Highly efficient tumor transduction and antitumor efficacy in experimental human malignant mesothelioma using replicating gibbon ape leukemia virus

Abstract

Retroviral replicating vectors (RRVs) have been shown to achieve efficient tumor transduction and enhanced therapeutic benefit in a wide variety of cancer models. Here we evaluated two different RRVs derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV), in human malignant mesothelioma cells. In vitro, both RRVs expressing the green fluorescent protein gene efficiently replicated in most mesothelioma cell lines tested, but not in normal mesothelial cells. Notably, in ACC-MESO-1 mesothelioma cells that were not permissive for AMLV-RRV, the GALV-RRV could spread efficiently in culture and in mice with subcutaneous xenografts by in vivo fluorescence imaging. Next, GALV-RRV expressing the cytosine deaminase prodrug activator gene showed efficient killing of ACC-MESO-1 cells in a prodrug 5-fluorocytosine dose-dependent manner, compared with AMLV-RRV. GALV-RRV-mediated prodrug activator gene therapy achieved significant inhibition of subcutaneous ACC-MESO-1 tumor growth in nude mice. Quantitative reverse transcription PCR demonstrated that ACC-MESO-1 cells express higher PiT-1 (GALV receptor) and lower PiT-2 (AMLV receptor) compared with normal mesothelial cells and other mesothelioma cells, presumably accounting for the distinctive finding that GALV-RRV replicates much more robustly than AMLV-RRV in these cells. These data indicate the potential utility of GALV-RRV-mediated prodrug activator gene therapy in the treatment of mesothelioma.

Oncolytic virotherapy for human malignant mesothelioma: recent advances

“…Finally, retroviral replicating vectors have been shown to efficiently transduce human MM cells both in vitro and in vivo in subcutaneous xenograft models. 49 , 50 The vectors that were used in this study encode a prodrug activator gene that sensitizes tumor cells to the prodrug, 5-fluorocytosine. Tumor cells and their healthy counterparts were reported to exhibit different expression levels of the retrovirus receptors, which could account for the oncolytic potential of retroviruses against MM.…”

Antinociceptive Effect of Intrathecal Injection of Genetically Engineered Human Bone Marrow Stem Cells Expressing the Human Proenkephalin Gene in a Rat Model of Bone Cancer Pain

“…(ii) BMSCs can also modulate spinal cord nociceptive signaling pathways, for example, by blocking the upregulation of inducible nitric oxide synthase expression to suppress pain transmission [ 34 ]. (iii) BMSCs have potential inhibitory effects on tumor cell growth in vitro and in vivo by inducing apoptotic cell death and G0/G1 phase arrest in cancer cells [ 35 , 36 ]. (iv) BMSCs also secrete a certain level of analgesic agents, such as L-EK when including the transgene producing L-EK, to act on the μ -opioid receptor, which is the most important of their antinociceptive effects.…”

Efficient Prodrug Activator Gene Therapy by Retroviral Replicating Vectors Prolongs Survival in an Immune-Competent Intracerebral Glioma Model

“…In particular, MLV-RRV currently in clinical development expresses the MLV 4070A strain amphotropic envelope, which binds the ubiquitous inorganic phosphate transporter, PiT-2 [17]. In contrast, gibbon ape leukemia virus (GALV) envelope enables cellular entry through another member of the same phosphate transporter family, PiT-1, and accordingly we have developed GALV-based RRV which also appears to show robust replicative spread in a wide variety of cancer cell lines [18][19][20][21][22].…”