Gene therapy is one of the frontiers of modern medicine. 2006

Gene therapy is one of the frontiers of modern medicine. 2006 to 2010 with mortality reaching 2 830 559 ( The existing therapeutic approaches such as medical procedures thermotherapy chemotherapy and radiotherapy often have severe side effects such as cytotoxicity to normal cells and strong host immune responses. Most critically some cancers barely respond to these therapies [1 2 5-hydroxymethyl tolterodine and so alternative therapeutic approaches are needed. Gene therapy is usually one such attempt. Gene therapy consists of three basic actions: (i) constructing a gene-carrying vector (ii) transferring genes into target cancer cells with the vector and (iii) expressing gene products BMP2 to kill malignancy cells. Constructing an effective vector for carrying therapeutic genes is essential for successful gene therapy. Gene-carrying vectors can be divided into two categories: non-viral vectors and viral vectors. Non-viral vectors such as naked plasmids microbubbles nanoparticles liposomes and polymers are safe low-cost and offer large insert size of genes; 5-hydroxymethyl tolterodine however in vivo gene transfection and expression is usually inefficient and transient despite low immunogenicity [3]. Viral vectors such as adenoviral vectors retroviral vectors and lentiviral vectors 5-hydroxymethyl tolterodine provide effective gene transduction and expression; however they have several disadvantages including high immunorejection possible tumorigenicity uncertain insertional mutagenesis and limited constructive sizes for gene insertion. These disadvantages have prevented translation into clinical practice. Thus it is imperative that gene-carrying vectors have (1) high transferring ability (2) low immunorejection and (3) long-term gene expression [4]. Adeno-associated computer virus (AAV) gene-carrying vectors meet these requirements. AAVs for cancer gene therapy are superior to other gene vectors with relatively low host immune response poor toxicity and long-term gene expression. AAVs have been successfully used to deliver and transfer a variety of therapeutic genes to cancer cells including suicide genes anti-angiogenic genes and immune-related genes to inhibit tumor initiation growth and metastasis. Herein we review the development and recent advances of AAV-mediated cancer gene therapy aiming to provide up-to-date information on the clinical application of AAV-based gene therapy. 2 Biology of AAVs The adeno-associated computer virus first discovered in the 1960s [5] is usually replication-deficient and belongs to the family of Parvoviridae. As the best known representative of all the AAVs AAV2 contains a single stranded DNA genome comprising of inverted terminal repeats (ITRs) and two open reading frames encoding replication and capsid proteins. The structure of AAV2 has been decided to 3-? resolution (Fig. 1) [6]. Recently Gao have obtained more than 120 novel primate AAVs[7]. The diverse tissue and cell tropisms of mainly used AAV vectors were listed in table 1. Fig. 1 Structure of the AAV-2 subunit and comparison with related structures Table 1 The different tissue and cell tropisms of mainly used AAV serotypes. 3 Advances of AAV vectors The AAV based gene delivery systems are more attractive comparing to other vectors. More benefits were discovered using AAV vectors such as more safety due to the lack of pathogenicity more varied host and cell-type tropisms long-term gene expression ability to transfect both dividing and nondividing cells absence of enormous immune response. Furthermore the discovery of more novel AAV serotypes will further extend the scope of application of AAV based gene delivery system. However several problems about this gene delivery system should be resolved. Firstly the effective packaging capacity of AAV is limited to 4.1 to 4.9kb [26] which restricts the transduction of larger genes. Secondly antibody neutralization rises because of prior exposure of human beings with multiple AAV serotypes [27]. Thirdly challenges with high-efficient transduction to specific cell populations remain in AAV mediated gene delivery system. Since 5-hydroxymethyl tolterodine these problems influenced the extended application of AAV based gene therapy a variety of attempts to improve this vector have been carried out. Self-complementary AAV (scAAV) vectors can fold into double-stranded DNA (dsDNA) without DNA synthesis or base-pairing between multiple vector genomes [28] bypassing the conversion to dsDNA. Naturally these vectors are more sufficient to transgene expression than normal AAV vectors. The.