Coexpression of Guanylate Kinase with Thymidine Kinase Enhances Prodrug Cell Killing in Vitro and Suppresses Vascular Smooth Muscle Cell Proliferation in Vivo
Molecular Therapy, ISSN: 1525-0016, Vol: 3, Issue: 5, Page: 779-786
2001
- 21Citations
- 7Captures
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Example: if you select the 1-year option for an article published in 2019 and a metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019. If you select the 3-year option for the same article published in 2019 and the metric category shows 90%, that means that the article or review is performing better than 90% of the other articles/reviews published in that journal in 2019, 2018 and 2017.
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Metrics Details
- Citations21
- Citation Indexes21
- 21
- CrossRef19
- Captures7
- Readers7
Article Description
Herpes simplex virus-thymidine kinase (HSV-TK) phosphorylates the prodrugs ganciclovir (GCV) and acyclovir (ACV), leading to disruption of DNA synthesis and inhibition of cell proliferation. HSV-TK vectors have been successfully employed in cardiovascular and cancer gene therapy. Activation of GCV and ACV, after an initial phosphorylation step by the viral thymidine kinase, is carried out by guanylate kinase. We reasoned that coexpression of guanylate kinase (GK) with HSV-TK would augment phosphorylation of GCV or ACV, leading to increased cell killing. To test this hypothesis, a vector expressing TK with GK (TKciteGK) was developed and tested on vascular smooth muscle cells (vsmcs) in vitro and in vivo. Compared to HSV-TK vectors, killing of vascular cells transduced with TKciteGK and exposed to GCV was significantly increased ( P = 0.03). The TKciteGK construct was evaluated with three promoters: CMV, EF1α, and SM22α. TKciteGK expression driven by a CMV promoter induced cell killing more effectively than SM22α or EF1α promoters in primary vsmcs. Based upon these in vitro findings, TKciteGK vectors with a CMV promoter were tested in two animal models of cardiovascular disease: balloon angioplasty and stent deployment in pig arteries. Following vascular injury, expression of CMV-TKciteGK with GCV significantly reduced vsmc proliferation and intimal lesion formation compared to control vectors with GCV. In the angioplasty model, there was an 80% reduction in intima-to-media area ratio ( P = 0.0002). These findings were paralleled in a stent model with 66% reduction in intimal lesions ( P = 0.006). Coexpression of GK with TK increases cell killing and permits administration of GCV at lower doses. These modifications in TKciteGK vectors and GCV showed enhanced efficacy at lower prodrug doses, leading to improved safety for cardiovascular gene therapy.
Bibliographic Details
http://www.sciencedirect.com/science/article/pii/S1525001601903156; http://dx.doi.org/10.1006/mthe.2001.0315; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=0034989201&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/11356082; https://linkinghub.elsevier.com/retrieve/pii/S1525001601903156; https://dx.doi.org/10.1006/mthe.2001.0315
Elsevier BV
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