Abstract
There is a need for more effective treatments for uveal melanoma. The recombinant oncolytic adenovirus H101 replicates specifically in p53-depleted tumor cells, and has been approved for use by the Chinese State Food and Drug Administration. However, this treatment is associated with subsequent remission. Transfection of uveal melanoma cells with a small interfering RNA against Notch1 (siNotch1) effectively suppressed Notch1 expression, resulting in significant cell growth inhibition when combined with H101 treatment. Combined treatment with siNotch1 and H101 (H101-Notch1-siRNA) greatly enhanced apoptosis and cell cycle arrest in vitro as compared to treatment with H101 or siNotch1 alone. For in vivo treatments, the combined treatment of siNotch1 and H101 showed remarkable tumor growth inhibition and prolonged mouse survival in the OCM1 xenograft model. We predict that Notch pathway deregulation could be a feature of uveal melanoma, and could be a therapeutic target, especially if p53 is concurrently targeted.
Highlights
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, with an incidence of seven cases per million [1,2]
Coxsackie adenovirus receptor (CAR) was expressed in both cell lines, with higher levels in VUP compared to OCM1 (Figures 2A, B, C, D, E)
The oncolytic adenovirus H101 only replicates in tumor cells in which p53 has been inactivated [9,10,12], and presents an exciting new cancer therapy modality [7,9,10,11,27,28]
Summary
Uveal melanoma (UM) is the most common primary intraocular malignant tumor in adults, with an incidence of seven cases per million [1,2]. The prognosis is poor, with survival averaging five to eight months [5] These poor outcomes underline the need for alternatives to traditional treatments such as surgery, radiotherapy and chemotherapy [6,7]. These viruses kill tumor cells while sparing normal cells; recombinant oncolytic adenovirus type 5 (H101) selectively proliferates in TP53 (p53)-deficient tumor cells and lyses tumor cells [9,10] This virus-based therapy takes advantage of the fact that the replication and production of adenoviral progeny requires the cell cycle gatekeeper p53 to be inactive, a very frequent characteristic of cancer cells [9]. H101 is the first therapeutic anticancer drug approved for clinical use by State FDA (China) that selectively attacks tumor cells with a modified virus and does not harm healthy cells
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