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Paramyxoviruses for Tumor-targeted Immunomodulation: Design and Evaluation Ex Vivo
Published on: January 7, 2019
Infectivity enhanced adenoviral-mediated mda-7/IL-24 gene therapy for ovarian carcinoma
Charles A Leath1, Manjula Kataram, Pradeep Bhagavatula
1Department of Obstetrics and Gynecology, University of Alabama at Birmingham, 901 19th Street South, Birmingham, AL 35294, USA.
Objective:
Melanoma differentiation associated gene-7 [mda-7/Interleukin (IL)-24] has been identified as a novel anti-cancer agent, which specifically induces apoptosis in cancer cells but not in normal epithelial, endothelial and fibroblast cells. The objective of this study was to evaluate the anti-tumor effect of adenovirus-mediated mda-7/IL-24 (Ad.mda-7) gene therapy in ovarian carcinoma and further improve anti-tumor effect by enhancing infectivity of Ad.mda-7.
Methods:
A panel of human ovarian carcinoma cells, OV-4, HEY, SKOV3, SKOV3.ip1 and control normal human mesothelial cells, were infected by a replication deficient recombinant adenovirus encoding mda-7/IL-24 and control virus Ad.CMV.Luc. After 72 h, apoptosis was evaluated by TUNEL and Hoechst staining and further quantified by fluorescent activated cell sorter (FACS) analysis. Infectivity of Ad.mda-7 was enhanced by retargeting it to CD40 or EGF receptors overexpressed on ovarian cancer cells. Subsequently, enhancement in apoptosis of CD40- or epidermal growth factor receptor (EGFR)-retargeted Ad.mda-7 was evaluated.
Results:
Adenoviral-mediated delivery of mda-7 induces apoptosis ranging from 10-23% in human ovarian cancer cells tested with the highest percentage of apoptosis noted in SKOV3 cells. Minimal apoptosis was noted in normal mesothelial cells. CD40- or EGFR-retargeted Ad.mda-7 increased apoptosis by 10-32% when compared to that achieved with untargeted Ad.mda-7.
Conclusion:
Ad.mda-7 exhibits ovarian cancer-specific apoptosis, but does not affect normal human mesothelial cells. Infectivity enhanced CD40- and EGFR-retargeted Ad.mda-7 augments apoptosis induction, thus increasing the therapeutic index and translational potential of Ad.mda-7 gene therapy.
Insights
Melanoma differentiation associated gene-7 (mda-7/IL-24) gene therapy effectively induces ovarian cancer cell apoptosis. Enhancing its infectivity via CD40 or EGFR retargeting significantly boosts anti-tumor effects.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Melanoma differentiation associated gene-7 (mda-7/Interleukin-24) is a novel anti-cancer agent.
- mda-7/IL-24 selectively induces apoptosis in cancer cells while sparing normal cells.
Purpose of the Study:
- To evaluate the anti-tumor efficacy of adenovirus-mediated mda-7/IL-24 (Ad.mda-7) in ovarian carcinoma.
- To enhance the anti-tumor effect of Ad.mda-7 by improving its infectivity.
Main Methods:
- Human ovarian carcinoma cells and normal mesothelial cells were infected with Ad.mda-7 or a control virus.
- Apoptosis was assessed using TUNEL and Hoechst staining, quantified by FACS.
- Ad.mda-7 infectivity was enhanced by retargeting to CD40 or EGF receptors.
Main Results:
- Ad.mda-7 induced apoptosis in ovarian cancer cells (10-23%), with minimal effect on normal cells.
- Retargeting Ad.mda-7 to CD40 or EGFR receptors increased apoptosis by 10-32% compared to untargeted virus.
- SKOV3 cells showed the highest apoptosis induction.
Conclusions:
- Ad.mda-7 demonstrates ovarian cancer-specific apoptosis induction.
- Enhanced infectivity of retargeted Ad.mda-7 augments apoptosis, improving its therapeutic potential for ovarian cancer.
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