Combination of Mesenchymal Stem Cells-delivered Oncolytic Virus and Prodrug Activation Increases Efficacy and Safety in Cancer Therapy

Autor: Mei-Hsuan Wu, 吳美萱
Rok vydání: 2014
Druh dokumentu: 學位論文 ; thesis
Popis: 102
Oncolytic viruses, such as conditionally replicative adenoviruses (CRAds), have been successfully approved in clinical trials for cancer therapy. However the anti-tumor efficacy was still not ideal. Gene-directed enzyme-prodrug therapy (GDEPT), that is prodrug activation-generated cytotoxic metabolites caused bystander effect to kill tumor, offers new approach to improve the cytotoxic efficacy in tumor. Our previous study demonstrated that mesenchymal stem cells (MSCs) when cultured under hypoxic conditions can function as a cellular vehicle to carry anti-tumor agents to tumor in vivo. In the current study, we first showed that hypoxic MSCs when pre-treated with trichostatin A (TSA) further increased the ability to migrate toward tumors through the up-regulation of chemokine receptors, such as CXCR4. We then demonstrated that hypoxic MSCs loaded with CRAds encoding Escherichia coli Nitroreductase (NTR) enzymes (CRAdNTR) successfully protected CRAdNTR from neutralization by anti- Adv antibodies both in vitro and in vivo and targeted to tumor cells when infused intravenously (i.v.). We finally revealed that hypoxic MSCs loaded with CRAdNTR when co-cultured with tumor cells or i.v. infused in mice carrying tumor converted prodrug CB1954 to potentially cytotoxic metabolites such as 4-hydroxylamine, 2-amine, which could induce oncolysis of cancer cells without causing harm to other neighboring normal cells and organs. Thus, the improvement of the efficacy of tumor suppression by the combination of MSCs-delivered oncolytic virus and prodrug activation increases efficacy and safety in cancer therapy may provide a new avenue to develop oncolytic viral therapy for various cancers by using this strategy.
Databáze: Networked Digital Library of Theses & Dissertations
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