| Objective: The morbidity of prostate carcinoma is upgrating ,which is part of genitourinary malignant tumor in our country. Prostate cancer management currently relies on the integration of a number of treatment modalities, including surgery, radiotherapy, hormonal therapy, and chemotherapy. But, A major problem with many cancer treatments is that they are lack of tumor specificity. Therefore, development of effective alternative approaches with novel tumor-targeting mechanism is needed. A new approach is suicide gene therapy ,it was also called enzyme/prodrug therapy. The most common enzyme/prodrug system used to date as gene therapy for prostate cancer is the herpes simplex virus (HSV) thymidine kinase (TK) in combination with the prodrug ganciclovir or acyclovir. The HSV-TK enzyme phosphorylates the prodrug, which is then available for further phosphorylation by cellular TK. The resulting nucleoside triphosphate can be incorporated into nascent DNA during synthesis, leading to chain termination, which inhibits DNA replication and thus cell division. mammalian cellular kinases cant not phosphorylate GCV into toxic triphosphate (GCV-TP) since herpes simplex virus thymidine kinase(HSV-TK) does not exist in mammalian cellular. construction of recombination adenoviruses (Ad) vedtor which delivery HSV-TK into cancer cells. And then administrated by GCV. Adverse effects are minimal because of the selective cytotoxicity of the prodrug for HSV-tk expressing cells, Moreover, since the toxicity of the prodrug is associated with DNA replication, cell kill will mainly occur in rapidly dividing cells (e.g. tumor cells) and not in normal tissue. Gene therapy was first administered to a prostate cancer patient in 1994. P Patel et al accounted that HSV-TK/GCV suicide therapy is feasible that a role in localised therapy may be established in the relatively near future. The selective reactivation of telomerase in tumor cells offers an attractive therapeutic target for developing new broad-spectrum antitumor agents. Telomerase are essential elements at chromosome termini that preserve chromosomal integrity by preventing DNA degradation, end-to-end fusion, rearrangements, and chromosome loss. Each cell replication is associated with the loss of 30-150 bp of telomeric DNA that can be compensated by telomerase, an RNA-dependent DNA polymerase. Most human somatic cells exhibit neither hTERT expression nor telomerase activity, whereby the number of cell divisions is limited because of the reduction of telomeres to a critical length. In contrast to quiescent somatic cells, in highly proliferative cells, such as germ-line, hematopoetic stem, or transformed cancer cells, diverse molecular mechanisms arenecessary to maintain telomere length. Although some tumors activated a yet unknown alternative mechanism of telomere extension, the majority (>90%) of human cancer cells acquire immortality by expression of the hTERT. It has been shown that hTERT expression is regulated at the transcriptional level, thereby providing a promising tool for tumor-specific gene expression. The other strategy involves the use of tumor-or tissue-specific promoters, such as AFP, PSAand pS2, to drive adenoviral genes that are essential for replication. This strategy has also been successful in animal models, and the prostate-specific CRADs CN-706 and CV-787 have been tested in clinical trials. This approach, however, is limited to specific tumor types that express the corresponding tumor-specific antigens.Meanwhile, there are more than 500 kinds of specific antigens of prostate cancer have been found to date. To evaluate human prostate carcinoma cells as targets for herpes simplex virus thymidine (HSV-TK)-mediated gene therapy, we tested the utility of adenoviral vectors on three human cell lines LNCaP,PC-3,andMRC-5.Our viral vectors were carring a fusion gene of HSV-TK and enchanced florescent protein for accurate detemination of the gene transfer rate and its contribution to the treatment outcome in each case. Methods and Results: we use a recombinant adenovirus ve... |
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