Therapeutic efficacy of replication-competent retrovirus vector-mediated suicide gene therapy in a multifocal colorectal cancer metastasis model.
Replication-competent retrovirus (RCR) vectors are intrinsically incapable of infecting quiescent cells and have been shown to achieve highly efficient and tumor-restricted replicative spread and gene transfer in vivo after direct intratumoral injection in a variety of primary cancer models. However, i.v. delivery of RCR vectors expressing therapeutic genes has never previously been tested, particularly in an immunocompetent tumor model. Therefore, in the present study, we sought to test the therapeutic effect of an RCR vector (ACE-CD) carrying the yeast cytosine deaminase (CD) gene, which converts the nontoxic prodrug 5-fluorocytosine (5FC) into the chemotoxin 5-fluorouracil, after delivery by infusion into the locoregional circulation in a multifocal hepatic metastasis model of colon cancer. After confirmation of suicide gene cytotoxicity in vitro, multifocal hepatic tumors were established in syngeneic mice with murine CT26 colorectal cancer cells expressing firefly luciferase (CT26-Luc), and the ACE-CD vector was infused via intrasplenic injection into the portal circulation. Fourteen days after locoregional infusion, systemic administration of 5FC resulted in significant inhibition of bioluminescent signals in mice whose tumors had been infected with RCR but not in control mice. Notably, there was no detectable RCR vector spread to normal liver or bone marrow by quantitative PCR analysis. Our results thus show that locoregional delivery of a suicide gene by RCR vectors infused into the portal circulation results in progressive transduction of multiple tumor foci in the liver, without evidence of spread to adjacent normal parenchyma or extrahepatic tissues, and can achieve significant tumor growth inhibition.
Hiraoka
Kei
K
Department of Medicine, University of California Los Angeles, Los Angeles, California 90095, USA.
Kimura
Takahiro
T
Logg
Christopher R
CR
Tai
Chien-Kuo
CK
Haga
Kazunori
K
Lawson
Gregory W
GW
Kasahara
Noriyuki
N
D000818:Animals; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000628:therapy* / Q000821:virology; D043525:Cytosine Deaminase / Q000235:genetics / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005437:Flucytosine / Q000493:pharmacokinetics; D005472:Fluorouracil / Q000493:pharmacokinetics / Q000494:pharmacology; D041722:Genes, Transgenic, Suicide; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000235:genetics; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000235:genetics / Q000556:secondary / Q000628:therapy / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D012190:Retroviridae / Q000235:genetics / Q000502:physiology*; D014779:Virus Replication
D005437:Flucytosine; D043525:Cytosine Deaminase; D005472:Fluorouracil