IMPACT OF INTERLEUKIN-2-RECEPTOR-TARGETED CYTOTOXINS ON A UNIQUE MODEL OF MURINE INTERLEUKIN-2-RECEPTOR-EXPRESSING MALIGNANCY

被引:25
作者
BACHA, PA [1 ]
FORTE, SE [1 ]
MCCARTHY, DM [1 ]
ESTIS, L [1 ]
YAMADA, G [1 ]
NICHOLS, JC [1 ]
机构
[1] OSAKA UNIV,INST MOLEC & CELLULAR BIOL,SUITA,OSAKA 565,JAPAN
关键词
D O I
10.1002/ijc.2910490118
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
DAB486IL-2 is a genetically engineered fusion protein consisting of a portion of diphtheria toxin fused to human IL-2. It is specifically cytotoxic for tumor cells which bear high-affinity IL-2 receptors (IL-2R). DAB389IL-2 is a similarly constructed hybrid protein which is smaller than DAB486IL-2 and is slightly more potent in vitro. We have developed a murine model of IL-2R-expressing malignancy to study the in vivo efficacy of these genetically engineered cytotoxins. Following intravenous administration of CP3 cells, C57BL/6 mice develop tumors which are lymphatic in distribution. When mice are injected i.v. with 10(6) CP3 cells, 90% of the animals show signs of observable tumor by day 10 to 20; death occurs in 50% of untreated animals by day 30. Intravenous treatment of mice with DAB486IL-2 (10-mu-g daily for 10 days), beginning 24 hr after administration of CP3 cells, increases mean survival time by approximately 50%. In comparative studies, DAB389IL-2 is more potent in vivo than DAB486IL-2, with approximately 90% of treated animals with no evidence of tumor at 60 days. The mechanism of action of tumor inhibition by DAB486IL-2 is specific, since treatment of animals which have IL-2R-negative EL4 tumors has not resulted in increased survival time. In addition, treatment of such tumors with DA(glu53)B486IL-2, a fusion protein which can bind to the IL-2R but is incapable of inhibiting protein synthesis, is ineffective.
引用
收藏
页码:96 / 101
页数:6
相关论文
共 31 条
  • [1] INTERLEUKIN-2 RECEPTOR TARGETED CYTO-TOXICITY INTERLEUKIN-2 RECEPTOR MEDIATED ACTION OF A DIPHTHERIA-TOXIN RELATED INTERLEUKIN-2 FUSION PROTEIN
    BACHA, P
    WILLIAMS, DP
    WATERS, C
    WILLIAMS, JM
    MURPHY, JR
    STROM, TB
    [J]. JOURNAL OF EXPERIMENTAL MEDICINE, 1988, 167 (02) : 612 - 622
  • [2] BARNETT D, 1988, DIS MARKERS, V6, P133
  • [3] BATRA JK, 1990, J BIOL CHEM, V265, P15198
  • [4] STUDIES ON INTERLEUKIN-2 RECEPTOR EXPRESSION AND IL-2 PRODUCTION BY MURINE T-CELL LYMPHOMAS
    DIAMANTSTEIN, T
    OSAWA, H
    GRAF, L
    SCHIRRMACHER, V
    [J]. BRITISH JOURNAL OF CANCER, 1985, 51 (01) : 23 - 30
  • [5] ETTINGHAUSEN SE, 1986, CANCER RES, V46, P2784
  • [6] GIANNINI G, 1984, NUCLEIC ACIDS RES, V12, P4063, DOI 10.1093/nar/12.10.4063
  • [7] LONG-TERM CULTURE OF TUMOR-SPECIFIC CYTOTOXIC T-CELLS
    GILLIS, S
    SMITH, KA
    [J]. NATURE, 1977, 268 (5616) : 154 - 156
  • [8] GORER PA, 1959, CANCER RES, V19, P824
  • [9] KIYOKAWA T, 1989, CANCER RES, V49, P4042
  • [10] KONDO T, 1988, J BIOL CHEM, V263, P9470