科研之友
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摘要
Oncolytic herpes simplex virus-1 (oHSV-1) vectors are promising therapeutic agents for cancer. The deletion of the gamma 34.5 gene eliminates the neurovirulence but attenuates virus replication at the same time. The carboxyl-terminus of protein phosphatase 1 regulatory subunit 15A (also known as MyD116/GADD34) is homologous to that of gamma 34.5; hence, it may substitute for gamma 34.5 to enhance the replication and cytotoxicity of the virus. To investigate whether the C-terminus of MyD116 can enhance the anti-tumour efficacy of G47 Delta on human breast cancer cells, a GD116 mutant was constructed by inserting a gamma 34.5-MyD116 chimaera into the G47 Delta genome using a bacterial artificial chromosome and two recombinase systems (Cre/loxP and FLPE/FRT). A GD-empty mutant containing only the cytomegalovirus sequence was also created as a control using the same method. Next, the replication and cytotoxicity of these two virus vectors were evaluated in breast cancer cells. Compared with the GD-empty vector, GD116 possessed an enhanced replication capability and oncolytic activity in MCF-7 and MDA-MB-231 cells. On the fifth day after infection with GD116 at MOIs of 0.01 and 0.1, 49.2 and 82.8% of MCF-7 cells, respectively, were killed, with 35.0 and 50.2% of MDA-MB-231 cells, respectively, killed by GD116 at MOIs of 0.1 and 0.3. Additionally, the insertion of the gamma 34.5-MyD116 chimaera promoted virus replication in MDA-MB-468 at 48 h after infection, although no increased cytotoxic effect was observed. The findings of the present study indicate that the C terminus of the MyD116 gene can be substituted for the corresponding domain of the gamma 34.5 gene of oHSV-1 to promote the replication of the virus in infected cells. Furthermore, the novel virus mutant GD116 armed with a gamma 34.5-MyD116 chimaera has enhanced anti-tumour efficacy against human breast cancer cells in vitro.
