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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-μm particle size, 50 × 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. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is characterized by a high incidence of benign and malignant tumors attributed to loss of function of Nf1, which encodes neurofibromin, a tumor suppressor with Ras-GAP activity. Neurofibromin deficiency typically causes chronic activation of Ras, considered the major contributor to manifestation of NF1. Resistance to radio- and chemotherapy are typical of NF1-associated tumors, but the underlying mechanism is unknown. Here, we investigated interrelationships between neurofibromin expression, Ras activity, and sensitivity to apoptosis. Neurofibromin-deficient mouse embryonic fibroblasts (MEFs) and human NF1 tumor cells were more resistant than neurofibromin-expressing cells to apoptosis. Moreover, Nf1−/−, Nf1+/−, and Nf1+/+ MEFs exhibited gene-dosage-related resistance to apoptosis. Resistance of the Nf1-deficient cells was mediated by two survival pathways: a Ras-dependent pathway, and a Ras-independent pathway promoted by the lack of an NF1-GRD-independent proapoptotic action of neurofibromin. Therefore, besides its Ras-dependent growth inhibition, neurofibromin can exert tumor suppression via a proapoptotic effect.Cell Death and Differentiation (2007) 14, 895–906. doi:10.1038/sj.cdd.4402057; published online 10 November 2006 [ABSTRACT FROM AUTHOR]

Presents a letter to the editor commenting on restoration of sensitivity to anoikis in Ras-transformed rat intestinal epithelial cells by a Ras inhibitor published in February 2004 issue of the journal "Cell Death and Differentiation."