The Characterization of Murine Colorectal Carcinoma Cell Line CT-26 for Susceptibility to Gene Therapy at a Primary and Secondary Tumor Level
Korcek, Andrew Stephen
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The murine colorectal carcinoma cell line CT-26, was transduced with the STK retroviral vector (containing the Herpes Simplex virus Thymidine Kinase gene) and tested for its susceptibility to treatment with Ganciclovir (GCV) and for the presence of a bystander effect. The bystander is a phenomenon in which healthy cancer cells die when in the presence of dying cancer cells. After observing a strong susceptibility to GCV and a large bystander effect (40% larger then expected values), a gene therapy treatment was applied to various animal models representing primary, secondary and diffuse tumor burdens. In the primary tumor models, CT -26 cells were injected into the liver of Balb/c mice. After five days STK-Vector producer cells (VPC) were injected into the site of the tumor and GCV treatment was begun. All treatment animals showed significant decrease in tumors volume as compared to the control animals. In the secondary tumor model, CT -26 cells (either containing STK or no vector(NV)) were injected into separate lobes of the "liver. In mice treated with GCV, 89% exhibited complete remission of both STK and NY tumors. This remission is attributed to an immune response mounted by the mouse against the tumor. In the diffuse tumor model, CT-26 NY cells were injected intraperitoneally (Lp.) into the mice and treated with standard STKVPC gene therapy. Mice receiving treatment showed a significant 14 day survival advantage over the non-treatment animals. To better test the in vivo bystander effect, a metastatic model was developed by injecting Cf-26 NY cells into the spleen. The spleens were then either removed or left in the mouse or placed subcutaneously. All models show development of hepatic metastasis, however, only the subcutaneous model prevented widespread peritoneal carcinomatosis before metastases were allowed to form.