Thymidine Kinase-based Tumor Selectivity Enhancement of Oncolytic Vaccinia Virus
Overview of Vaccinia Virus and Thymidine Kinase
Vaccinia virus (VV) is a large double-stranded DNA virus and a member of the poxvirus family, which replicates primarily in the cytoplasm of susceptible host cells. This virus has several unique features that make it useful as a vector, including its large size, extensive host range, retention of infectivity after insertion of an exogenous gene, along with the ability to hold up to 25,000 bp of foreign DNA and modify the synthesized gene products. Homologous recombination in VV DNA has been shown to occur with near-perfect fidelity of 99%. Various methods have been developed for the introduction of foreign DNA into the VV genome. One of the approaches is to insert a foreign gene into the thymidine kinase (TK) gene of the vaccinia virus, inactivating the TK gene and allowing for the selection of recombinants due to the TK-negative phenotype.
Role of TK in Cancer
The cytoplasmatic enzyme TK1 is a candidate for the early detection of tumor cell division and proliferation. The use of TK1 and its antibodies has been investigated in different studies in different types of solid tumors. This makes TK1 feasible for monitoring therapeutic outcome and efficacy especially in the post-surgery phase of treatment. In breast cancer patients, TK1 antibodies are capable of monitoring the response to therapy. Hence, they may be a valuable adjunct to the standard imaging-based follow-up. An important finding is that higher sTK1 concentration in breast cancer patients correlates with the development of distant and/or loco-regional recurrence early after surgery. Moreover, various studies could document that sTK1 might be used as a prognostic tool and marker to monitor the response to surgery in non-small cell lung cancer (NSCLC) patients. In renal cell carcinoma (RCC), measurement of TK1 before nephrectomy can be applied for stratifying the patients into risk groups for a consecutive early adjuvant treatment based on targeted therapies.
Fig.1 Expression pattern of thymidine kinase 1 in the human cell cycle. (Aufderklamm, 2012)
Mechanism of Action of Oncolytic Virus in Tumor Cells
TK is one of the key enzymes for the synthesis of vaccinia virus DNA. TK expression is generally decreased in normal cells but increased in rapidly proliferating tumor cells. The TK-deleted vaccinia virus can selectively infect tumor tissues, whereas, in most normal cells, deletion of the TK gene greatly reduces the virus infectivity and replicability. Even if normal cells are infected with the vaccinia virus, antiviral responses will be stimulated, leading to the production of antiviral proteins or the initiation of apoptosis. These mechanisms can regulate the infected cells and surrounding cells by inducing cell-cycle arrest, promoting apoptosis, inhibiting protein synthesis, and activating an immune response. These processes can delay or terminate viral replication and proliferation.
Fig.2 The expression of TK is generally decreased in normal cells but increased in rapidly proliferating tumor cells. (Yang, 2018)
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References
- Aufderklamm, S.;et al. Thymidine kinase and cancer monitoring. Cancer Lett. 2012, 316(1): 6-10.
- Yang, X.;et al. Progress in gene therapy using oncolytic vaccinia virus as vectors. J Cancer Res Clin Oncol. 2018, 144(12): 2433-2440.