Expression Of Survivin In Non-hodgkin's Lymphoma And Effects Of Anti Survivin Oligonucleotides On Growth And Apoptosis Of Lymphoma Cells

Non-Hodgkin's lymphomas (NHL) represent the most frequent type of lymphoma -80% to 90% of lymphoma. Conventional treatment for patients with NHL includes radiation or chemotherapy. Although these tumors can be treated successfully with chemotherapy or radiotherapy, primary chemoresistance and relapse often occur and are the major causes of death in these patients. Therapies directed against rapidly dividing cells will result in death of epithelium (such as the lining of the gastrointestinal tract) or may affect hematopoietic progenitors resulting in cytopenias. These side effects not only reduce the quality of life of cancer patients, but also limit dose intensification and ultimately therapeutic antitumor activity. So it is important for longer survival period to find available therapeutic approaches. This goal may be approached by activating alternate death signaling pathways and inhibiting the key molecular determinants of lymphoma cell survival. Using molecular approaches such as antisense ODNs is one way of achieving this goal.Considerable experimental evidence points to a critical role for dysregulation of apoptosis in the onset and progression of cancer. In the case of cancer, an abnormally increased cellular lifespan as a consequence of reduced apoptosis is ideal to favor the insurgence of genetic mutations, as well as to shield tumor cells from death induced by chemotherapy or radiotherapy, and to promote their survival at distant sites. Therefore, it is not surprising that manipulation of apoptosis has emerged as a new therapeutic strategy to preserve tissue integrity or to help eliminate cancer cells. The antiapoptotic proteins, IAPs are a widely expressed gene family of apoptotic inhibitors . A novel member of the IAP gene family, designated Survivin, was recently identified byhybridization screening of human genomic libraries with the cDNA of a factor Xa receptor, effector cell protease receptor-1 (EPR-l). Survivin is expressed in the G2-M phase of the cell cycle in a cell cycle-regulated manner and associates with microtubules of the mitotic spindle. Unlike all other IAP proteins, Survivin contained a single baculovirus IAP repeat. Survivin is an apoptosis inhibitor, which is, unlike other members of the Bcl-2 and IAP gene families, preferentially expressed in most human cancers. Survivin is expressed in cancer and not in normal adult tissue. In fact, it is expressed in virtually all malignancies so far examined, regardless of their embryonic lineage, differentiation, or histologic type. This differential expression carries important practical implications. Several studies have consistently shown that expression of Survivin inhibits cell death induced by various apoptotic stimuli. Differently from Bcl-2 proteins, Survivin has been proposed to function as a direct Caspase inhibitor, potentially affecting both initiator and terminal Caspases. Survivin were shown to bind and potently inhibit Caspases-3, 7 and 9, this step occurs downstream of anti-apoptotic Bcl-2 proteins that are thought to preserve mitochondrial integrity by inhibiting cytochrome c release. Presently, Survivin as a unique apoptosis inhibitor is believed to play a role in oncogenesis. Moreover, inhibition of apoptosis by Survivin predicts poor prognosis and shorter survival in human cancers. In the types of cancer for which predictive/prognostic data are available, Survivin expression consistently correlates with a more aggressive behavior, associated with reduced in vivo apoptosis. increased dissemination and recurrences, and, unfortunately, reduced life expectancy. In in-vitro and in-vivo studies, Survivin targeting with antisense and Survivin mutants induces apoptosis, reduces tumor growth potential, and sensitizes cells to chemotherapeutic drugs and X-irradiation. These results suggest that Survivin is a useful bio-marker to assess tumour biology and may have the potential to function as a new target for the diagnosis of cancer. Survivin may be a potential new target for apoptosis-based selective therapy in neoplasms as the expr...