DELAYED MORBIDITY AND MORTALITY OF ALBUMIN/SV40 T-ANTIGEN TRANSGENIC MICE AFTER INSERTION OF AN ALPHA-FETOPROTEIN/HERPES VIRUS THYMIDINE KINASE TRANSGENE AND TREATMENT WITH GANCICLOVIR

被引:39
作者
MACRI, P
GORDON, JW
机构
[1] MT SINAI SCH MED,DEPT OBS GYN & REPROD SCI,NEW YORK,NY 10029
[2] MT SINAI SCH MED,DEPT GERIATR & ADULT DEV,NEW YORK,NY 10029
关键词
D O I
10.1089/hum.1994.5.2-175
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The alpha-fetoprotein (AFP) gene is normally expressed in fetal liver and transcriptionally silent in adult tissues, but can be abnormally reactivated in hepatocellular carcinoma (HCC). We linked 7.6 kb of 5'-flanking DNA from the mouse AFP gene to the herpes simplex virus (HSV) thymidine kinase gene (tk), and a line of transgenic mice was produced that expressed TK in a pattern similar to endogenous AFP. When these AFP/tk transgenic mice were crossed to another transgenic line that develops multifocal HCC due to expression of a SV40 large T-antigen transgene under regulation of the albumin promoter/enhancer complex, a significant delay of tumor progression could be achieved by administration of ganciclovir (GCV), a cytotoxic compound that is a substrate for phosphorylation by viral, but not mammalian, TK. Control animals carrying only the tk gene were unaffected by GCV treatment. These results illustrate the feasibility of prophylactic gene therapy for ablation of cancer, utilizing a strategy in which the tk gene is regulated by a promoter expected to be active only in tumor cells.
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页码:175 / 182
页数:8
相关论文
共 30 条
[1]  
ALPINI G, 1992, AM J PATHOL, V141, P623
[2]  
BECKER FF, 1985, CANCER RES, V45, P768
[3]   GENETIC-ANALYSIS OF ALPHA-FETOPROTEIN SYNTHESIS IN MICE [J].
BELAYEW, A ;
TILGHMAN, SM .
MOLECULAR AND CELLULAR BIOLOGY, 1982, 2 (11) :1427-1435
[4]   SOMATIC EXPRESSION OF HERPES THYMIDINE KINASE IN MICE FOLLOWING INJECTION OF A FUSION GENE INTO EGGS [J].
BRINSTER, RL ;
CHEN, HY ;
TRUMBAUER, M ;
SENEAR, AW ;
WARREN, R ;
PALMITER, RD .
CELL, 1981, 27 (01) :223-231
[5]   MOLECULAR PATHOGENESIS OF HEPATOCELLULAR-CARCINOMA IN HEPATITIS-B VIRUS TRANSGENIC MICE [J].
CHISARI, FV ;
KLOPCHIN, K ;
MORIYAMA, T ;
PASQUINELLI, C ;
DUNSFORD, HA ;
SELL, S ;
PINKERT, CA ;
BRINSTER, RL ;
PALMITER, RD .
CELL, 1989, 59 (06) :1145-1156
[6]   INVIVO GENE-TRANSFER WITH RETROVIRAL VECTOR PRODUCER CELLS FOR TREATMENT OF EXPERIMENTAL BRAIN-TUMORS [J].
CULVER, KW ;
RAM, Z ;
WALLBRIDGE, S ;
ISHII, H ;
OLDFIELD, EH ;
BLAESE, RM .
SCIENCE, 1992, 256 (5063) :1550-1552
[7]   9-([2-HYDROXY-1-(HYDROXYMETHYL)ETHOXY]METHYL)GUANINE - A SELECTIVE INHIBITOR OF HERPES GROUP VIRUS-REPLICATION [J].
FIELD, AK ;
DAVIES, ME ;
DEWITT, C ;
PERRY, HC ;
LIOU, R ;
GERMERSHAUSEN, J ;
KARKAS, JD ;
ASHTON, WT ;
JOHNSTON, DBR ;
TOLMAN, RL .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1983, 80 (13) :4139-4143
[8]   RIBONUCLEIC-ACID ISOLATED BY CESIUM-CHLORIDE CENTRIFUGATION [J].
GLISIN, V ;
CRKVENJAKOV, R ;
BYUS, C .
BIOCHEMISTRY, 1974, 13 (12) :2633-2637
[9]  
GORDON JW, 1983, METHOD ENZYMOL, V101, P411
[10]   GENETIC-TRANSFORMATION OF MOUSE EMBRYOS BY MICRO-INJECTION OF PURIFIED DNA [J].
GORDON, JW ;
SCANGOS, GA ;
PLOTKIN, DJ ;
BARBOSA, JA ;
RUDDLE, FH .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1980, 77 (12) :7380-7384