POTENTIATION OF ANTITUMOR IMMUNOTOXINS BY LIPOSOMAL MONENSIN

被引:41
作者
GRIFFIN, T
RYBAK, ME
RECHT, L
SINGH, M
SALIMI, A
RASO, V
机构
[1] SYNPHAR LABS INC, EDMONTON, AB, CANADA
[2] UNIV MASSACHUSETTS, SCH MED, DEPT MED ONCOL, WORCESTER, MA 01605 USA
[3] UNIV MASSACHUSETTS, SCH MED, DEPT NEUROL, WORCESTER, MA 01605 USA
[4] BOSTON BIOMED RES INST, BOSTON, MA 02114 USA
来源
JNCI-JOURNAL OF THE NATIONAL CANCER INSTITUTE | 1993年 / 85卷 / 04期
关键词
D O I
10.1093/jnci/85.4.292
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Background: The cytotoxicity of specific ricin A-chain immunotoxins is greatly enhanced in vitro by the carboxylic ionophore monensin. However, the highly lipophilic nature of monensin, which is reflected in its poor solubility and short half-life, has restricted its use in in vivo animal studies. Purpose: The purpose of this study was to assess the ability of monensin incorporated in unilamellar vesicles (liposomes) to potentiate anti-tumor immunotoxins in vitro and in vivo. Methods: Monensin was incorporated into liposomes and used in combination with specific immunotoxins against human tumor cell lines in vitro and in vivo. Inhibition of [H-3]leucine incorporation was used to evaluate the cytotoxic action of immunotoxin with or without monensin in vitro on the following human tumor cell lines: H-MESO-1 malignant mesothelioma, LS174T colorectal carcinoma, and U373, U87, and MG-1 glioblastomas. For the in vivo studies of immunotoxins and liposomal monensin, BALB/c nu/nu mice were inoculated intraperitoneally with H-MESO-1 cells. Results: Liposomal monensin potentiated the cytotoxic action of cell-specific anti-human transferrin receptor immunotoxin on H-MESO-1 target cells at a molar concentration of monensin that was 160-fold lower than the concentration of monensin in buffer that produced the same effect (0.3 nM versus 0.05 muM). Moreover, immunotoxin plus 0.1 muM liposomal monensin was fivefold more toxic for H-MESO-1 cells and 1000-fold and 2200-fold more toxic for human glioblastoma U373 and U87 cells, respectively, than immunotoxin plus 0.1 muM free monensin in buffer. Liposomal monensin produced similar effects when it was combined with different specific immunotoxins and other target cell lines (i.e., LS174T, U87, and CEM). Immunotoxin specificity was preserved with liposomal monensin, as shown by the absence of effect with non-cell-binding immunotoxins or on antigen-negative cell lines. In mice, liposomal monensin in combination with specific immunotoxin substantially prolonged survival, and three (21%) of 14 mice bearing H-MESO-1 xenografts treated with the liposomes showed no evidence of tumor at day 160 after treatment. Treatment with control immunotoxin plus liposomal monensin was ineffective. Conclusion: These findings suggest that encapsulation of monensin into liposomes increased the capacity of monensin to enhance the potency of cell-specific immunotoxin in vitro and in vivo.
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页码:292 / 298
页数:7
相关论文
共 42 条
[31]  
RECHT LD, 1990, CANCER RES, V50, P6696
[32]  
ROTH JA, 1988, CANCER RES, V48, P3496
[33]   ABSORPTION CHARACTERISTICS OF THE LIPOPHILIC PRODRUG OF MITOMYCIN-C FROM INJECTED LIPOSOMES OR AN EMULSION [J].
SASAKI, H ;
KAKUTANI, T ;
HASHIDA, M ;
SEZAKI, H .
JOURNAL OF PHARMACY AND PHARMACOLOGY, 1985, 37 (07) :461-465
[34]   INTRAVENOUS-INFUSION OF HIGH-DOSES OF LIPOSOMES CONTAINING NSC-251635, A WATER-INSOLUBLE CYTOSTATIC AGENT - A PILOT-STUDY WITH PHARMACOKINETIC DATA [J].
SCULIER, JP ;
COUNE, A ;
BRASSINNE, C ;
LADURON, C ;
ATASSI, G ;
RUYSSCHAERT, JM ;
FRUHLING, J .
JOURNAL OF CLINICAL ONCOLOGY, 1986, 4 (05) :789-797
[35]  
SINGH M, 1989, CANCER RES, V49, P3976
[36]   ENDOCYTOSIS AND INTRACELLULAR FATE OF LIPOSOMES USING PYRANINE AS A PROBE [J].
STRAUBINGER, RM ;
PAPAHADJOPOULOS, D ;
HONG, K .
BIOCHEMISTRY, 1990, 29 (20) :4929-4939
[37]   PERTURBATION OF VESICULAR TRAFFIC WITH THE CARBOXYLIC IONOPHORE MONENSIN [J].
TARTAKOFF, AM .
CELL, 1983, 32 (04) :1026-1028
[38]   ANTI-TRANSFERRIN RECEPTOR MONOCLONAL-ANTIBODY AND TOXIN-ANTIBODY CONJUGATES AFFECT GROWTH OF HUMAN-TUMOR CELLS [J].
TROWBRIDGE, IS ;
DOMINGO, DL .
NATURE, 1981, 294 (5837) :171-173
[39]  
VITETTA ES, 1986, J IMMUNOL, V136, P1880
[40]  
WATANABE Y, 1987, CHEM PHARM BULL, V35, P740