Systemic Gene-Directed Enzyme Prodrug Therapy of Hepatocellular Carcinoma Using a Targeted Adenovirus Armed with Carboxypeptidase G2

Abstract

Hepatocellular carcinoma is the fifth most common cancer worldwide, and there is no effective therapy for unresectable disease. We have developed a targeted systemic therapy for hepatocellular carcinoma. The gene for a foreign enzyme is selectively expressed in the tumor cells and a nontoxic prodrug is then given, which is activated to a potent cytotoxic drug by the tumor-localized enzyme. This approach is termed gene-directed enzyme prodrug therapy (GDEPT). Adenoviruses have been used to target cancer cells, have an intrinsic tropism for liver, and are efficient gene vectors. Oncolytic adenoviruses produce clinical benefits, particularly in combination with conventional anticancer agents and are well tolerated. We rationalized that such adenoviruses, if their expression were restricted to telomerase-positive cancer cells, would make excellent gene vectors for GDEPT therapy of hepatocellular carcinoma. Here we use an oncolytic adenovirus to deliver the prodrug-activating enzyme carboxypeptidase G2 (CPG2) to tumors in a single systemic administration. The adenovirus replicated and produced high levels of CPG2 in two different hepatocellular carcinoma xenografts (Hep3B and HepG2) but not other tissues. GDEPT enhanced the adenovirus-alone therapy to elicit tumor regressions in the hepatocellular carcinoma models. This is the first time that CPG2 has been targeted and expressed intracellularly to effect significant therapy, showing that the combined approach holds enormous potential as a tumor-selective therapy for the systemic treatment of hepatocellular carcinoma. (Cancer Res 2005; 65(12): 5003-8)

On Advances in Cancer Suicide-genes Therapy

“…This system has been used in hepatocellular carcinoma cells and xenografts exhibiting inhibition of tumour growth and extending the lifespan of the mice. [29] Similar results have been shown in human colon carcinoma xenografts. [30] According to this reaction, other prodrugs have been studied.…”

“…CPG2 has been used as antitumor therapy in breast, colon, hepatocellular and colon carcinomas. [26][27][28][29][30] The ZD2767P prodrug is a substrate of GPG2, which activates this prodrug as a bifunctional DNA interstrand cross-linking alkylating agent. This system has been used in hepatocellular carcinoma cells and xenografts exhibiting inhibition of tumour growth and extending the lifespan of the mice.…”

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

“…Most commonly investigated anticancer prodrugs, such as ganciclovir, 5-fluorocytosine (5-FC), 4-[N,N-bis(2-iodoethyl) amino] phenoxycarbonyl L-glutamic acid (ZD2767P) and 5-(azaridin-1-yl) 2,4-dinotrobenzamide (CB1954) are chemically synthesized ex vivo and then directly administered to patients. 28,[34][35][36] By contrast, SN-38G is generated in vivo by UDPglucuronosyl transferases acting on SN-38, the active metabolite of CPT-11. 8 In vivo generation of SN-38G may be particularly advantageous as hydrophilic glucuronide metabolites are rapidly eliminated from the circulation.…”

The cooperative effect of p53 and Rb in local nanotherapy in a rabbit VX2 model of hepatocellular carcinoma

“…6,7 Of these, combined therapy has proven the best solution to date. [8][9][10] A previous study 11 successfully combined p53 gene therapy, embolic therapy, and nanotherapy at the liver tumor site by exploiting poly-L-lysine (PLL)-modified hydroxyapatite nanoparticles (nHAPs) to serve as embolic material and gene vector at the same time. However, complete tumor elimination was not observed in any of the animals and the survival prolongation was limited, thus further improvements to the therapy are necessary before clinical application.…”