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


METHODS
A 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.


RESULTS
The 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.


CONCLUSIONS
Our 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.
RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA, 70125, USA. qzhong@xula.edu.
Qiu
Q
Zhong
RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA, 70125, USA. czhang1@xula.edu.
Changde
C
Zhang
RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA, 70125, USA. qzhang1@xula.edu.
Qiang
Q
Zhang
Department of Genetics and LSU Stanley Scott Cancer Center, LSU Health Sciences Center, 1 Drexel Dr., New Orleans, LA, 70112, USA. lmiele@lsuhsc.edu.
Lucio
L
Miele
RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA, 70125, USA. szheng@xula.edu.
Shilong
S
Zheng
RCMI Cancer Research Center and Department of Chemistry, Xavier University of Louisiana, 1 Drexel Dr., New Orleans, LA, 70125, USA. gwang@xula.edu.
Guangdi
G
Wang
D000818:Animals; D000970:Antineoplastic Agents / Q000493:pharmacokinetics* / Q000627:therapeutic use; D001682:Biological Availability; D001943:Breast Neoplasms / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D045744:Cell Line, Tumor; D002851:Chromatography, High Pressure Liquid; D019389:Cytochrome P-450 CYP2D6 / Q000378:metabolism*; D004353:Drug Evaluation, Preclinical; D005260:Female; D064593:Heterografts; D051379:Mice; D008819:Mice, Nude; D023421:Models, Animal; D011355:Prodrugs; D013629:Tamoxifen / Q000031:analogs & derivatives* / Q000493:pharmacokinetics / Q000627:therapeutic use; D053719:Tandem Mass Spectrometry; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D011355:Prodrugs; D013629:Tamoxifen; C016601:afimoxifene; D019389:Cytochrome P-450 CYP2D6