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An Experimental Study Of The Synergistic Effect Of TRAIL Combined With Cisplatin In RD Rhabdomyosarcoma Cell Line

Posted on:2006-10-11Degree:DoctorType:Dissertation
Country:ChinaCandidate:Y S XuFull Text:PDF
GTID:1104360152493166Subject:Surgery
Abstract/Summary:PDF Full Text Request
Rhabdomyosarcoma (RMS) is composed of cells with histologic features of striated muscle in various stages of embryogenesis. It is the most common soft tissue sarcoma in the pediatric population, accounting for approcimately 4%—8% of all childhood cancers and for about 50% —60% of malignant soft tissue sarcomas, and has received considerable attention.In 1972,the Intergroup Rhabdomyosarcoma Study(now called IRSG) was established to increase knowledge and to improve therapeutic results for rhabdomyosarcoma from all locations. Historically,most children died from this meoplasm,more recently,emphasis has been placed on improved methods of management,particularly adjunctive chemotherapy and irradiation. Although the introduction of adjuvant chemotherapy in combination with surgical treatment has substantially improved the long-term survival rate of patients with RMS in recent years, there is inherent or acquired resistance to these chemotherapeutic agents in some cases.Thus, a new approach for treatment of RMS patients is greatly required.Apoptosis (programmed cell death) plays a critical role in embryonic development, metamorphosis, hormone-dependent atrophy and tumor growth, as a physiological event regulating the cell number or eliminating damaged cells, and it prevents the development of tumor cells. Recently, much attention has been drawn by apoptosis regulators such as death receptors belonging to the tumor necrosis factor (TNF) family of cytokines,consisting of TNF, Fas (CD95), and TNF-related apoptosis- inducing ligand (TRAIL). Tumor necrosis factor-related apoptosis -inducing ligand (TRAIL),also known as Apo2 ligand (Apo2L),is another member of the TNF family, represents a type II transmembrane protein exerting sequence homology to TNF-alpha and FasL, that triggers rapid apoptosis in vitro and in vivo in various tumor cells without marked toxicity on normal cells.TRAIL is the subject of intense study currently because it can induce cell death in a wide variety of tumor cell lines. Preclinical studies of recombinant TRAIL in animal models have demonstrated potent antitumor effect. Based on these data, TRAIL merits further investigation as a possible safe alternative and potential candidate for cancer treatment. Of great potential therapeutic importance, Apo2L/TRAIL synergizes with conventional DNA-damaging chemotherapeutic drugs, which has the dual benefits of enhanced tumor killing at a lower drug dose, and therefore reducing the toxicity to normal cells associated with conventional chemotherapy.Chemotherapy plays an important role in the treatment of cancer.Cisplatin , the one of the most widely used cytotoxic drugs in the chemotherapy of human cancers,is a potent DNA-damaging anticancer agent,and its cytotoxic action is exerted by the induction of apoptosis. we investigated its ability to induce apoptosis in rhabdomyosarcoma cells. Unfortunately,high-dose cisplatin therapy is often associated with significant toxicity affecting the kidney,peripheral neurons,and cochlea,which may affect quality of life and can be life threatening,in addition to toxicity a major problem associated with medicine resistance.Approaches for improving the therapeutic index of treatment have included measures of enhancing sensitivity of the tumour relative to normal tissue or,alternatively,reducing toxicity to normal tissues while leaving tumour resistance unchanged.Gene therapy for cancer can provide a new treatment option for this fatal disease. The application of gene therapy has brought new hopes to the cure of cancer and other severe diseases in the past decades. The core strategy of cancer gene therapy is the apoptosis induction of the carcinoma cells through deliverying the useful DNA fragments into thecarcinoma cells by means of the gene recombination.The main advantage of this strategy is overcoming the dose-limiting toxicity of traditional chemotherapy. Because TRAIL gene can be peculiar to kill tumor cells,attract attention in tumor gene therapy at present.TRAIL Gene is one attractive candidate to be used in combination wi...
Keywords/Search Tags:Rhabdomyosarcoma, TRAIL, Apoptosis, Cisplatin, Gene therapy
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