TRANSFORMING GROWTH FACTOR-ALPHA PSEUDOMONAS EXOTOXIN FUSION PROTEIN PROLONGS SURVIVAL OF NUDE-MICE BEARING TUMOR XENOGRAFTS

被引:76
作者
HEIMBROOK, DC
STIRDIVANT, SM
AHERN, JD
BALISHIN, NL
PATRICK, DR
EDWARDS, GM
DEFEOJONES, D
FITZGERALD, DJ
PASTAN, I
OLIFF, A
机构
[1] MERCK SHARP & DOHME LTD,DEPT CANC RES,W POINT,PA 19486
[2] NCI,MOLEC BIOL LAB,BETHESDA,MD 20892
关键词
D O I
10.1073/pnas.87.12.4697
中图分类号
O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];
学科分类号
07 ; 0710 ; 09 ;
摘要
Transforming growth factor α (TGFα)-Pseudomonas exotoxin 40 (PE40) is a chimeric protein consisting of an N-terminal TGFα domain fused to a C-terminal 40-kDa segment of the Pseudomonas exotoxin A protein. TGFα-PE40 exhibits the receptor-binding activity of TGFα and the cell-killing activity of PE40. These properties make TGFα-PE40 an effective cytotoxic agent for cells that possess epidermal growth factor receptors (EGFR). However, the utility of this protein as an anticancer agent has been unclear because many normal tissues express EGFR and may be damaged by exposure to TGFα-PE40. To address this issue, we injected nude mice with a lethal inoculum of either A431 or HT29 human tumor cells that possess EGFR or with Chinese hamster ovary (CHO) tumor cells that lack EGFR. Animals were treated with a derivative of TGFα-PE40 in which the cysteine residues are replaced by alanine, termed 'TGFα-PE40δcys', or with saline once a day for 5 days. Mice bearing EGFR+ tumor cells lived significantly (P < 0.001) longer when treated with TGFα-PE40δcsy compared with saline-treated controls (median survival: A431 cells, 51.5 vs. 25.5 days; HT29 cells, 101 vs. 47.5 days). TGFα-PE40δcys did not prolong the survival of mice bearing tumor cells that lack EGFR (median survival: CHO cells, 15.5 vs. 19.5 days). The only toxicity to normal tissues was mild periportal hepatic necrosis. These studies indicate that a therapeutic window exists in vivo for the use of some growth factor-toxin fusion proteins as anticancer agents.
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页码:4697 / 4701
页数:5
相关论文
共 35 条
  • [11] IN-VITRO CULTIVATION OF HUMAN TUMORS - ESTABLISHMENT OF CELL LINES DERIVED FROM A SERIES OF SOLID TUMORS
    GIARD, DJ
    AARONSON, SA
    TODARO, GJ
    ARNSTEIN, P
    KERSEY, JH
    DOSIK, H
    PARKS, WP
    [J]. JOURNAL OF THE NATIONAL CANCER INSTITUTE, 1973, 51 (05) : 1417 - 1423
  • [12] GIRARD DJ, 1973, J NATL CANCER I, V51, P1417
  • [13] CLONING, NUCLEOTIDE-SEQUENCE, AND EXPRESSION IN ESCHERICHIA-COLI OF THE EXOTOXIN-A STRUCTURAL GENE OF PSEUDOMONAS-AERUGINOSA
    GRAY, GL
    SMITH, DH
    BALDRIDGE, JS
    HARKINS, RN
    VASIL, ML
    CHEN, EY
    HEYNEKER, HL
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1984, 81 (09): : 2645 - 2649
  • [14] GUSTERSON B, 1985, INT J CANCER, V36, P689
  • [15] VISUALIZATION BY FLUORESCENCE OF BINDING AND INTERNALIZATION OF EPIDERMAL GROWTH-FACTOR IN HUMAN CARCINOMA CELLS A-431
    HAIGLER, H
    ASH, JF
    SINGER, SJ
    COHEN, S
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1978, 75 (07) : 3317 - 3321
  • [16] FUNCTIONAL DOMAINS OF PSEUDOMONAS EXOTOXIN IDENTIFIED BY DELETION ANALYSIS OF THE GENE EXPRESSED IN ESCHERICHIA-COLI
    HWANG, J
    FITZGERALD, DJ
    ADHYA, S
    PASTAN, I
    [J]. CELL, 1987, 48 (01) : 129 - 136
  • [17] NAD-DEPENDENT INHIBITION OF PROTEIN-SYNTHESIS BY PSEUDOMONAS-AERUGINOSA TOXIN
    IGLEWSKI, BH
    KABAT, D
    [J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1975, 72 (06) : 2284 - 2288
  • [18] KINETIC-ANALYSIS OF INVIVO RECEPTOR-DEPENDENT BINDING OF HUMAN EPIDERMAL GROWTH-FACTOR BY RAT-TISSUES
    KIM, DC
    SUGIYAMA, Y
    SATOH, H
    FUWA, T
    IGA, T
    HANANO, M
    [J]. JOURNAL OF PHARMACEUTICAL SCIENCES, 1988, 77 (03) : 200 - 207
  • [19] KONDO T, 1988, J BIOL CHEM, V263, P9470
  • [20] LEE ET, 1980, STATISTICAL METHODS, P129