THE EFFLUX OF ANTHRACYCLINES IN MULTIDRUG-RESISTANT CELL-LINES

被引:31
作者
COLEY, HM [1 ]
TWENTYMAN, PR [1 ]
WORKMAN, P [1 ]
机构
[1] MRC,CLIN ONCOL & RADIOTHERAPEUT UNIT,CAMBRIDGE CB2 2QH,ENGLAND
关键词
D O I
10.1016/0006-2952(93)90094-D
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
In order to address the association of enhanced drug efflux with the multidrug-resistant (MDR) phenotype, we have studied the cellular pharmacokinetics of anthracyclines in the P-glycoprotein (Pgp)-positive MDR cell lines H69/LX4 (human small cell lung cancer) and EMT6/AR1.0 (mouse mammary tumour). Both doxorubicin (DOX) and daunorubicin (DNR) were accumulated to a lesser extent and effluxed at a higher rate by MDR cells than by their drug-sensitive counterparts. In contrast, the 9-alkyl substituted compound, aclacinomycin A (ACL), was accumulated and effluxed from parent and MDR cells at an identical rate. In experiments designed to examine energy-dependent efflux, DOX and DNR were shown to be efficiently effluxed against the concentration gradient in the presence of glucose. However, in the same experiments the analogues ACL and Ro 31-3294 (9-alkyl and morpholinyl substituted), which have previously been shown to retain activity against MDR cell lines, were accumulated and effluxed at identical rates in parent and MDR EMT6 cells. Hence, 9-alkyl and morpholinyl substituted compounds appear to behave less favourably as substrates for energy-driven drug efflux by Pgp-positive MDR cells than do DOX or DNR. Resistance modifiers verapamil and cyclosporin A appeared to abolish energy-dependent efflux for DOX and DNR in both the EMT6 and H69 MDR lines whereas they had no effect on the cellular efflux of ACL. The altered cellular pharmacology in MDR cell lines may provide a rational basis for the use of modified anthracycline analogues (e.g. 9-alkyl and morpholinyl substituted) and resistance of modifying agents in the treatment of tumours expressing a Pgp-mediated phenotype.
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页码:1317 / 1326
页数:10
相关论文
共 46 条
[1]  
ACTON EM, 1980, ANTHRACYCLINES CURRE, pCH3
[2]   THE CELL BIOLOGY OF MULTIPLE-DRUG RESISTANCE [J].
BECK, WT .
BIOCHEMICAL PHARMACOLOGY, 1987, 36 (18) :2879-2887
[3]   MECHANISMS OF MULTIDRUG RESISTANCE IN HUMAN TUMOR-CELLS - THE ROLES OF P-GLYCOPROTEIN, DNA TOPOISOMERASE-II, AND OTHER FACTORS [J].
BECK, WT .
CANCER TREATMENT REVIEWS, 1990, 17 :11-20
[4]  
BIEDLER JL, 1970, CANCER RES, V30, P1174
[5]   INDUCTION BY VERAPAMIL OF A RAPID INCREASE IN ATP CONSUMPTION IN MULTIDRUG-RESISTANT TUMOR-CELLS [J].
BROXTERMAN, HJ ;
PINEDO, HM ;
KUIPER, CM ;
KAPTEIN, LCM ;
SCHUURHUIS, GJ ;
LANKELMA, J .
FASEB JOURNAL, 1988, 2 (07) :2278-2282
[6]   CYTOFLUORESCENCE LOCALIZATION OF ADRIAMYCIN IN RESISTANT COLON CANCER-CELLS [J].
CHAUFFERT, B ;
MARTIN, F ;
CAIGNARD, A ;
JEANNIN, JF ;
LECLERC, A .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1984, 13 (01) :14-18
[7]   INTERNAL DUPLICATION AND HOMOLOGY WITH BACTERIAL TRANSPORT PROTEINS IN THE MDR1 (P-GLYCOPROTEIN) GENE FROM MULTIDRUG-RESISTANT HUMAN-CELLS [J].
CHEN, CJ ;
CHIN, JE ;
UEDA, K ;
CLARK, DP ;
PASTAN, I ;
GOTTESMAN, MM ;
RONINSON, IB .
CELL, 1986, 47 (03) :381-389
[8]   9-ALKYL, MORPHOLINYL ANTHRACYCLINES IN THE CIRCUMVENTION OF MULTIDRUG RESISTANCE [J].
COLEY, HM ;
TWENTYMAN, PR ;
WORKMAN, P .
EUROPEAN JOURNAL OF CANCER, 1990, 26 (06) :665-667
[9]   IDENTIFICATION OF ANTHRACYCLINES AND RELATED AGENTS THAT RETAIN PREFERENTIAL ACTIVITY OVER ADRIAMYCIN IN MULTIDRUG-RESISTANT CELL-LINES, AND FURTHER RESISTANCE MODIFICATION BY VERAPAMIL AND CYCLOSPORINE-A [J].
COLEY, HM ;
TWENTYMAN, PR ;
WORKMAN, P .
CANCER CHEMOTHERAPY AND PHARMACOLOGY, 1989, 24 (05) :284-290
[10]   IMPROVED CELLULAR ACCUMULATION IS CHARACTERISTIC OF ANTHRACYCLINES WHICH RETAIN HIGH-ACTIVITY IN MULTIDRUG RESISTANT CELL-LINES, ALONE OR IN COMBINATION WITH VERAPAMIL OR CYCLOSPORINE-A [J].
COLEY, HM ;
TWENTYMAN, PR ;
WORKMAN, P .
BIOCHEMICAL PHARMACOLOGY, 1989, 38 (24) :4467-4475