Rh2 and its aglycone aPPD in combination therapy with docetaxel - pre-clinical evaluation in a PC-3 human prostate

• Main Author: Musende, Alain G.
• Format: Others
• Language: English
• Published: University of British Columbia 2009
• Online Access: http://hdl.handle.net/2429/5740

PURPOSE: The purpose of this thesis is to establish the therapeutic potential of ginsenoside Rh2, a 20(S)-protopanaxadiol type and its aglycone aPPD, two gastrointestinal metabolites of Panax Ginseng C.A. Meyer, for use in advanced prostate cancer. This thesis assesses (i) the pharmacokinetics, biodistribution and efficacy of Rh2 and aPPD as single agents, and (ii) the combination of Rh2 or aPPD with docetaxel with the goal of optimizing their therapeutic potential. METHODS: The solubility and stability of Rh2 and aPPD in ethanol was determined and an oral dosage formulation was prepared. Rh2 and aPPD levels in blood and tissues following administration to nulnu nude mice were determined by LC/MS. Their efficacy as single agents and in combination with docetaxel was determined in a PC-3 human prostate cancer xenograft model. Serum levels of AST, ALT, and creatinine were measured for toxicity. Tumor analysis for apoptotic indices and Ki-67 was performed. In vitro, PC-3, LNCaP, DU145, and C4-2 prostate cancer cells were treated with a combination of Rh2 or aPPD with docetaxel, according to the constant ratio combination design. RESULTS: The solubility of Rh2 and aPPD in ethanol was 130 and 68.4 mg/ml respectively. In vitro, Rh2+docetaxel and aPPD+docetaxel both showed synergy (CI < 1) against PC-3 and DU145 cells. In vivo, Rh2 and aPPD exhibited a Cmax of 19.0 ± 2.0 and 3.9 ± 1.4 jtg/ml, respectively, while no toxicity was observed. They engendered a significant delay in PC-3 tumor growth, an increase in apoptotic index, and a decrease in Ki-67 levels. Docetaxel alone inhibited tumor growth by 84% but could not induce tumor regression while Rh2+docetaxel and aPPD+docetaxel caused established PC-3 tumors to regress from their initial size by 15 and 27% respectively. CONCLUSIONS: We have shown that Rh2 and aPPD are stable compounds that can be formulated for oral gavage. Pharmacokinetic studies demonstrate their ability to be absorbed following oral administration. Rh2 and aPPD can be combined with docetaxel to yield synergistic inhibition of cancer cell growth in vitro. Their in vivo combinations with docetaxel in a PC-3 xenograft model induce significant tumor regression compared to docetaxel dosed alone. === Medicine, Faculty of === Pathology and Laboratory Medicine, Department of === Graduate