An essential relationship between ATP depletion and chemosensitizing activity of Pluronic® block copolymers

被引:116
作者
Kabanov, AV
Batrakova, EV
Alakhov, VY
机构
[1] Univ Nebraska, Med Ctr, Coll Pharm, Dept Pharmaceut Sci, Omaha, NE 68198 USA
[2] Supratek Pharma Inc, Laval, PQ H7B 1B7, Canada
关键词
anthracycline antibiotics; cancer; multiple drug resistance; P-glycoprotein; multidrug resistant protein; block copolymer; poloxamer;
D O I
10.1016/S0168-3659(03)00211-6
中图分类号
O6 [化学];
学科分类号
0703 ;
摘要
Pluronic(R) block copolymers are known to sensitize multidrug resistant (MDR) tumors with respect to various anticancer agents, particularly, anthracycline antibiotics. After completion of the Phase I clinical trial, the formulation containing doxorubicin and Pluronic(R), SP1049C, is undergoing Phase II clinical trials. Studies of the mechanism of the sensitization effect of Pluronic(R) suggested an essential role of ATP depletion in MDR tumors by the block copolymer. The ATP depletion phenomenon was further examined using a panel of cells with varying levels of expression of P-glycoprotein (Pgp) and multidrug resistance-associated proteins (MRPs). Cell responses were characterized in terms of EC50, a concentration of Pluronic(R) P85 resulting in a 50% decrease in ATP intracellular levels. These studies suggested that the cells displaying high responses in ATP depletion with EC50<0.01 % were strongly sensitized by the block copolymer resulting in drastic increases of doxorubicin cytotoxic activity (over 100-fold). In contrast, the less responsive cells with EC50>ca. 0.02% were practically not sensitized by the block copolymer. The responses of the cells to P85 in ATP depletion studies correlated with the levels of expression of the drug efflux transport proteins, primarily Pgp. This provided initial evidence that Pgp may be useful as a gene expression marker for predicting potential responses to doxorubicin/Pluronic(R) formulation in chemotherapy of cancer. (C) 2003 Elsevier B.V. All rights reserved.
引用
收藏
页码:75 / 83
页数:9
相关论文
共 41 条
[1]   Hypersensitization of multidrug resistant human ovarian carcinoma cells by pluronic P85 block copolymer [J].
Alakhov, VY ;
Moskaleva, EY ;
Batrakova, EV ;
Kabanov, AV .
BIOCONJUGATE CHEMISTRY, 1996, 7 (02) :209-216
[2]   Defective acidification in human breast tumor cells and implications for chemotherapy [J].
Altan, N ;
Chen, Y ;
Schindler, M ;
Simon, SM .
JOURNAL OF EXPERIMENTAL MEDICINE, 1998, 187 (10) :1583-1598
[3]   Fundamental relationships between the composition of Pluronic block copolymers and their hypersensitization effect in MDR cancer cells [J].
Batrakova, E ;
Lee, S ;
Li, S ;
Venne, A ;
Alakhov, V ;
Kabanov, A .
PHARMACEUTICAL RESEARCH, 1999, 16 (09) :1373-1379
[4]  
Batrakova EV, 2001, J PHARMACOL EXP THER, V299, P483
[5]   Anthracycline antibiotics non-covalently incorporated into the block copolymer micelles: In vivo evaluation of anti-cancer activity [J].
Batrakova, EV ;
Dorodnych, TY ;
Klinskii, EY ;
Kliushnenkova, EN ;
Shemchukova, OB ;
Goncharova, ON ;
Arjakov, SA ;
Alakhov, VY ;
Kabanov, AV .
BRITISH JOURNAL OF CANCER, 1996, 74 (10) :1545-1552
[6]   Mechanism of sensitization of MDR cancer cells by Pluronic block copolymers: Selective energy depletion [J].
Batrakova, EV ;
Li, S ;
Elmquist, WF ;
Miller, DW ;
Alakhov, VY ;
Kabanov, AV .
BRITISH JOURNAL OF CANCER, 2001, 85 (12) :1987-1997
[7]  
Benderra Z, 1998, INT J ONCOL, V12, P711
[8]  
Benderra Z, 1999, ADV EXP MED BIOL, V457, P151
[9]   Purines and their roles in apoptosis [J].
Chow, SC ;
Kass, GEN ;
Orrenius, S .
NEUROPHARMACOLOGY, 1997, 36 (09) :1149-1156
[10]  
Cleary I, 1997, BIOCHEM PHARMACOL, V53, P1493