Orally administered FTS (salirasib) inhibits human pancreatic tumor growth in nude mice

Abstract

S-trans,trans-farnesylthiosalicylic acid (salirasib, FTS) is a synthetic small molecule that acts as a potent Ras inhibitor. Salirasib inhibits specifically both oncogenically activated Ras and growth factor receptor-mediated Ras activation, resulting in the inhibition of Ras-dependent tumor growth. The objectives of this study were to develop a sensitive LC-MS/MS assay for determination of FTS in plasma, to assess the bioavailabilty of FTS after oral administration to mice, and then to examine the efficacy of orally administered FTS for inhibition of tumor growth in a nude mouse model. FTS was isolated from mouse plasma by liquid chromatography on a Columbus 5-mum particle size, 50 x 2 mm id column with a methanol/5 mM ammonium acetate (80/20) mobile phase (isocratic elution) at a flow rate of 0.3 ml/min. MS/MS was performed on a PE Sciex API 365 with Turbo Ion Spray as interface and negative ion ionization; parent ion (m/z): 357.2; daughter ion (m/z) 153.2; retention time 2.3 min. For plasma analysis, the amount of analyte in each sample was calculated by comparing response of the analyte in that sample to a nine-point standard curve linear over the range 3-1000 ng/ml. Pharmacokinetic studies were performed in mice following intraperitoneal dosing (20 mk/kg in PBS) or oral dosing (40 mg/kg in either 0.5% aqueous CMC or corn oil). Panc-1 tumor growth in nude mice was determined following daily oral dosing with FTS in 0.5% CMC (40, 60, or 80 mg/kg), or in combination with weekly gemcitabine (30 mg/kg). Salirasib was readily detected in mouse plasma by LC-MS/MS at a detection limit of 3 ng/ml. For each route of administration, t (max) was 1 h and t (1/2) ranged from 1.86 to 2.66 h. Compared to IP administration, the oral bioavailabilty of FTS was 69.5% for oral CMC and 55% for oral corn oil suspensions, while clearance and volume of distribution were higher in both oral preparations. The orally administered salirasib inhibited panc-1 tumor growth in a dose dependent manner (67% reduction in tumor weight at the highest dose, P < 0.002 vs. control, n = 10 mice per group) and at a 40 mg/kg daily dose was synergistic with gemcitabine (83% increase in survival rate, n = 8 mice per group). Salirasib exhibits good bioavailabilty after oral administration, as determined by a highly sensitive method for quantification in plasma. The orally available Ras inhibitor salirasib inhibited growth in nude mice, and may thus be considered for clinical trials.