Oncolytic recombinant herpes simplex virus for treatment of orthotopic liver tumors in nude mice

Abstract

Abstract. Cell-specific, replicating viruses are being developed as a new class of oncolytic agents. A novel approach to viral gene therapy with the use of replication-competent herpes simplex virus has been described; G92A is a replicationcompetent, multimutant oncolytic herpes simplex virus (HSV) that has been evaluated for anticancer effects and selectivity in the treatment of subcutaneous tumors. G92A replicates efficiently in albumin-producing tumor cell lines but not in non-albumin-producing tumor cell lines, whereas both types are equally susceptible to a non-tissue-specific recombinant HSV, hrR3. In this study, we analyzed the antitumoral efficacy of a single intrasplenic G92A or hrR3 injection in nude mice. In vivo, G92A replicated well in liver xenografts of human albumin-producing hepatoma cells (Hep3B) but not in liver xenografts of a non-albumin-producing malignant colon tumor cell line (HT29), whereas hrR3 replicated well in both tumor types. G92A effectively and selectively replicated throughout liver tumors without apparent hepatotoxicity and inhibited tumor growth, leading to a significantly increased survival time. By monitoring lacZ histochemical staining, we determined the oncolytic potential of recombinant HSV against liver tumors. Our results indicate that G92A warrants further investigation as a clinical therapy against malignant liver tumors.

Oncolytic Viruses Driven by Tumor-Specific Promoters

“…G92A also demonstrated potent antitumor activity in mouse subcutaneous xenografts obtained from human hepatoma, but not in nonhuman hepatoma xenografts [85]. In addition to its antitumor activity against subcutaneous mouse xenografts, it was also effective in causing selective and efficient oncolysis of liver tumors in mice without apparent hepatotoxicity [86]. Similarly, the promoter region of breast-specific α lacta albumin (ALA) has been employed to generate two CRAds: AdALAE1a with E1a under the control of ALA promoter and AdE1aALAE1b with both E1a and E1b genes driven by α lacta albumin promoter, respectively.…”

Gene therapy of liver cancer: an update

“…The HSV-1 mutant G92A replicates preferentially in cancer cells due to a deletion in the TK gene. In addition, an essential viral gene (ICP4) was placed under the transcriptional control of the albumin promoter to further restrict the activity to HCC cells [128]. The virus showed replication in orthotopic HCC xenografts in mice without liver toxicity.…”

Advances in Experimental and Translational Research in the Treatment of Hepatocellular Carcinoma

“…HSV also possesses other characteristics that make it an appealing agent for cancer therapy. Many recombinant versions of HSV have been created and characterized in preclinical studies for a wide spectrum of cancers, including brain, colorectal, lung, gastric, prostrate, breast, bladder, and head and neck cancers, and HCC [25,37]. Song et al studied the effects of G207, a replication competent attenuated HSV currently in human brain cancer trials, in the treatment of HCC cell lines.…”

“…Oncolytic viruses have also been investigated as potential vectors for combined oncolytic therapy and gene therapy for HCC. Interleukin (IL)-12 has been genetically engineered into strains of HSV that enable the virus to lyse primary hepatic tumors while producing this immunostimulatory cytokine at the local site of cancer [37].…”