Suicidal gene therapy in the effective control of primary human hepatocellular carcinoma as monitored by noninvasive bioimaging

Abstract

Hepatocellular carcinoma (HCC) is usually refractory to the available treatments. For cancer gene therapy purposes, real-time imaging of therapeutic gene expression is of great importance because there are multiple factors that modulate the therapeutic gene expression in a complex tumor microenvironment. As a consequence, multiple doses of therapeutic viral vectors may be required for improved efficacy. In the present study, the luciferase reporter gene and the yeast cytosine deaminase (yCD) genes were bicistronically expressed using the foot-and-mouth disease virus 2A peptide under the regulation of the cytomegalovirus (CMV) promoter. The effectiveness of the yCD/5-FC (5-fluorocytosine) killing efficacy mediated by the herpes simplex virus type 1 (HSV-1) amplicon viral vector was shown using HCC and non-HCC cell lines in vitro. In addition, in vivo experiment also showed tumor regression of a primary HCC 26-1004 tumor xenograft in tumor expressing high levels of the yCD gene (as determined by noninvasive imaging) after intratumoral injection of 1.5Â10 6 TU HGCX-L2C HSV-1 amplicon viral vector and 5-FC administration. The HSV-1 amplicon viral vector coupled with the yCD/5-FC prodrug activated suicide gene could potentially be of use in clinical gene therapy for HCC.

Retroviral Replicating Vectors Deliver Cytosine Deaminase Leading to Targeted 5-Fluorouracil-Mediated Cytotoxicity in Multiple Human Cancer Types

“…CD also catalyzes, by means of a deamination step, the conversion of the prodrug 5-FC to the chemotherapeutic drug 5-FU 9,10 within cancer cells expressing gene therapy-delivered CD. CDbased prodrug activating gene therapy has been investigated in preclinical animal models and clinical trials for many cancer types, including colon, 11,12 liver, 13,14 head and neck, 25,26 sarcomas, 27,28 melanoma, 11,29 and ovarian 13,30 cancers. CD-based cancer gene therapy has proven to be effective in chemotherapyresistant cancer cell lines, 31,32 in combination with chemotherapy, 4 and to enhance the effect of radiotherapy.…”

In Vitro Radionuclide Therapy and In Vivo Scintigraphic Imaging of Alpha-Fetoprotein-Producing Hepatocellular Carcinoma by Targeted Sodium Iodide Symporter Gene Expression

“…Until recently, diverse gene therapy strategies for HCC have been examined, such as gene augmentation therapy for tumor suppressor gene [5], drug sensitization therapy including the HSV1-tk/ganciclovir [6,24] or cytosine deaminase/5-fluorocytosine [25], and genetic immunotherapy using a cytokine gene [4]. Also, since the NIS gene was first cloned in 1996 [26], many studies have demonstrated the efficacy of molecular imaging or radioiodide gene therapy using NIS in vitro and in vivo [16,17,[27][28][29].…”

Gene Therapy in Liver Diseases: State-of-the-Art and Future Perspectives

“…More specifically, Foka et al, [168] identified and experimentally characterized novel hepatoma-specific promoters, which were valuable for cancer-specific gene therapy, by using HSV-1 vectors. Sia et al, [170] used as a viral vector the HSV-1 amplicon in HCC and non-HCC cell lines in vitro and in vivo with promising results. Several other reports characterized different kinds of HSV-1 vectors as platforms for virotherapy against liver cancer [167,168,[171][172][173].…”