Purpose: Oncolytic replication competent herpes simplex virus type-1 (HSV) mutants have the ability to replicate in and kill malignant cells. We have previously reported the ability of replication competent HSV to control bladder cancer growth in an orthotopic murine model. We hypothesized that the combination of a chemotherapeutic agent used for intravesical treatment, namely mitomycin C (MMC) (Bristol-Myers Squibb Oncology, Princeton, New Jersey), and oncolytic HSV would exert a synergistic effect for the treatment of human transitional cell carcinoma. Materials and Methods: We used mutant HSV NV1066 (Medigene, San Diego, California), which is deleted for viral genes ICPO and ICP4, and selectively infects cancer cells, to treat the transitional cell carcinoma lines KU19-19 and SKUB. Cell survival was determined by lactate dehydrogenase assay for each agent as well as for drug-viral combinations from days 1 to 5. The isobologram method and the combination index method of Chou-Talalay were used to assess the synergistic effect. Results: NV1066 enhanced MMC mediated cytotoxicity at all combinations tested for KU19-19 and SKUB. The combination of the 2 agents demonstrated a synergistic effect and allowed dose reduction by 12 and 10.4 times (NV1066), and by 3 and 156 times (MMC) for the treatment of KU19-19 and SKUB, respectively, while achieving an estimated 90% cell kill. Conclusions: These data provide the cellular basis for the clinical investigation of combined MMC and oncolytic HSV therapy for the treatment of bladder cancer.
Bibliographical noteFunding Information:
Supported by an AACR-AstraZeneca Cancer Research and Prevention grant (PSA), National Institutes of Health Grants R01 CA 76416 and R01 CA/DK80982 (YF), American Cancer Society Grant MBC-99366 (YF), United States Army Grant BC024118 (YF), Susan Komen Foundation Grant IMG0402501 (YF) and Flight Attendant Medical Research Institute Grant 032047 (YF and PSA).
Copyright 2017 Elsevier B.V., All rights reserved.
- Carcinoma, transitional cell
- Gene therapy
- Herpesvirus 1, human