TY - JOUR TI - Stem cell-based ovarian cancer suicide gene therapy DO - https://doi.org/doi:10.7282/T38W3G9H PY - 2015 AB - Cancer is a leading cause of death worldwide, resulting in 8.2 million deaths in 2012. Tumor suicide gene therapy is among the novel targeted therapeutics that has demonstrated promising results. There are two important factors that specify the efficiency and safety of the suicide gene therapy systems. One is vector safety and efficiency and the other enzyme/prodrug anticancer efficacy. Among the vectors employed for delivery of therapeutics, mesenchymal stem cells (MSCs) have attracted tremendous amount of attention due to their unique features such as inherent tumor tropism and low immunogenicity. The objective of this research was to take advantage of MSCs as cell-based vectors to develop an efficient and safe suicide gene therapy system for cancer. As a first step towards achieving the objective, I engineered a panel of MSCs that were genetically modified to express five different suicide genes and compared their anti-tumor efficiency in vitro and in vivo. Among the enzyme/prodrug systems tested, genetically modified MSCs that expressed yeast cytosine deaminase enzyme (yCD-UPRT) in combination with prodrug 5-fluorocytosine (5FC) demonstrated the highest anti-tumor efficacy. In the next step we focused on developing a safe and efficient method for stem cell engineering. Since current commercially available transfection agents are inefficient and toxic to MSCs, I made an attempt to develop a safe and efficient gene delivery system suitable for MSC engineering. Using a previously developed vector in Dr. Hatefi’s lab as a template, I recombinantly engineered a new vector for MSC transfection. This vector is comprised of a cell penetrating peptide for penetration into MSCs, four histone H2A repeats to condense plasmid DNA (pDNA) into nanosize particles and a fusogenic peptide named GALA to facilitate endosomal escape. The results of this study illustrated that the newly developed recombinant vector could efficiently and safely transfect MSCs. In conclusion we not only successfully developed a safe and efficient method for stem cell engineering but also identified an enzyme/prodrug system that could be used for effective treatment of ovarian cancer. KW - Pharmaceutical Science KW - Cancer--Gene therapy KW - Ovaries--Cancer KW - Stem cells LA - eng ER -