Combined oral delivery of ebselen and allopurinol reduces multiple cisplatin toxicities in rat breast and ovarian cancer models while enhancing anti-tumor activity

Abstract

The chemoprotective effects of combined ebselen and allopurinol in breast (MTLn3) and ovarian (NuTu-19) cancer models using a repeated cisplatin dosing schedule (6 mg/kg i.p.x3 weeks) were studied. Otoprotection was evaluated using auditory evoked brainstem response (ABR) to determine threshold and latency shifts, and outer hair cell counts. Nephroprotection was analyzed by serological markers [blood urea nitrogen (BUN) and creatinine] and histological evaluation. Myelotoxicity was quantified using cytological counts for platelets and changes in hematocrit. Hepatotoxicity was determined by changes in the serological markers amino alanine transferase (ALT) and aspartate amino transferase. Significant chemoprotective effects were observed for multiple organ systems including oto- (ABR threshold shifts for click and 24-kHz stimuli, p<0.05, 8 and 16 kHz, p<0.01, MTLn3 group; hair cell counts, p<0.05 both groups), nephro- (BUN and creatinine, p<0.01), myelo- (platelet p<0.05, hematocrit p<0.05) and hepatotoxicity (ALT p<0.05) in rats receiving oral ebselen and allopurinol. Importantly, the anti-tumor activity of cisplatin was not compromised. On the contrary, improved mortality, morbidity and outcome were observed in the ovarian cancer model. This combined oral formulation of ebselen and allopurinol is an attractive candidate for clinical evaluation.