Antiangiogenic therapy enhances the efficacy of transcatheter arterial embolization for hepatocellular carcinomas

Abstract

Transcatheter arterial embolization (TAE) is a well-established technique for unresectable hepatic malignancies. However, TAE can temporally halt the growth of hepatic tumors by blocking their arterial supply, but often tumors rapidly develop collateral blood vessels via angiogenesis. We have previously demonstrated that intraportal delivery of adeno-associated viral particles expressing angiostatin leads to long-term expression of angiostatin capable of inhibiting angiogenesis and suppressing the outgrowth of tumors in the liver. Thus, we hypothesize that adeno-associated virus (AAV)-mediated antiangiogenic therapy could enhance the efficacy of TAE to combat liver cancers. To achieve this objective, we engineered a recombinant AAV vector encoding rat angiostatin. Intraportal delivery of this vector led to long term and stable transgenic expression of angiostatin locally in rat hepatocytes and suppressed the growth of CBRH7919 hepatocellular carcinomas established in rat livers by inhibiting formation of neovessels. Although TAE therapy led to necrosis of liver tumors and suppressed their growth, the neovessels of tumors were rapidly reformed 3 weeks after TAE. However, intraportal injection of AAV-angiostatin inhibited the angiogenesis stimulated by TAE, synergized with TAE in suppressing growth of tumors established in livers and prolonged the survival of rats. In conclusion, these encouraging results warrant future investigation of the use of antiangiogenic therapy for enhancing the therapeutic efficacy of TAE to treat unresectable liver cancers. ' 2007 Wiley-Liss, Inc.Key words: hepatocellular carcinoma; transcatheter arterial embolization; angiogenesis; adeno-associated virus; angiostatin; gene therapy Hepatocellular carcinoma (HCC) is one of the most common malignancies in the world with an estimated incidence of more than one million new cases per year.1,2 HCC has a very poor prognosis with less than a 6% 5-year survival rate. Only surgery offers a cure, but liver resection is feasible for less than 15% of patients, and recurrence rates remain high after tumor resection.3 Chemotherapy and radiotherapy offer unsatisfactory response rates. Therefore, new strategies to combat HCC are urgently needed.The application of transcatheter arterial embolization (TAE) to treat liver cancers has developed conceptually based on the observation that both primary and secondary liver tumors derive their blood supply mainly from the hepatic artery, 4 while blood supply to normal liver mainly depends on the portal system. 5,6 Thus, artery obstruction by embolization can cause extensive ischemic tumor necrosis, which provides the rational for its wide use as a standard treatment for unresectable HCC. 7,8 However, the effectiveness of TAE in treating HCC is debatable as any beneficial results are short-lived because collateral arterial circulations rapidly develop. It has been reported that TAE enhances the rate of intrahepatic and extrahepatic metastases, and even results in a shorter survival.9-11 Recanalization of the embo...

Hepatic Overexpression of Heme Oxygenase-1 Improves Liver Allograft Survival by Expanding T Regulatory Cells

“…Similar results have been obtained in rats by using this method [20,21]. Here, we demonstrated in a rat model of orthotopic liver transplantation (OLT) that persistent overexpression of HO-1 in transplanted livers induced by intraportal delivery of AAV prolonged the survival of allografts, and induced tolerance of grafts by expanding a population of T reg cells.…”

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“…The tissues were homogenized in protein lysate buffer as described previously [18][19][20][21], the debris was removed by centrifugation, and the protein content was determined. Samples containing 30 mg of total JOURNAL OF SURGICAL RESEARCH: VOL.…”

Natural and genetically engineered viral agents for oncolysis and gene therapy of human cancers

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Molecular targeted therapy with transarterial chemoembolization

“…This combination causes a reduction in tumor volume and vessel density, as well as a prolongation in survival compared with TAE alone. 21 Therefore, one improvement in the treatment of HCC with TACE would be to prevent the recruitment of these secondary vessels.…”