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

Bilbao, Roberto; Bustos, Matilde; Alzuguren, Pilar; Pajares, MJ; Droździk, Marek; Qian, Chen; Prieto, Jesús

doi:10.1038/sj.gt.3301312

Cited by 65 publications

(57 citation statements)

References 38 publications

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“…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.…”

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confidence: 99%

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

et al. 2001

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Gene therapy for cancer requires efficient, selective gene transfer to cancer cells. In gene therapy for hepatocellular carcinoma ( HCC ) , gene transfer is efficient for small tumors, but not for large tumors. The delivery of anticancer agents and of iodized oil esters as embolic agents through tumor -feeding arteries is known as transarterial embolization. We speculate that genes may be efficiently and selectively transferred for HCC using iodized oil esters because these esters may remain together with a genetic vector within HCC selectively. Hence, we have studied the effect of iodized oil esters on adenovirus vector -mediated gene transfer for HCC in vivo. A rat model of HCC induced with diethylnitrosamine and phenobarbital was injected with either AxCALacZ, which expresses the -galactosidase of Escherichia coli, or AxCALacZ and iodized oil esters into the hepatic artery. Histological comparisons revealed that the -galactosidase expression in the rats with HCC injected with AxCALacZ and iodized oil esters was greater ( P < .0001 ) in small tumors ( P = .0046 ) and large tumors ( P = .0023 ) , and more selective ( P = .0229 ) than in only AxCALacZinjected rats. These results suggest that iodized oil esters are injected into hepatic artery together with adenovirus vector, and that genes may be efficiently and cancer -selectively transferred to HCC. Cancer Gene Therapy ( 2001 ) 8, 713 -718

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confidence: 99%

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

et al. 2001

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“…Viral spreading through tumour tissue is not very efficient, owing to physical barriers emerging from normal connective tissues and endothelial cells within tumours and/or high intratumoral pressure. [9][10][11] In addition, in situ tumour tissues support viral replication much less efficiently than cultured cell lines, for example, owing to the lack of viral receptors. To accelerate cell lysis, release and cell-tocell spread of virus, modifications of Ad genes regulating cell death have been suggested.…”

Section: Introductionmentioning

confidence: 99%

Melanoma cultures show different susceptibility towards E1A-, E1B-19 kDa- and fiber-modified replication-competent adenoviruses

et al. 2006

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Replicating adenovirus (Ad) vectors with tumour tissue specificity hold great promise for treatment of cancer. We have recently constructed a conditionally replicating Ad5 AdDEP-TETP inducing tumour regression in a xenograft mouse model. For further improvement of this vector, we introduced four genetic modifications and analysed the viral cytotoxicity in a large panel of melanoma cell lines and patient-derived melanoma cells. (1) The antiapoptotic gene E1B-19 kDa (D19 mutant) was deleted increasing the cytolytic activity in 18 of 21 melanoma cells. (2) Introduction of the E1A 122-129 deletion (D24 mutant), suggested to attenuate viral replication in cell cycle-arrested cells, did not abrogate this activity and increased the cytolytic activity in two of 21 melanoma cells. (3) We inserted an RGD sequence into the fiber to extend viral tropism to av integrinexpressing cells, and (4) swapped the fiber with the Ad35 fiber (F35) enhancing the tropism to malignant melanoma cells expressing CD46. The RGD-fiber modification strongly increased cytolysis in all of the 11 CAR-low melanoma cells. The F35 fiber-chimeric vector boosted the cytotoxicity in nine of 11 cells. Our results show that rational engineering additively enhances the cytolytic potential of Ad vectors, a prerequisite for the development of patient-customized viral therapies. Gene Therapy (2006) 13, 893-905.

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“…We have reported this previously in the rat sarcoma model particularly at the viable rim of the tumour (de Roos et al, 2000). Bilbao et al (2000) found that a blood -tumour barrier in hepato-cellular carcinoma in rats limits the gene transfer in tumours greater than 5 mm in diameter. Moreover, they also concluded that tumours between 2 and 5 mm could only be transfected by hepatic artery infusion.…”

Section: Discussionmentioning

confidence: 99%

Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

et al. 2002

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Ras mutations are present in 40 -50% of colorectal cancers. Inactivating this oncogene may therefore reduce proliferation capacity. In order to target ras we studied the transduction efficacy and anti tumour activity of an adenoviral vector expressing an intracellular, neutralizing single chain antibody to p21-ras (Y28). In in vitro studies transfection levels of the K-ras mutated rat colon carcinoma cell line CC531 were studied using the LacZ marker gene. In our in vivo liver metastases model different routes of administration were evaluated to determine which regimen resulted in the best transfection levels and tumour responses: intravenous injection, intratumoural injection, isolated liver perfusion, or hepatic artery infusion. CC531 cells are readily transfected in vitro, resulting in significant inhibition of tumour cell proliferation by the Y28 construct. Intravenous injection did not result in any measurable transfection. Intratumoural injection resulted only in the transfection of tumour cells along the needle track. IHP as well as single HAI achieved low transfection levels of tumour tissue. Expression of Y28 was demonstrated in tumours after IT injection, HAI and IHP. Whereas, repeated HAI's clearly achieved expression in and around tumour associated vessels. Only five times repeated HAI's with Y28 resulted in a tumour response: in all animals tumour growth was inhibited, and in three rats out of eight a complete regression of the liver tumours was observed.

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

Cited by 65 publications

References 38 publications

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

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

Melanoma cultures show different susceptibility towards E1A-, E1B-19 kDa- and fiber-modified replication-competent adenoviruses

Prerequisites for effective adenovirus mediated gene therapy of colorectal liver metastases in the rat using an intracellular neutralizing antibody fragment to p21-Ras

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