Enhanced in vivo adenovirus-mediated gene transfer to rat hepatocarcinomas by selective administration into the hepatic artery

Abstract

Adenovirus-mediated gene therapy of experimental hepaarterial blood supply, 67% of the total liver blood supply. tocarcinoma is hindered by low transduction efficacy in Compared with intraportal administration, arterial injection vivo. We evaluated the extent of gene expression following improved gene transfer into tumors whereas that to the various routes of administration of recombinant adenovirus non-tumor areas was diminished. In addition, this route of AdCMVlacZ in diethylnitrosamine-induced rat hepatocarciinjection allowed the efficient transduction of dysplastic noma. We first characterized the vascularization of dinodules. Diethylnitrosamine-induced hepatocarcinoma in ethylnitrosamine-induced hepatocarcinomas using a comrats is a relevant model for the study of human hepatocarputerized tomography scanner approach. The efficacy of cinoma due to its vascularization. Arterial infusion gene transfer was then evaluated by three routes of adminimproved the ratio of transduced tumorous to nontumorous istration: intraportal, selective injection through the hepatic cells and allowed targeting of gene transfer to dysplastic artery and direct injection into the tumor. Diethylnitronodules. This will be useful in the design of gene therapy samine-induced hepatocarcinomas had predominantly an for hepatocarcinoma.

A blood–tumor barrier limits gene transfer to experimental liver cancer: the effect of vasoactive compounds

“…[13][14][15] In previous reports we and others have shown that in this animal model, gene transfer to large tumor nodules was very low by intraportal administration of adenoviral vectors. 7,16,17 Since primary liver tumors receive blood supply mainly from the hepatic artery, 18 some authors have compared the intraportal and intra-arterial route for vector administration in DENAinduced HCC. 17 These investigators found better gene transfer efficiency by intra-arterial injection than by intraportal administration of adenovirus but large tumors were not transduced even by the intra-arterial route.…”

“…7,16,17 Since primary liver tumors receive blood supply mainly from the hepatic artery, 18 some authors have compared the intraportal and intra-arterial route for vector administration in DENAinduced HCC. 17 These investigators found better gene transfer efficiency by intra-arterial injection than by intraportal administration of adenovirus but large tumors were not transduced even by the intra-arterial route. 17 In a previous work we have proposed that there is a physical barrier between blood and tumor cells that would be responsible for poor transduction of tumor nodules with vectors used in gene therapy.…”

“…17 These investigators found better gene transfer efficiency by intra-arterial injection than by intraportal administration of adenovirus but large tumors were not transduced even by the intra-arterial route. 17 In a previous work we have proposed that there is a physical barrier between blood and tumor cells that would be responsible for poor transduction of tumor nodules with vectors used in gene therapy. 7 Capillarization of sinusoids, formation of basement membrane and activation of hepatic stellate cells (HSC) have been described to occur in HCC.…”

Efficient and cancer-selective gene transfer to hepatocellular carcinoma in a rat using adenovirus vector with iodized oil esters

“…Nevertheless, gene therapy could not be effective in HCC because the efficiency of gene transfer in hepatic tumor tissue and the cancer selectivity are not sufficient, especially in large tumors. 3,4 HCC has often been studied because of its unusual blood flow. 2 Unlike normal hepatocytes, which receive blood from both the hepatic artery and the portal vein, the cells of HCC receive 80 -100% of their blood supply from the hepatic artery.…”

Liver gene therapy: advances and hurdles

“…In this setting, numerous studies have shown that liver tumor cells are poorly susceptible to gene transfer vectors, thus emphasizing the importance of endothelium permeability in in vivo liver gene transfer strategies. [13][14][15] For all these reasons, the past decade has witnessed the blossoming of studies devoted to liver gene transfer using a wide array of viral and nonviral vectors. However, no clinical treatment of a liver genetic disease has been obtained in patients so far.…”