Abstract 2826: Equimolar vs. pharmacokinetics-guided dosing in anti-cancer efficacy assessment of precursor-product pairs: Example with pyranocoumarins from Korean Angelica

Abstract

Abstract Prostate cancer is a malignant disease quite unique to men and has the second highest mortality rate next to lung cancer in the United States, with an estimated 233,000 new cases to be diagnosed in 2014. Angelica gigas Nakai (AGN) is a traditional medicinal herb in Korea and China. Ethanol extract of dried AGN root has been shown by us and others to exert anti-cancer activity in several allograft and xenograft models. In recently completed studies in primary carcinogenesis model (TRAMP mice), our group has demonstrated that AGN ethanol extract can significantly suppress the growth of neuroendocrine (NE)-lineage cancers and inhibit prostate epithelial lineage lesions. These studies also found that major pyranocoumarin isomer compounds decursin (D) and decursinol angelate (DA) from AGN when provided at equimolar intake to that provided by AGN accounted for the epithelial lineage suppression efficacy, but was less active than AGN extract against NE-Ca growth. Because rodent models and humans convert D/DA rapidly and extensively (>95%) into decusinol (DOH), we hypothesize that DOH (and/or its metabolites) may be the true “active” chemical for suppressing the epithelial cancer. To test this, we compared oral gavage of DOH at equimolar dose as D/DA in SCID mice carrying human LNCaP/AR-Luc cells inoculated subcutaneously. Whereas DOH treated mice showed greater suppression of tumor growth than D/DA, measurement of plasma DOH levels showed 1.7 fold higher in the former at 3 h post-dose. Our earlier work has shown in a rat model that gavage of DOH led to 2.4 fold area under curve (AUC) over that achieved by equimolar dosing of D/DA, suggesting differences for absorption, distribution, metabolism, and excretion (ADME) of DOH vs. D/DA in other species as well. We are currently conducting PK studies of DOH and D/DA in mice to establish their PK parameters in order to achieve bio-equivalent dosing to critically test DOH efficacy and our hypothesis. In summary, PK-evaluation of precursor-product pairs might be important to determine bio-equivalent dosing before costly anti-cancer efficacy tests are conducted to ensure valid efficacy comparison. Citation Format: Wei Wu, Manohar Puppala, Suni Tang, Jinhui Zhang, Chengguo Xing, Cheng Jiang, Junxuan Lu. Equimolar vs. pharmacokinetics-guided dosing in anti-cancer efficacy assessment of precursor-product pairs: Example with pyranocoumarins from Korean Angelica. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2826. doi:10.1158/1538-7445.AM2015-2826