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Replicase-based plasmid DNA shows anti-tumor activity
B Leticia Rodriguez1, Zhen Yu, Woon-Gye Chung
1Pharmaceutics Division, College of Pharmacy, University of Texas, Austin, TX 78712, USA.
Background:
Double stranded RNA (dsRNA) has multiple anti-tumor mechanisms. Over the past several decades, there have been numerous attempts to utilize synthetic dsRNA to control tumor growth in animal models and clinical trials. Recently, it became clear that intracellular dsRNA is more effective than extracellular dsRNA on promoting apoptosis and orchestrating adaptive immune responses. To overcome the difficulty in delivering a large dose of synthetic dsRNA into tumors, we propose to deliver a RNA replicase-based plasmid DNA, hypothesizing that the dsRNA generated by the replicase-based plasmid in tumor cells will inhibit tumor growth.
Methods:
The anti-tumor activity of a plasmid (pSIN-β) that encodes the sindbis RNA replicase genes (nsp1-4) was evaluated in mice with model tumors (TC-1 lung cancer cells or B16 melanoma cells) and compared to a traditional pCMV-β plasmid.
Results:
In cell culture, transfection of tumor cells with pSIN-β generated dsRNA. In mice with model tumors, pSIN-β more effectively delayed tumor growth than pCMV-β, and in some cases, eradicated the tumors.
Conclusion:
RNA replicase-based plasmid may be exploited to generate intracellular dsRNA to control tumor growth.
Insights
A novel RNA replicase-based plasmid effectively generates intracellular double-stranded RNA (dsRNA) within tumor cells, significantly inhibiting tumor growth and offering a promising new strategy for cancer therapy.
Area of Science:
- Molecular Biology
- Immunology
- Oncology
Background:
- Double-stranded RNA (dsRNA) exhibits potent anti-tumor properties.
- Intracellular dsRNA is more effective than extracellular dsRNA for inducing apoptosis and immune responses.
- Challenges exist in delivering sufficient synthetic dsRNA to tumors.
Purpose of the Study:
- To investigate the anti-tumor efficacy of an RNA replicase-based plasmid DNA system.
- To determine if in-situ generated dsRNA can inhibit tumor growth.
Main Methods:
- A plasmid encoding sindbis RNA replicase genes (pSIN-β) was designed.
- The anti-tumor activity of pSIN-β was assessed in mouse tumor models (TC-1 lung cancer, B16 melanoma).
- pSIN-β's efficacy was compared against a control plasmid (pCMV-β).
Main Results:
- Transfection with pSIN-β successfully generated dsRNA in tumor cells in vitro.
- pSIN-β significantly delayed tumor growth in vivo compared to pCMV-β.
- Complete tumor eradication was observed in some cases with pSIN-β treatment.
Conclusions:
- RNA replicase-based plasmids can be utilized to generate intracellular dsRNA.
- This approach shows potential for controlling tumor growth.
- Further development may lead to novel cancer therapeutics.
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