Integrated preclinical and clinical development of S-trans, trans-Farnesylthiosalicylic Acid (FTS, Salirasib) in pancreatic cancer.

PURPOSE: S-trans,trans-Farnesylthiosalicylic Acid (FTS, salirasib) inhibits Ras-dependent cell growth by dislodging all isoforms of Ras, including mutant Ras, from the plasma membrane. This study evaluated the activity, safety, and toxicity of salirasib in preclinical models and patients with metastatic pancreatic adenocarcinoma (PDA). PATIENTS AND METHODS: In the preclinical study, salirasib was tested, alone and in combination with gemcitabine, in patient derived xenografts (PDX) of PDA. In the clinical study, treatment-naïve patients with advanced, metastatic PDA were treated with a standard dose schedule of gemcitabine and salirasib 200-800 mg orally (PO) twice daily (bid) for 21 days every 28 days. Tissue from preclinical models and patients' biopsies were collected pre-treatment and on Cycle (C) 1, Day (D) 9 to characterize the effect of gemcitabine and salirasib on activated Ras protein levels. Plasma samples for pharmacokinetics were collected for salirasib administered alone and in combination. RESULTS: Salirasib inhibited the growth of 2/14 PDX models of PDA and modulated Ras signaling in these tumors. Nineteen patients were enrolled. No DLTs occurred. Common adverse events included hematologic and gastrointestinal toxicities and fatigue. The median overall survival was 6.2 months and the 1 year survival 37 %. In 2 patients in whom paired tissue biopsies were available, Ras and KRas protein levels were decreased on C1D9. Salirasib exposure was not altered by gemcitabine and did not correlate with PD outcomes. CONCLUSION: The combination of gemcitabine and salirasib appears well-tolerated, with no alteration of salirasib exposure, and exerted clinical and PD activity in PDA.

Determination of salirasib (S-trans,trans-farnesylthiosalicylic acid) in human plasma using liquid chromatography-tandem mass spectrometry.

A liquid chromatography/tandem mass spectrometric (LC/MS/MS) assay was developed for the quantitative determination of salirasib (S-trans,trans-farnesylthiosalicylic acid, FTS) in human plasma. Sample pretreatment involved liquid-liquid extraction with methyl t-butyl ether of 0.5-mL aliquots of lithium heparin plasma spiked with the internal standard, S-trans,trans-5-fluoro-farnesylthiosalicylic acid (5-F-FTS). Separation was achieved on Waters X-Terra C(18) (50 mm x 2.1 mm i.d., 3.5 microm) at room temperature using isocratic elution with acetonitrile/10 mM ammonium acetate buffer mobile phase (80:20, v/v) containing 0.1% formic acid at a flow rate of 0.20 mL/min. Detection was performed using electrospray MS/MS by monitoring the ion transitions from m/z 357.2-->153.0 (salirasib) and m/z 375.1-->138.8 (5-F-FTS). Calibration curves were linear in the concentration range of 1-1000 ng/mL. A 5000 ng/mL sample that was diluted 1:10 (v/v) with plasma was accurately quantitated. The values for both within day and between day precision and accuracy were well within the generally accepted criteria for analytical method (<8.0%). This assay was subsequently used for the determination of salirasib concentrations in plasma of cancer patients after oral administration of salirasib at a dose of 400 mg.

Modulation of hepatic and renal drug metabolizing enzyme activities in rats by subchronic administration of farnesol.

Farnesol demonstrates antitumor activity in several animal models for human cancer and was being considered for development as a cancer chemopreventive agent. This study was performed to characterize the effects of minimally toxic doses of farnesol on the activity of phase I and II drug metabolizing enzymes. CD((R)) rats (20/sex/group) received daily gavage exposure to farnesol doses of 0, 500, or 1000 mg/kg/day for 28 days; 10 rats/sex/group were necropsied at the termination of farnesol exposure; remaining animals were necropsied after a 28-day recovery period. No deaths occurred during the study, and farnesol had no significant effects on body weight, food consumption, clinical signs, or hematology/coagulation parameters. Modest but statistically significant alterations in several clinical chemistry parameters were observed at the termination of farnesol exposure; all clinical pathology effects were reversed during the recovery period. At the termination of dosing, the activities of CYP1A, CYP2A1-3, CYP2B1/2, CYP2C11/12, CYP2E1, CYP3A1/2, CYP4A1-3, CYP19, glutathione reductase, NADPH/quinone oxidoreductase and UDP-glucuronosyltransferase were significantly increased in the livers of farnesol-treated rats; farnesol also increased the activity of glutathione S-transferase in the kidney. The effects of farnesol on hepatic and renal enzymes were reversed during the recovery period. At the end of the dosing period, increases in absolute and relative liver and kidney weights were seen in farnesol-treated rats. These increases may be secondary to induction of drug metabolizing enzymes, since organ weight increases were not associated with histopathologic alterations and were reversed upon discontinuation of farnesol exposure. Administration of farnesol at doses of up to 1000 mg/kg/day induced reversible increases in the activities of several hepatic and renal drug metabolizing enzymes in rats, while inducing only minimal toxicity. It is concluded that non-toxic or minimally toxic doses of farnesol could alter the metabolism, efficacy, and/or toxicity of drugs with which it is co-administered.

Farnesol as antibiotics adjuvant in Staphylococcus epidermidis control in vitro.

