Rh2 or its aglycone aPPD in combination with docetaxel for treatment of prostate cancer.

BACKGROUND: Docetaxel is one of the few chemotherapeutic drugs that are considered highly effective when used to treat prostate cancer patients that have relapsed and/or metastatic disease, it is therefore reasonable to expect further improvements in treatment outcomes when it is combined with other therapeutic agents active in prostate cancer. This study assesses the combination of well tolerated and orally bioavailable formulations of ginsenoside Rh2 or its aglycone aPPD with docetaxel. METHODS: The in vitro activity of Rh2, aPPD, and docetaxel was determined in four prostate cancer cell lines: PC-3, LNCaP, DU145, and C4-2. Combinations of Rh2 or aPPD with docetaxel were assessed using the constant ratio combination design. Combination Indices (CI) and Dose Reduction Indices (DRI) were subsequently estimated using Calcusyn. In vivo efficacy studies and Immunohistochemical analyses (PC-3 model) were also evaluated. RESULTS: In PC-3, DU145 and C4-2 prostate cancer cells combinations of Rh2 or aPPD with docetaxel were predominantly additive or synergistic. Combinations of Rh2 + docetaxel and aPPD + docetaxel caused established PC-3 tumors to regress from their initial size by 15% and 27%, respectively. Tumor cell proliferation rate (measured by Ki-67 positive cells) was significantly lower for combinations of Rh2 + docetaxel and aPPD + docetaxel, compared to animals treated with docetaxel alone. CONCLUSIONS: Rh2 and aPPD can be combined with docetaxel to yield additive or synergistic activity in vitro and in vivo. Pending further assessment of toxicity and pharmacodynamic behavior, this study supports testing of combinations of ginsenoside Rh2 or its aglycone aPPD with docetaxel in a clinical setting.

Pre-clinical evaluation of Rh2 in PC-3 human xenograft model for prostate cancer in vivo: formulation, pharmacokinetics, biodistribution and efficacy.

PURPOSE: This study assesses the pharmacokinetics, biodistribution and efficacy of ginsenoside Rh2 as a single agent administered in a novel oral dosage formulation. METHODS: A novel oral dosage formulation of Rh2 has been described. Rh2 levels in blood and tissues following administration to nu/nu nude mice were determined by high performance liquid chromatography tandem mass spectroscopy. Efficacy was determined in an established PC-3 human prostate cancer model. RESULTS: Rh2 administered at a dose of 120 mg/kg exhibited a peak plasma concentration of 19.0 +/- 2.0 microg/ml. Rh2 levels were measurable in prostate and tumor tissues, with as much as 0.3% of the administered dose being detected in tumors. This formulation exhibited no measurable toxicity as judged by weight loss or changes in serum levels of aspartate aminotransferase, alanine aminotransferase, and creatinine. This dose engendered a significant delay in PC-3 tumor growth, an increase in apoptotic index, and a decrease in tumor cell proliferation. CONCLUSIONS: Rh2 is a stable compound that can be formulated for oral gavage. Pharmacokinetics studies demonstrate its ability to be absorbed following oral administration. Future studies will assess the pharmacokinetics of Rh2 when administered in combination with docetaxel.