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Growth Retardation of Poorly Transfectable Tumor by Multiple Injections of Plasmids Encoding PE40 Based Targeted
Yuriy Khodarovich1, Darya Rakhmaninova1, German Kagarlitskiy1
1Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow, Russian Federation.
Background:
One of the approaches to cancer gene therapy relies on tumor transfection with DNA encoding toxins under the control of tumor-specific promoters.
Methods:
Here, we used DNA plasmids encoding very potent anti-ERBB2 targeted toxin, driven by the human telomerase promoter or by the ubiquitous CAG promoter (pTERT-ETA and pCAG-ETA) and linear polyethylenimine to target cancer cells.
Results:
We showed that the selectivity of cancer cell killing by the pTERT-ETA plasmid is highly dependent upon the method of preparation of DNA-polyethylenimine complexes. After adjustment of complex preparation protocol, cell lines with high activity of telomerase promoter can be selectively killed by transfection with the pTERT-ETA plasmid. We also showed that cells transfected with pTERT-ETA and pCAG-ETA plasmids do not exert any detectable bystander effect in vitro.
Conclusion:
Despite this, three intratumoral injections of a plasmid-polyethylenimine complex resulted in substantial growth retardation of a poorly transfectable D2F2/E2 tumor in mice. There were no significant differences in anti-tumor properties between DNA constructs with telomerase or CAG promoters in vivo.
Insights
Cancer gene therapy using DNA plasmids encoding toxins showed tumor growth retardation in mice. Selectivity depends on DNA-polyethylenimine complex preparation, with no bystander effect observed.
Area of Science:
- Oncology
- Gene Therapy
- Molecular Biology
Background:
- Cancer gene therapy utilizes tumor transfection with DNA encoding toxins.
- Tumor-specific promoters control the expression of these therapeutic toxins.
Purpose of the Study:
- To evaluate DNA plasmids encoding an anti-ERBB2 toxin driven by telomerase or CAG promoters for cancer cell targeting.
- To assess the efficacy of DNA-polyethylenimine complexes in cancer gene therapy.
Main Methods:
- Utilized DNA plasmids (pTERT-ETA and pCAG-ETA) encoding a potent anti-ERBB2 toxin.
- Employed linear polyethylenimine for targeted delivery of DNA plasmids to cancer cells.
- Investigated the impact of DNA-polyethylenimine complex preparation on transfection selectivity and efficacy.
Main Results:
- Selectivity of cancer cell killing by pTERT-ETA was dependent on DNA-polyethylenimine complex preparation.
- Optimized protocols enabled selective killing of cells with high telomerase promoter activity.
- No significant bystander effect was observed in vitro for pTERT-ETA and pCAG-ETA transfected cells.
- Intratumoral injections of plasmid-polyethylenimine complexes significantly retarded D2F2/E2 tumor growth in mice.
Conclusions:
- Optimized DNA-polyethylenimine complex preparation enhances the selectivity of cancer gene therapy.
- The anti-ERBB2 toxin delivered via plasmids shows in vivo anti-tumor activity.
- Both telomerase and CAG promoters demonstrated comparable anti-tumor properties in vivo.
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