Phenoxodiol-topotecan co-administration exhibit significant anti-tumor activity without major adverse side effects

Abstract

Objective: We previously showed that Phenoxodiol is able to sensitize epithelial ovarian cancer cells to Paclitaxel, Carboplatin, Gemcitabine, and Docetaxel. The aim of this study was to determine the value of Phenoxodiol-Topotecan co-administration. Methods: Nine epithelial ovarian cancer cell lines isolated from ascites or ovarian tissue were treated with increasing concentrations of Topotecan (5-500 ng/ml) with or without Phenoxodiol pre-treatment (10 μg/ml) for 24h and cell viability was measured using CellTiter 96® AQueous One Solution Cell Proliferation Assay. The effect of Phenoxodiol-Topotecan combination therapy in vivo was determined using the topotecan resistant A2780 mouse xenograft model. Results: In vitro, pre-treatment with Phenoxodiol lowers the topotecan IC50 from >500 ng/ml to 2.5-100 ng/ml in 5 out of 9 cell lines tested. Results from animal experiments confirmed the advantage of Phenoxodiol-Topotecan combination therapy over monotherapy controls. Median tumour kinetics from animals receiving Phenoxodiol-Topotecan in combination was significantly slower compared to those animals receiving the respective monotherapies. In addition, co-administration with Phenoxodiol reversed Topotecan-induced myelosuppression. Conclusion: Phenoxodiol-Topotecan combination therapy allows the administration of both agents at lower doses while retaining significant anti-tumor activity compared to monotherapy. These findings suggest that the Phenoxodiol-Topotecan combination may represent an alternative treatment modality for the management of ovarian cancer and justifies further investigation in the clinical setting.