Chemoinducible Virotherapy for advanced ovarian cancer

Objective of Study: Resistance of antineoplastic agents remains a barrier to the establishment of curative chemotherapy regimens for advanced ovarian cancer. Overexpression of the p-glycoprotein encoded by the MDR1 gene is known to mediate resistance to antineoplatstic drugs. We describe a chemoinducible virotherapy for chemoresistant OvCa using the MDR1 promoter controlling replication of conditionally replicating Adenovirus (CRAds). Methods: The inducibility of MDR1 by Doxorubicin (DOX) was analysed by RT-PCR and by luciferase reporter assays. Two CRAds were generated: Ad5/3mdrE1 was constructed by replacing the E1A promoter by the MDR1 promoter. Ad5/3mdrD24 exhibits an additional 24 bp mutation in the E1A gene attenuating viral replication in quiescent cells. The oncolytic potential of Ad5/3mdrE1 and Ad5/3mdrD24 in DOX-resistant SkOv-3 cells was tested using cytotoxicity assays. Results: MDR1 gene expression and MDR1 promoter activity were enhanced in DOX-resistant SkOv-3 cells. In normal control cells MDR1 promoter activity was absent. In SkOv-3, SkOv i.p. and Ov-4 OvCa cells, the cytotoxicity mediated by MDR-CRAds was superior to Ad5 wild type. Regarding DOX-resistant SkOv-3 cells, the oncolytic potential of both MDR-CRAds was highly enhanced compared with parental SkOv-3 cells. Conclusion: We prove the functionality of the MDR1 promoter in the context of CRAd vectors mediating enhanced oncolysis in chemoresistant tumor cells. Due to improved killing of DOX-resistant tumor cells the MDR-CRAds are promising candidates for a chemoinducible virotherapy as a novel treatment option for advanced OvCa.

Eingereicht von: Isabell Herrmann

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