REVERSAL OF MULTIDRUG RESISTANCE BY SURFACTANTS

被引:209
作者
WOODCOCK, DM [1 ]
LINSENMEYER, ME [1 ]
CHOJNOWSKI, G [1 ]
KRIEGLER, AB [1 ]
NINK, V [1 ]
WEBSTER, LK [1 ]
SAWYER, WH [1 ]
机构
[1] UNIV MELBOURNE,DEPT BIOCHEM,PARKVILLE,VIC 3052,AUSTRALIA
关键词
D O I
10.1038/bjc.1992.217
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Cremophor EL, a pharmacologically inactive solubilising agent, has been shown to reverse multidrug resistance (MDR). Using flow cytometric evaluation of equilibrium intracellular levels of daunorubicin (DNR), we found that eight other surface active agents will also reverse MDR. All the active detergents contain polyethoxyl moieties but have no similarities in their hydrophobic components. The properties of three polyethoxylated surfactants that showed the lowest toxicities, Cremophor, Tween 80 and Solutol HS15, were examined in more detail. The concentrations of Tween 80 and Solutol required to reverse DNR exclusion were 10-fold lower than for Cremophor. However while concentrations greater-than-or-equal-to 1:10(2) of the former two surfactants resulted in breakdown of cells, even 1:10 of Cremophor did not lyse cells. Studies of the effects of Cremophor on the uptake and efflux of DNR in normal and MDR cell types showed that Cremophor increases intracellular DNR primarily by locking the rapid efflux from the cells. This blockage of drug efflux may be mediated by a substantial alteration in the fluidity of cell membranes induced by Cremophor, as shown by decreased fluorescence anisotropy of a membrane probe. Consistent with these data, coinjection of adriamycin plus Cremophor into mice carrying a multidrug resistant P388 transplantable tumour significantly increased the survival time of the mice compared with adriamycin treatment alone.
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页码:62 / 68
页数:7
相关论文
共 17 条
  • [1] MECHANISM OF MULTIDRUG RESISTANCE
    BRADLEY, G
    JURANKA, PF
    LING, V
    [J]. BIOCHIMICA ET BIOPHYSICA ACTA, 1988, 948 (01) : 87 - 128
  • [2] COON JS, 1991, CANCER RES, V51, P897
  • [3] CRISPENS CG, 1988, ANTICANCER RES, V8, P1341
  • [4] DRUG-RESISTANCE IN MULTIPLE-MYELOMA AND NON-HODGKINS LYMPHOMA - DETECTION OF P-GLYCOPROTEIN AND POTENTIAL CIRCUMVENTION BY ADDITION OF VERAPAMIL TO CHEMOTHERAPY
    DALTON, WS
    GROGAN, TM
    MELTZER, PS
    SCHEPER, RJ
    DURIE, BGM
    TAYLOR, CW
    MILLER, TP
    SALMON, SE
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 1989, 7 (04) : 415 - 424
  • [5] REVERSAL OF DRUG-RESISTANCE IN MULTIPLE-MYELOMA WITH VERAPAMIL
    DURIE, BGM
    DALTON, WS
    [J]. BRITISH JOURNAL OF HAEMATOLOGY, 1988, 68 (02) : 203 - 206
  • [6] EXPRESSION OF A MULTIDRUG-RESISTANCE GENE IN HUMAN-TUMORS AND TISSUES
    FOJO, AT
    UEDA, K
    SLAMON, DJ
    POPLACK, DG
    GOTTESMAN, MM
    PASTAN, I
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1987, 84 (01) : 265 - 269
  • [7] INTRINSIC DRUG-RESISTANCE IN HUMAN-KIDNEY CANCER IS ASSOCIATED WITH EXPRESSION OF A HUMAN MULTIDRUG-RESISTANCE GENE
    FOJO, AT
    SHEN, DW
    MICKLEY, LA
    PASTAN, I
    GOTTESMAN, MM
    [J]. JOURNAL OF CLINICAL ONCOLOGY, 1987, 5 (12) : 1922 - 1927
  • [8] FRANKFURT OS, 1987, J NATL CANCER I, V79, P831
  • [9] FRICHE E, 1990, CANCER COMMUN, V2, P297
  • [10] KAHEHI Y, 1988, J UROLOGY, V139, P862