CONDITIONAL EXPRESSION OF HUMAN TNF-ALPHA - A SYSTEM FOR INDUCIBLE CYTOTOXICITY

被引:11
作者
SPARMANN, G
WALTHER, W
GUNZBURG, WH
UCKERT, W
SALMONS, B
机构
[1] GSF,INST MOLEC VIROL,D-85764 OBERSCHLEISSHEIM,GERMANY
[2] MAX DELBRUCK CTR MOLEC MED,D-13125 BERLIN,GERMANY
[3] UNIV MUNICH,D-80539 MUNICH,GERMANY
关键词
D O I
10.1002/ijc.2910590119
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
Tumour necrosis factor-alpha (TNF-alpha) is currently being used in clinical trials for cancer treatment, but toxic side effects, due to systemic administration and high doses, are observed. Inducible expression of TNF may permit selective killing of tumour cells in gene therapy protocols without need for prolonged and/or high-level TNF expression. A conditional TNF expression vector has been constructed in which the coding sequences of human TNF have been placed under the transcriptional control of the glucocorticoid-regulated murine mammary tumour virus long terminal repeat (MMTV-LTR). Negligible levels of TNF expression, associated with no phenotypic alterations, are observed in cells transfected with MMTV-TNF vectors in the absence of glucocorticoid. Expression levels could be stimulated by the addition of the synthetic glucocorticoid dexamethasone. Increasing expression levels of TNF were associated with enhanced cytotoxicity. Our results suggest the potential use of inducible TNF systems for the treatment of tumours in gene therapy protocols. (C) 1994 Wiley-Liss, Inc.
引用
收藏
页码:103 / 107
页数:5
相关论文
共 22 条
[1]   INHIBITION BY GLUCOCORTICOIDS OF TUMOR NECROSIS FACTOR-MEDIATED CYTOTOXICITY - EVIDENCE AGAINST LIPOCORTIN INVOLVEMENT [J].
BEYAERT, R ;
SUFFYS, P ;
VANROY, F ;
FIERS, W .
FEBS LETTERS, 1990, 262 (01) :93-96
[2]   TUMOR SUPPRESSION AFTER TUMOR-CELL TARGETED TUMOR-NECROSIS-FACTOR-ALPHA GENE-TRANSFER [J].
BLANKENSTEIN, T ;
QIN, ZH ;
UBERLA, K ;
MULLER, W ;
ROSEN, H ;
VOLK, HD ;
DIAMANTSTEIN, T .
JOURNAL OF EXPERIMENTAL MEDICINE, 1991, 173 (05) :1047-1052
[3]   DEXAMETHASONE INCREASES THE NUMBER OF RNA POLYMERASE-II MOLECULES TRANSCRIBING INTEGRATED MOUSE MAMMARY-TUMOR VIRUS-DNA AND FLANKING MOUSE SEQUENCES [J].
FIRZLAFF, JM ;
DIGGELMANN, H .
MOLECULAR AND CELLULAR BIOLOGY, 1984, 4 (06) :1057-1062
[4]   COMPARISON OF INVITRO-CELL CYTO-TOXIC ASSAYS FOR TUMOR NECROSIS FACTOR [J].
FLICK, DA ;
GIFFORD, GE .
JOURNAL OF IMMUNOLOGICAL METHODS, 1984, 68 (1-2) :167-175
[5]   MOUSE MAMMARY-TUMOR VIRUS MEDIATED TRANSFER AND EXPRESSION OF NEOMYCIN RESISTANCE TO INFECTED CULTURED-CELLS [J].
GUNZBURG, WH ;
SALMONS, B .
VIROLOGY, 1986, 155 (01) :236-248
[6]  
GUNZBURG WH, 1992, BIOCHEM J, V283, P625
[7]   GLUCOCORTICOID AND CAMP INDUCTION MECHANISMS ARE DIFFERENTIALLY AFFECTED BY THE P85GAG-MOS ONCOPROTEIN [J].
HAMILTON, BJ ;
DEFRANCO, D .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1989, 86 (02) :597-601
[8]   DEXAMETHASONE AND PENTOXIFYLLINE INHIBIT ENDOTOXIN-INDUCED CACHECTIN TUMOR-NECROSIS-FACTOR SYNTHESIS AT SEPARATE POINTS IN THE SIGNALING PATHWAY [J].
HAN, J ;
THOMPSON, P ;
BEUTLER, B .
JOURNAL OF EXPERIMENTAL MEDICINE, 1990, 172 (01) :391-394
[9]   MOLECULAR APPROACHES TO CANCER-THERAPY [J].
ISRAEL, MA .
ADVANCES IN CANCER RESEARCH, VOL 61, 1993, 61 :57-85
[10]   THE V-MOS AND H-RAS ONCOGENE EXPRESSION REPRESSES GLUCOCORTICOID HORMONE-DEPENDENT TRANSCRIPTION FROM THE MOUSE MAMMARY-TUMOR VIRUS LTR [J].
JAGGI, R ;
SALMONS, B ;
MUELLENER, D ;
GRONER, B .
EMBO JOURNAL, 1986, 5 (10) :2609-2616