Abstract
Gene therapy has been evaluated for the treatment of prostate cancer and includes the application of adenoviral vectors encoding a suicide gene or oncolytic adenoviruses that may be armed with a functional transgene. In parallel, versions of adenoviral vector expressing the p53 gene (Ad-p53) have been tested as treatments for head and neck squamous cell carcinoma and non-small cell lung cancer. Although Ad-p53 gene therapy has yielded some interesting results when applied to prostate cancer, it has not been widely explored, perhaps due to current limitations of the approach. To achieve better functionality, improvements in the gene transfer system and the therapeutic regimen may be required. We have developed adenoviral vectors whose transgene expression is controlled by a p53-responsive promoter, which creates a positive feedback mechanism when used to drive the expression of p53. Together with improvements that permit efficient transduction, this new approach was more effective than the use of traditional versions of Ad-p53 in killing prostate cancer cell lines and inhibiting tumor progression. Even so, gene therapy is not expected to replace traditional chemotherapy but should complement the standard of care. In fact, chemotherapy has been shown to assist in viral transduction and transgene expression. The cooperation between gene therapy and chemotherapy is expected to effectively kill tumor cells while permitting the use of reduced chemotherapy drug concentrations and, thus, lowering side effects. Therefore, the combination of gene therapy and chemotherapy may prove essential for the success of both approaches.
Highlights
Prostate cancer In the United States, prostate carcinoma is the most frequent cancer among men, accounting for 19% of cancers in 2017
Though incidence rates vary by region and are higher in developed countries, an estimated 1.1 million men were diagnosed with prostate cancer in 2012, making it the second most common cancer in men worldwide
The highest rates are in Australia, North America, and Northern and Western Europe, which are regions where testing for prostate-specific antigen (PSA) has become commonplace
Summary
Improving adenoviral vectors and strategies for prostate cancer gene therapy Rodrigo Esaki Tamura, Igor Vieira de Luna, Marlous Gomes Lana, Bryan E. We showed that Ad-PGp53 was better able to induce cell death in vitro and in vivo than Ad-CMVp53, and in situ gene therapy resulted in reduced tumor volume and increased overall survival only with Ad-PGp53 In this same work, we observed that the PC3 prostate carcinoma cell line was not efficiently transduced by Ad5 [72]. We made an additional improvement, incorporating the RGD motif in the fiber protein, creating AdRGD-PGp53, which offers both enhanced transduction efficiency in PC3 cells and a high level of p53 expression due to the positive feedback mechanism This vector showed strong antitumor activity in vitro and in vivo, inducing high levels of reactive oxygen species (ROS), DNA damage and alteration of mitochondrial membrane permeability and resulting in apoptosis [21]. Gene therapy may work in cooperation with traditional chemotherapy, benefiting both approaches and bringing about synergistic activity as an effective prostate cancer treatment
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