| BackgrOun--:Cancer gene theraPy represents one of the most rapidly evolving areas inpre-clinical and clinical cancer research. In the last decades,there were more than 270cancer gene theraPy trials being implemeflted worldwide. Howevef, most of the resultsis disappointed. lt has become increasingly appareflt that the exishng gene deliveryvehic1es (vectors) should be improved significant1y prior to any meaningfu1incorporation of gene transfer techniques into the care of cancer patients. TWo of themost imPOrtam obforles to overcome are poor therapeutic index and low efficiency ofgene transfeL Wth the development of a kind of geneticallly-engineered virus, theabective situaion was changed, which is so-called trior-specificreplicationcompetent adenoviral vector(or replication-selective oncolytic adenoviralvector). Abnormal biological characters shared by multiple cancers have made itPOssible for us to oPtimize virus so that the geneticallly-engineered virus replicateexclusive1y in tUInor ce1ls Whi1e 1eaving normal cells intact by using the fo1lowing twobroad approaches, one is to complemellt loss-of function mlltations in cancers withloss-of function mutations within the virus genome,altematively, regUlate theexPression of important gene products in the viral life circle by utilizing tissue/tumorspecific Promoters. Decades of study of adenovirus have resulted in a detailed pictUreof life cycle and the fimtions of the majority of viral proteins. In addition. anenovirusis a mildly pathogenic human virus that Propagates prolifically in ePithe1ial cells, theorigin of most human cancers. There is no surprising that adenovirus is seleCted as thefirst candidate using for boor-specific replicaton-competCnt adenoviral veCtOrONYX-015, Which is mentioned above, is an attenuaed adenovirus WhoseElB-55kD(encoding by the ElB region of an adenovirus binds and inactiVates p53)has been deleted. Because p53 function must be blocked in order to allow efficientadenoviral replication, the ONYX-0l5 is limited in its replication in normal cells:7$=vsXq x x w M @f#&&xcancer cells with malfunction p53,howevef, should suPport virus replication and celllysis. Fortunately, the p53 is lost or mutallted in rough1y 50% of al1 human cancers.Although the precise mechanism that in this process is cofltroversial, the anii-tumorefficacy of ONYX-0l5, however, is significant. Combining with chemotheraPy(5-Fu/cisPlatin), ONYX-0l5 led to objective clinical responses in 63% of 30 evaluablepatients with neck and head tumors, recurrent despite surgery and radiaton in a PhaseIII trial. Used as a single agent, hOwever, ONYX-015 is disaPpointng(wt 15%)fOr thecomplex virus-cell interactions. It is necessary therefor, to combine with othertherapelltic apPrOaches. To be used as a platform for gene delivery is anotherpromising approach to be explored (which is known as vi ro - genetherapy), bes ideschemo-therapyRecentl y, interi e ukin- l 2 (IL - 12 )has generated much interest due to its central ro le inthe immune system and its potential anti-tumor effects. Of all the cytokines tested,IL-l2 seems to possess the strongest anti-tUInor activity IL-l2 plays a key role inactivating ce11u1ar immedty by augInenting the cytotoxic achvity of T-cel1s and NKcells, by inducing the production of IFN-yand other cytokines, and by promoting thedifferentiation of uncommthed T cells(Th0) tO Th1 cells which subsequently haiatethe cell-mediated immunity pathway An amiangio-genic effect of IL-l2 has also beenrePorted. In fac, systemic adIninistration of IL-12 has been shOwn tO be highlyeffective in inducing tUInor regression and reducing metastaSes in diverse murinemodls Of solid tUmors. HOwever severe hematologic, hePatotokic and muscular sideeffeCts limit the use of recombinam IL-l2 as an anti-drior ageni. Implementation ofProcedures, therefOT, allowing high local production of lL-l2 at the site of tuxnor fOciwithout increasing syst... |
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