Tumor-specific intravenous gene delivery using oncolytic adenoviruses.
In this report, we describe a vector system that specifically delivers transgene products to tumors following intravenous (i.v.) administration. The Escherichia coli cytosine deaminase (CD) gene was placed in the E3B region of the tumor-selective, replication-competent adenovirus ONYX-411, under the control of endogenous viral late gene regulatory elements. Thus, CD expression was directly coupled to the tumor-selective replication of the viral vector. In vitro, CD was expressed efficiently in various human cancer cell lines tested but not in cultured normal human cells, including human hepatocytes. Following i.v. administration into nude mice carrying human tumor xenografts, robust CD activity was detected only in tumors but not in liver or other normal tissues. Levels of CD activity in the tumors increased progressively following i.v. virus administration, correlating closely with virus replication in vivo. Subsequent administration of 5-fluorocytosine (5-FC) demonstrated a trend to improve the antitumor efficacy of these viruses in a mouse xenograft model, presumably due to the intratumoral conversion of 5-FC to the chemotherapeutic drug 5-fluorouracil. We show that the combination of a highly selective oncolytic virus, ONYX-411, with the strategic use of the viral E3B region for transgene insertion provides a powerful platform that allows for tumor-specific, persistent and robust transgene expression after i.v. administration. This technology provides an opportunity to enhance greatly both safety and efficacy of cancer gene therapy.
Zhan
Jinghui
J
Onyx Pharmaceuticals Inc., Richmond, California 94806, USA.
Gao
Yi
Y
Wang
Wensheng
W
Shen
Annie
A
Aspelund
Amy
A
Young
Mandy
M
Laquerre
Sylvie
S
Post
Leonard
L
Shen
Yuqiao
Y
D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D043525:Cytosine Deaminase / Q000096:biosynthesis* / Q000235:genetics*; D004926:Escherichia coli / Q000235:genetics; D005437:Flucytosine / Q000494:pharmacology; D005786:Gene Expression Regulation; D018014:Gene Transfer Techniques; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors; D022781:Hepatocytes; D006801:Humans; D007262:Infusions, Intravenous; D051379:Mice; D008819:Mice, Nude; D019076:Transgenes; D014183:Transplantation, Heterologous; D014407:Tumor Cells, Cultured; D014779:Virus Replication
D000963:Antimetabolites; D005437:Flucytosine; D043525:Cytosine Deaminase