Boronic prodrug of 4-hydroxytamoxifen is more efficacious than tamoxifen with enhanced bioavailability independent of CYP2D6 status

BMC Cancer

Research Article

Lucio Miele¹  Qiang Zhang²  Qiu Zhong²  Guangdi Wang²  Shilong Zheng²  Changde Zhang² 

[1] Department of Genetics and LSU Stanley Scott Cancer Center, LSU Health Sciences Center, 1 Drexel Dr., 70112, New Orleans, LA, USA;RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., 70125, New Orleans, LA, USA;

关键词: Tamoxifen;    Oral Gavage;    Boronic Acid;    Total Drug Concentration;    Average Tumor Size;   

DOI  :  10.1186/s12885-015-1621-2

 received in 2015-04-10, accepted in 2015-08-21,  发布年份 2015

来源: Springer

【 摘 要 】

BackgroundPoor initial response to tamoxifen due to CYP2D6 polymorphism and adverse side effects are two clinical challenges in tamoxifen therapy. We report the development and preclinical testing of a boronic prodrug to orally deliver 4-OHT at therapeutically effective concentrations but at a fraction of the standard tamoxifen dose.MethodsA mouse xenograft tumor model was used to investigate the efficacy of ZB497 in comparison with tamoxifen. Pharmacokinetic studies were conducted to evaluate the metabolism and bioavailability of the drug in mice. Drug and metabolites distribution in xenograft tumor tissues was determined by high performance liquid chromatography-tandem mass spectrometry.ResultsThe boronic prodrug, ZB497, can not only be efficiently converted to 4-OHT in mice, but also afforded over 30 fold higher plasma concentrations of 4-OHT than in mice given either the same dose of 4-OHT or tamoxifen. Further, ZB497 was more effective than tamoxifen at lowered dosage in inhibiting the growth of xenograft tumors in mice. Consistent with these observations, ZB497 treated mice accumulated over 6 times higher total drug concentrations than tamoxifen treated mice.ConclusionsOur study demonstrates that ZB497 effectively delivers a markedly increased plasma concentration of 4-OHT in mice. The boronic prodrug was shown to have far superior bioavailability of 4-OHT compared to tamoxifen or 4-OHT administration as measured by the area under the plasma concentration time curve (AUC), plasma peak concentrations, and drug accumulation in tumor tissues. Further, ZB497 proves to be a more efficacious hormone therapy than tamoxifen administered at a reduced dose in mice.

【 授权许可】

CC BY   
© Zhong et al. 2015