Fractionated radiation therapy in combination with adenoviral delivery of the cytosine deaminase gene and 5-fluorocytosine enhances cytotoxic and antitumor effects in human colorectal and cholangiocarcinoma models
MA StackhouseLC PedersonWE GrizzleDT CurielJohannes GebertKarin HaackSM VickersMS MayoDonald J. Buchsbaum
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Effective delivery of therapeutic genes to target cells is an essential goal of all innovative gene therapy endeavours and recombinant vaccine technology. Current use of viral vectors in achieving this goal has been associated with minimal success and plethora of unwanted adverse events. As a result, there is an ongoing search for suitable vector platforms for the delivery of therapeutic genes to target cells. Such agent should be easily manipulated to accommodate small and large gene inserts and safely deliver Transgenes. This will ensure effective expression of the gene in target cells. The resulting optimal expression of this gene may correct defective or deficient gene in individuals receiving gene therapy. This chapter examines the applications of biopolymers as non-viral gene delivery vectors either alone or as copolymers.
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1. Present and Future Status of Gene Therapy 2. DNA Packaging in Non Viral Systems 3. Biological Barriers to Gene Transfer 4. Therapeutic Applications of Lipid-Based Gene Delivery Systems 5. Polycation-based Delivery Systems for Receptor-Mediated Gene Delivery 6. DNA Delivery Systems Based on Synthetic Peptides 7. Expression Plasmids for Non-Viral Gene Therapy 8. Gene Therapy Clinical Trials for Cystic Fibrosis 9. Polymeric Gene Delivery Systems for In Vivo Gene Therapy 10. Intravascular Delivery of Naked Plasmid DNA 11. Cationic Lipid-Based Gene Delivery Systems 12. Gene-based Vaccines 13. Gene Therapy for Cancer: Strategies and Review of Clinical Trials
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Anticancer enzyme / prodrug approaches to therapy are designed to activate prodrugs specifically at tumor loci, to achieve antitumor responses with minimal toxicity. The equivocal success of these approaches thus far has led to searches for more efficient combinations. This mini-review evaluates and compares characteristics of seven selected enzyme / prodrug combinations, and discusses goals for future development of effective combinations.
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Gene Therapy for Inherited Genetic Disease Possibilities and Problems C. Coutelle. Gene Delivery and Therapy: The Case for Cystic Fibrosis E.W.F.W. Alton. Immune Responses with Direct Gene Transfer: DNA Vaccines and Implications for Gene Therapy H.L. Davis. Oligonucleotides: Molecular Versions for Optimal Use In Vivo E. Saison-Behmoaras, et al. Retrovirus Vectors in Gene Therapy: Targeting to Specific Cells A.J. Kingsman, et al. Adenovirus as Vectors for Gene Therapy M.G. Lee. Receptor-mediated Gene Delivery with Synthetic Virus-Like Particles E. Wagner, et al. Controllable Gene Therapy-Recent Advances in Non-Viral Gene Delivery A. Rolland. Genetic Chemistry: Towards Non-Enzymatic Ligation. Sequence-Selective Recognition of DNA and Self-Assembling Systems for Gene Delivery J.-P. Behr. Integrin-Mediated Gene Delivery S.L. Hart, et al. Design, Synthesis and Cellular Delivery of Antibody Targeted, Radiolabelled Oligonucleotide Conjugates for Cancer Therapy C.S.R. Gooden, A.A. Epenetos. 7 Additional Articles. Index.
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Abstract Purpose: The success of enzyme/prodrug cancer therapy is limited by the uncertainty in the delivery of the enzyme in vivo. This study shows the use of noninvasive magnetic resonance (MR) and optical imaging to image the delivery of a prodrug enzyme. With this capability, prodrug administration can be timed so that the enzyme concentration is high in the tumor and low in systemic circulation and normal tissue, thereby minimizing systemic toxicity without compromising therapeutic efficiency. Experimental Design: The delivery of a multimodal imaging reporter functionalized prodrug enzyme, cytosine deaminase, was detected by MR and optical imaging in MDA-MB-231 breast cancer xenografts. Stability of the enzyme in the tumor was verified by 19F MR spectroscopy, which detected conversion of 5-fluorocytosine to 5-flurouracil. The optimal time window for prodrug injection determined by imaging was validated by immunohistochemical, biodistribution, and high-performance liquid chromatographic studies. The therapeutic effect and systemic toxicity of this treatment strategy were investigated by histologic studies and tumor/body weight growth curves. Results: The delivery of the functionalized enzyme in tumors was successfully imaged in vivo. The optimal time window for prodrug administration was determined to be 24 h, at which time the enzyme continued to show high enzymatic stability in tumors but was biodegraded in the liver. Significant tumor growth delay with tolerable systemic toxicity was observed when the prodrug was injected 24 h after the enzyme. Conclusion: These preclinical studies show the feasibility of using a MR-detectable prodrug enzyme to time prodrug administration in enzyme/prodrug cancer therapy.
Cytosine deaminase
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