANESE FDN CANC RES,CTR CANC CHEMOTHERAPY,TOKYO 170,JAPAN
[3] SANDOZ PHARMACEUT LTD,TSUKUBA RES INST,IBARAKI,JAPAN
关键词
D O I
10.3109/02841869509093961
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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, PSCS33, 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.
引用
收藏
页码:235 / 241
页数:7
相关论文
共 29 条
[1]  
BOEKHORST PAW, 1992, CANCER CHEMOTHER PHA, V30, P238
[2]   RESTORATION OF DAUNOMYCIN RETENTION IN MULTIDRUG-RESISTANT P388 CELLS BY SUBMICROMOLAR CONCENTRATIONS OF SDZ PSC-833, A NONIMMUNOSUPPRESSIVE CYCLOSPORINE DERIVATIVE [J].
BOESCH, D ;
MULLER, K ;
POURTIERMANZANEDO, A ;
LOOR, F .
EXPERIMENTAL CELL RESEARCH, 1991, 196 (01) :26-32
[3]  
BOESCH D, 1991, CANCER RES, V51, P4226
[4]  
CHIN KV, 1993, ADV CANCER RES, V60, P157
[5]   INVIVO EVIDENCE OF COMPLETE CIRCUMVENTION OF VINCRISTINE RESISTANCE BY A NEW TRIAZINOAMINOPIPERIDINE DERIVATIVE S-9788 IN P388/VCR LEUKEMIA MODEL [J].
CROS, S ;
GUILBAUD, N ;
BERLION, M ;
DUNN, T ;
REGNIER, G ;
DHAINAUT, A ;
ATASSI, G ;
BIZZARI, JP .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1992, 30 (06) :491-494
[6]  
FORD JM, 1990, PHARMACOL REV, V42, P155
[7]  
FOXWELL BMJ, 1989, MOL PHARMACOL, V36, P543
[8]   COMPARISON OF CYCLOSPORINE-A AND SDZ-PSC833 AS MULTIDRUG-RESISTANCE MODULATORS IN A DAUNORUBICIN-RESISTANT EHRLICH ASCITES TUMOR [J].
FRICHE, E ;
JENSEN, PB ;
NISSEN, NI .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1992, 30 (03) :235-237
[9]  
Gaveriaux C, 1991, J CELL PHARM, V2, P225
[10]  
HAMADA H, 1988, J BIOL CHEM, V263, P1454