Phenoxodiol-Topotecan co-administration exhibit significant anti-tumor activity without major adverse side effects.
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 coadministration.


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 pretreatment (10 microg/ml) for 24 h 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, pretreatment with Phenoxodiol lowers the topotecan IC50 from >500 ng/ml to 2.5-100 ng/ml in five out of nine 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.


CONCLUSIONS
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.
Alvero
Ayesha B
AB
Department of Obstetrics & Gynecology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
Brown
David
D
Montagna
Michele
M
Matthews
Marissa
M
Mor
Gil
G
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000009:adverse effects / Q000032:analysis / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D005260:Female; D006801:Humans; D007529:Isoflavones / Q000009:adverse effects / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D010051:Ovarian Neoplasms / Q000188:drug therapy*; D019772:Topotecan / Q000009:adverse effects / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
D007529:Isoflavones; D019772:Topotecan; C471183:phenoxodiol