Adeno-associated Virus Vector-mediated Trail And Dr5 Single-chain Antibody Expression In The Treatment Of Lung Cancer Experimental Research

Lung carcinoma is the leading cause of malignancy-related mortality. Despite the recent advances in diagnostic techniques and the significant improvement in surgery, chemotherapy and radiotherapy, there is still little change in survival rates over the past two decades. This failure of conventional therapy is due primarily to a propensity to metastasize and to resistance to chemotherapy and radiation. Consequently, other treatment options must be explored in order to get around this problem. For this reason, gene theapy became the most promising treatment modality for lung cancer.Apoptosis, known as programmed cell death, is defined as a cell's preferred form of death under hectic conditions through genetically conserved and complex pathways. There is a decisive balance between stimulatory and inhibitory signaling pathways to maintain homeostasis in cells. In order to shift the balance towards apoptosis, the modulation of both apoptotic and anti-apoptotic pathways represents an attractive target for cancer therapy. At present, death ligands are being evaluated as potential cancer therapeutic agents.TNF-related apoptosis inducing ligand (TRAIL/Apo-2L) is a typical member of the TNF ligand family that induces apoptosis through activating the death receptors. In recent years, considerable attention has been focused on the potential benefits of TRAIL in cancer therapy, as the majority of cancer cells are sensitive to TRAIL-induced apoptosis, while most normal cells are TRAIL-resistant. Five TRAIL receptors identified in humans are TRAIL receptor 1 (death receptor 4, DR4), TRAIL receptor 2 (death receptor 5, DR5), TRAIL receptor 3 (decoy receptor 1, DcR1), TRAIL receptor4 (decoy receptor 2, DcR2) and osteoprotegerin (OPG). They display high sequence homology in their extracellular domains. DR4 and DR5 contain a cytoplasmic region consisting of a stretch of 80 amino acids designated as the death domain (DD) which can trigger an apoptotic response upon TRAIL binding via the activation of caspase cascade. Whereas the other three, DcRl, DcR2 and OPG have not a completed DD, are therefore unable to induce apoptosis.In this study we used a rAAV2/5 vector, expressing TRAIL_114-281,to examine the...