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

Our plain-English summary of Highly efficient tumor transduction and antitumor efficacy in experimental human malignant mesothelioma using replicating gibbon ape leukemia virus, by S. Kubo, M. Takagi-Kimura, C.R. Logg, et al (Cancer Gene Therapy, 2013).

The study

• Authors: S. Kubo, M. Takagi-Kimura, C.R. Logg, N. Kasahara
• Journal: Cancer Gene Therapy
• Published: 2013;20(12):671-7
• Cited by: 14 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This laboratory study used human cell lines and mouse xenografts, not people or asbestos exposure. The authors compared retroviral replicating vectors derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV) in four human malignant mesothelioma cell lines and in non-malignant mesothelial cells. Both GFP-carrying vectors spread through most mesothelioma lines but were severely attenuated in the non-malignant cells. In MESO1 cells, GALV-GFP reached more than 95% GFP-positive cells within 12 days, while AMLV-GFP stayed below 20% at day 40. In nude mice bearing MESO1 tumours, four weeks after a single intratumoral injection, GFP-positive cells were 97.3±4.9% with GALV-GFP and 1.1±0.2% with AMLV-GFP. With the cytosine deaminase gene, at the highest 5-fluorocytosine dose tested (10 mM, three days of exposure after 15 days of vector spread), MESO1 viability was 11.9±4.4% with GALV-CD versus 83.3±12.7% with AMLV-CD. In mice given 5-fluorocytosine from day 14 to day 28, MESO1 tumours on day 28 measured 1715.5±212.7 mm3 after GALV-CD versus 3171.0±485.8 mm3 after AMLV-CD. MESO1 cells expressed high PiT-1 and low PiT-2.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Laboratory experimental study: in vitro cell-line experiments plus subcutaneous xenograft experiments in nude mice
• Who was studied: Human mesothelioma cell lines MSTO-211H, NCI-H2052, NCI-H2452 and ACC-MESO-1, normal human adult mesothelial cells and SV40-transformed Met5A cells, and BALB/c nude mice bearing subcutaneous MSTO or MESO1 xenografts (n=8 per group for imaging, n=10 per group for therapy); work done in Japan and the USA
• Exposure: Retroviral replicating vectors derived from amphotropic murine leukemia virus (AMLV) and gibbon ape leukemia virus (GALV), carrying either green fluorescent protein or the yeast cytosine deaminase prodrug activator gene, given at a multiplicity of infection of 0.01 in vitro or as a single intratumoral injection of 1 x 10^4 transducing units, with 5-fluorocytosine prodrug (500 mg per kg per day intraperitoneally)
• Main results:
  • In vitro, GALV-GFP reached more than 95% GFP-expressing MESO1 cells within 12 days, whereas AMLV-GFP remained under 20% at day 40
  • In normal mesothelial cells and Met5A, both vectors spread poorly
  • In MESO1 xenografts at week 4 after a single intratumoral injection, GFP-positive tumour cells were 4.7±2.7% (LV-GFP), 1.1±0.2% (AMLV-GFP) and 97.3±4.9% (GALV-GFP)
  • In MSTO xenografts at week 4, GFP-positive tumour cells were 7.9±4.1% (LV-GFP), 92.7±6.1% (AMLV-GFP) and 94.4±5.8% (GALV-GFP)
  • In cultured MESO1 cells transduced at a multiplicity of infection of 0.01 and exposed to 5-fluorocytosine for three days from day 15, viability at the highest dose level (10 mM) was 11.9±4.4% with GALV-CD versus 83.3±12.7% with AMLV-CD
  • In the mouse MESO1 xenograft model, tumour volume on day 28 after vector injection, with 5-fluorocytosine given every other day from day 14 to day 28, was 1715.5±212.7 mm3 after GALV-CD (P less than 0.01 versus AMLV-CD), compared with 3171.0±485.8 mm3 after AMLV-CD and 3209.2±510.7 mm3 in the phosphate-buffered saline control group
  • By quantitative PCR, MESO1 cells showed high PiT-1 (GALV receptor) and low PiT-2 (AMLV receptor) messenger RNA; PiT-1 was expressed in all four mesothelioma lines but was low in NMC and Met5A, while PiT-2 was higher in NMC and Met5A
• The authors' conclusion: The authors concluded that GALV-based replicating retroviral vectors replicated efficiently and transduced human malignant mesothelioma cells with minimal spread in normal mesothelial cells, and that their results show therapeutic efficacy of GALV-RRV-mediated cytosine deaminase/5-fluorocytosine prodrug activator gene therapy in this mesothelioma model

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Malignant Mesothelioma, Mesothelioma, Mesothelial Cells.

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