INTRODUCTION: Farnesol is a sesquiterpenoid that has been described as impairing bacterial growth. Therefore, the goal of this study was to compare the in vitro postantimicrobial effect (PAE) of farnesol against Staphylococcus epidermidis with the corresponding values of most common practice antibiotics and also to evaluate the combined effect of farnesol with these antibiotics against planktonic and biofilm cells. METHODS: After exposure of S epidermidis cells to farnesol and antibiotics at minimum inhibitory concentration for 1 hour, the cells were regrown in medium without any antimicrobial agent. Cellular viability was assessed by colony-forming units, every hour for 12 hours, and then, the PAE was determined. The combined effect of farnesol (0, 30, 100 and 300 µM) with vancomycin, tetracycline and rifampicin was also evaluated, by using these antibiotics at peak serum concentration. RESULTS: When PAE is concerned, it was found that cells grown in 100 µM of farnesol behaved similarly to cells that had never been in contact with farnesol, whereas a clear difference was obtained with cells exposed to 300 µM of farnesol, displaying a longer PAE. Farnesol showed a combined effect with the tested antibiotics against planktonic cells, although this was not so evident against biofilm cells. CONCLUSIONS: Despite the reduced efficacy against biofilm cells, farnesol seems to be a potential adjuvant therapeutic agent to antibiotics against S epidermidis planktonic cells. Moreover, its long PAE makes farnesol a potential candidate in the prevention of biofilm formation because it showed to be very effective against planktonic cells alone as well.

Effect of farnesol on a mouse model of systemic candidiasis, determined by use of a DPP3 knockout mutant of Candida albicans.

This work extends our previous observation that the fungus Candida albicans secretes micromolar levels of farnesol and that accumulation of farnesol in vitro prevents the yeast-to-mycelium conversion in a quorum-sensing manner. What does farnesol do in vivo? The purpose of this study was to determine the role of farnesol during infection with a well-established mouse model of systemic candidiasis with C. albicans A72 administered by tail vein injection. This question was addressed by altering both endogenous and exogenous farnesol. For endogenous farnesol, we created a knockout mutation in DPP3, the gene encoding a phosphatase which converts farnesyl pyrophosphate to farnesol. This mutant (KWN2) produced six times less farnesol and was ca. 4.2 times less pathogenic than its SN152 parent. The strain with DPP3 reconstituted (KWN4) regained both its farnesol production levels and pathogenicity. These mutants (KWN1 to KWN4) retained their full dimorphic capability. With regard to exogenous farnesol, farnesol was administered either intraperitoneally (i.p.) or orally in the drinking water. Mice receiving C. albicans intravenously and farnesol (20 mM) orally had enhanced mortality (P < 0.03). Similarly, mice (n = 40) injected with 1.0 ml of 20 mM farnesol i.p. had enhanced mortality (P < 0.03), and the onset of mortality was 30 h sooner than for mice which received a control injection without farnesol. The effect of i.p. farnesol was more pronounced (P < 0.04) when mice were inoculated with a sublethal dose of C. albicans. These mice started to die 4 days earlier, and the percent survival on day 6 postinoculation (p.i.) was five times lower than for mice receiving C. albicans with control i.p. injections. In all experiments, mice administered farnesol alone or Tween 80 alone remained normal throughout a 14-day observation period. Finally, beginning at 12 h p.i., higher numbers of C. albicans cells were detected in kidneys from mice receiving i.p. farnesol than in those from mice receiving control i.p. injections. Thus, reduced endogenous farnesol decreased virulence, while providing exogenous farnesol increased virulence. Taken together, these data suggest that farnesol may play a role in disease pathogenesis, either directly or indirectly, and thus may represent a newly identified virulence factor.

Farnesol, a sesquiterpene alcohol in essential oils, ameliorates serum allergic antibody titres and lipid profiles in ovalbumin-challenged mice

BACKGROUND: Farnesol, a natural sesquiterpene alcohol in essential oils, was found to have potential for alleviating massive inflammation, oxidative stress and lung injury. However, effects of farnesol supplementation on allergic asthma remain unclear. OBJECTIVES: To clarify the puzzle, this work investigates the effects of farnesol on allergic asthma using an ovalbumin (OVA)-sensitised and challenged mouse model. METHODS: Farnesol was administered to OVA-sensitised and challenged mice for 5 weeks. Three farnesol doses, namely 5, 25 and 100 mg farnesol/kg BW/day, non-sensitised control, dietary control, and positive control (dexamethasone 3 mg/kg BW by gavage) were included. Sera and bronchoalveolar lavage fluids from the experimental mice were collected to measure farnesol concentrations, serum lipid profiles, antibody titres, differential cell counts or Th1/Th2 cytokines levels. RESULTS: The results showed that farnesol supplementation increased serum farnesol concentration dose-dependently, significantly increased (P < 0.05) OVA-specific IgG2a/IgE antibody titre ratios, but decreased total IgE levels. Farnesol supplementation markedly reversed the aberrated LDL-c/HDL-c and HDL-c/TC ratios in the sera of asthmatic mice, suggesting that farnesol supplementation might ameliorate serum lipid profiles in the OVA-sensitised and challenged mice. CONCLUSION: Our results evidenced that farnesol supplementation might improve serum allergic antibody titres and lipid profiles in asthmatic mice

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