ABSTRACT
Dysregulation of PI3K/PTEN pathway components, resulting in hyperactivated PI3K signaling, is frequently observed in various cancers and correlates with tumor growth and survival. Resistance to a variety of anticancer therapies, including receptor tyrosine kinase (RTK) inhibitors and chemotherapeutic agents, has been attributed to the absence or attenuation of downregulating signals along the PI3K/PTEN pathway. Thus, PI3K inhibitors have therapeutic potential as single agents and in combination with other therapies for a variety of cancer indications. XL147 (SAR245408) is a potent and highly selective inhibitor of class I PI3Ks (α, ß, γ, and δ). Moreover, broad kinase selectivity profiling of >130 protein kinases revealed that XL147 is highly selective for class I PI3Ks over other kinases. In cellular assays, XL147 inhibits the formation of PIP3 in the membrane, and inhibits phosphorylation of AKT, p70S6K, and S6 in multiple tumor cell lines with diverse genetic alterations affecting the PI3K pathway. In a panel of tumor cell lines, XL147 inhibits proliferation with a wide range of potencies, with evidence of an impact of genotype on sensitivity. In mouse xenograft models, oral administration of XL147 results in dose-dependent inhibition of phosphorylation of AKT, p70S6K, and S6 with a duration of action of at least 24 hours. Repeat-dose administration of XL147 results in significant tumor growth inhibition in multiple human xenograft models in nude mice. Administration of XL147 in combination with chemotherapeutic agents results in antitumor activity in xenograft models that is enhanced over that observed with the corresponding single agents.
Subject(s)
Antineoplastic Agents/pharmacology , Phosphoinositide-3 Kinase Inhibitors , Quinoxalines/pharmacology , Sulfonamides/pharmacology , Animals , Antineoplastic Agents/administration & dosage , Cell Line, Tumor , Cell Movement/drug effects , Cell Proliferation/drug effects , Disease Models, Animal , Humans , Male , Mice , Mice, Nude , Neovascularization, Pathologic/drug therapy , Phosphorylation , Proto-Oncogene Proteins c-akt/metabolism , Quinoxalines/administration & dosage , Ribosomal Protein S6 Kinases/metabolism , Signal Transduction/drug effects , Sulfonamides/administration & dosage , Xenograft Model Antitumor AssaysABSTRACT
INTRODUCTION: Measuring adherence to smoking cessation pharmacotherapy is important to evaluating its effectiveness. Blood levels are considered the most accurate measure of adherence but are invasive and costly. Pill counts and self-report are more practical, but little is known about their relationship to blood levels. This study compared the validity of pill count and self-report against plasma varenicline concentration for measuring pharmacotherapy adherence. METHODS: Data were obtained from a randomized pilot study of varenicline for smoking cessation among African American smokers. Adherence was measured on Day 12 via plasma varenicline concentration, pill count, 3-day recall, and a visual analogue scale (VAS; adherence was represented on a line with two extremes "no pills" and "all pills"). RESULTS: The sample consisted of 55 African American moderate to heavy smokers (average 16.8 cigarettes/day, SD = 5.6) and 63.6% were female. Significant correlations (p < .05) were found between plasma varenicline concentration and pill count (r = .56), 3-day recall (r = .46), and VAS (r = .29). Using plasma varenicline concentration of 2.0 ng/ml as the cutpoint for adherence, pill count demonstrated the largest area under the receiver operating characteristic curve (AUC = 0.85, p = .01) and had 88% sensitivity (95% CI = 75.0-95.0) and 80% specificity (95% CI = 30.0-99.0) for detecting adherence. CONCLUSIONS: Of 3 commonly used adherence measures, pill count was the most valid for identifying adherence in this sample of African American smokers. Pill count has been used across other health domains and could be incorporated into treatment to identify nonadherence, which, in turn, could maximize smoking cessation pharmacotherapy use and improve abstinence rates.
Subject(s)
Benzazepines/administration & dosage , Black or African American , Medication Adherence/psychology , Nicotinic Agonists/administration & dosage , Quinoxalines/administration & dosage , Self Report , Smoking Cessation/methods , Tobacco Use Disorder/drug therapy , Adult , Attitude to Health , Biomarkers/blood , Female , Humans , Male , Medication Adherence/ethnology , Middle Aged , Pilot Projects , Smoking Cessation/ethnology , Tobacco Use Disorder/blood , Treatment Outcome , Varenicline , Young AdultABSTRACT
The nicotine metabolite cotinine is widely used to assess the extent of tobacco use in smokers, and secondhand smoke exposure in non-smokers. The ratio of another nicotine metabolite, trans-3'-hydroxycotinine, to cotinine in biofluids is highly correlated with the rate of nicotine metabolism, which is catalyzed mainly by cytochrome P450 2A6 (CYP2A6). Consequently, this nicotine metabolite ratio is being used to phenotype individuals for CYP2A6 activity and to individualize pharmacotherapies for tobacco addiction. In this paper we describe a highly sensitive liquid chromatography-tandem mass spectrometry method for determination of the nicotine metabolites cotinine and trans-3'-hydroxycotinine in human plasma, urine, and saliva. Lower limits of quantitation range from 0.02 to 0.1ng/mL. The extraction procedure is straightforward and suitable for large-scale studies. The method has been applied to several thousand biofluid samples for pharmacogenetic studies and for studies of exposure to low levels of secondhand smoke. Concentrations of both metabolites in urine of non-smokers with different levels of secondhand smoke exposure are presented.
