Experiment Studies On Treatment Of Liver Cancer With Double-Regulated Replicative Adenovirus CHNK500

Background:Hepatocellular carcinoma accounts for more than 90% of all primary liver cancers. It ranks fifth in frequency among all malignancies worldwide and causes nearly 1 million deaths annually. As it is known, surgery such as hepatic resection and liver transplantation is the choice of treatment for liver cancers. Yet the most of patients with HCC have little opportunity to undergo surgery. General treatment or combined treatment has drawn great attention due to the poor prognosis of HCC. Palliative treatments including chemoembolization, hepatic artery infusion, percutaneous interstitial ablation, cryosurgery, radiation therapy and systemic chemotherapy have been beneficial complementarities for liver cancer treatment. 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. Replication-selective virotherapy holds great promise for the treatment of cancer. Appealing features include tumor-selective targeting, viral self-spreading in cancer cells, and no cross-resistance to current treatments. Several types of conditionally replicative viruses have already been tested in clinical trials, including conditionally replicative adenovirus (CRAD), herpes simplex virus, vaccinia virus, reovirus and Newcastle disease virus. Conditionally replicative adenovirus has attracted considerable interest among these replicating viruses. Two molecular strategies have been exploited to target the CRAD selectively to tumor cells. The first strategy involves the deletion of adenovirus genes that are necessary for virus replication in normal cells but not in tumor cells. These include the adenovirus E1A and E1B genes, which are responsible for the inactivation of tumor suppressor Rb and p53 genes that are often mutated in cancer cells. This strategy has been effective in animal models, and led to clinical trials combining the application of the E1B/55 Kda-deleted Onyx-015 adenovirus with chemotherapy. The second strategy involves the use of tumor- or tissue-specific promoters, such as AFP, MUC1, PSA, kallikrein-1 and 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.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 are necessary 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.Besides high telomerase activity in tumor cells, hypoxia is another outstanding characteristic of solid tumors. Hypoxia, a unique feature of human solid tumors, with median oxygen tensions of 1.3~3.9% compared to 3.1~8.7% in normal tissues, has been considered to be a major factor in the resistance of cancers to radiotherapy and chemotherapy. Hypoxia in the tu...