A UHPLC-MS/MS-based method for the simultaneous monitoring of eight antiblastic drugs in plasma and urine of exposed healthcare workers.

Exposure of healthcare workers to anticancer drugs requires the combined action of environmental and biological monitoring to assess the effective level of exposure to these chemicals, to improve awareness and to avoid adverse health effects on this category of workers. Cancer chemotherapeutic drugs show different mechanisms of action due to diverse chemical structures; consequently, they differ in hydrophobicity, pharmacokinetics and pharmacodynamics. Therefore, the appearance, accumulation and elimination of each of these molecules in body fluids and tissues might be extremely variable; this prompts the need for a rapid and versatile analytical protocol for the biological monitoring of possible exposure of workers involved in the manipulation, administration and disposal of cancer chemotherapeutic drugs. In this paper we describe the development, optimization and validation of a UHPLC-MS/MS method for the simultaneous quasi-quantitative analysis of eight widely used antineoplastic drugs, which can be used for the analysis of both urine and blood samples. This methodology was applied to the biological monitoring of healthcare workers exposed to different extents to antiblastic drugs at the University Hospital "San Giovanni di Dio e Ruggi d'Aragona" in Salerno (Italy), and allowed to identify two subjects exposed to irinotecan out of a total of fifteen workers analyzed.

Association of USF1 and APOA5 polymorphisms with familial combined hyperlipidemia in an Italian population.

BACKGROUND: Familial combined hyperlipidemia (FCH) is a polygenic and multifactorial disease characterized by a variable phenotype showing increased levels of triglycerides and/or cholesterol. The aim of this study was to identify single nucleotides (SNPs) in lipid-related genes associated with FCH. METHODS AND RESULTS: Twenty SNPs in lipid-related genes were studied in 142 control subjects and 165 FCH patients after excluding patients with mutations in the LDLR gene and patients with the E2/E2 genotype of APOE. In particular, we studied the 9996G > A (rs2073658) and 11235C > T (rs3737787) variants in the Upstream Stimulatory Factor 1 gene (USF1), and the -1131T > C (rs662799) and S19W (rs3135506) variants in the Apolipoprotein A-V gene (APOA5). We found that the frequencies of these variants differed between patients and controls and that are associated with different lipid profiles. At multivariate logistic regression SNP S19W in APOA5 remained significantly associated with FCH independently of age, sex, BMI, cholesterol and triglycerides. CONCLUSIONS: Our results show that the USF1 and APOA5 polymorphisms are associated with FCH and that the S19W SNP in the APOA5 gene is associated to the disease independently of total cholesterol, triglycerides and BMI. However, more extensive studies including other SNPs such as rs2516839 in USF1, are required.

Pro-apoptotic and cytostatic activity of naturally occurring cardenolides.

PURPOSE: Cardenoliddes are steroid glycosides which are known to exert cardiotonic effects by inhibiting the Na(+)/K(+)-ATPase. Several of these compounds have been shown also to possess anti-tumor potential. The aim of the present work was the characterization of the tumor cell growth inhibition activity of four cardenolides, isolated from Periploca graeca L., and the mechanisms underlying such an effect. METHODS: The pro-apoptotic and cytostatic effect of the compounds was tested in U937 (monocytic leukemia) and PC3 (prostate adenocarcinoma). Characterization of apoptosis and cell cycle impairment was obtained by cytofluorimetry and WB. RESULTS: Periplocymarin and periplocin were the most active compounds, periplocymarin being more effective than the reference compound ouabain. The reduction of cell number by these two cardenolides was due in PC3 cells mainly to the activation of caspase-dependent apoptotic pathways, while in U937 cells to the induction of cell cycle impairment without extensive cell death. Interestingly, periplocymarin, at cytostatic but non-cytotoxic doses, was shown to sensitize U937 cells to TRAIL. CONCLUSIONS: Taken together, our data outline that cardiac glycosides are promising anticancer drugs and contribute to the identification of new natural cardiac glycosides to obtain chemically modified non-cardioactive/low toxic derivatives with enhanced anticancer potency.

Cytotoxic furostanol saponins and a megastigmane glucoside from tribulus parvispinus.

Two new furostanol saponins, (25R)-26-O-beta-D-glucopyranosyl-5alpha-furostan-2alpha,3beta,22alpha,26-tetraol 3-O-{beta-D-galactopyranosyl-(1-->2)-O-[beta-D-xylopyranosyl-(1-->3)]-O-beta-D-glucopyranosyl-(1-->4)-beta-D-galactopyranoside} (1) and (25R)-26-O-beta-D-glucopyranosyl-5alpha-furostan-3beta,22alpha,26-triol 3-O-{beta-D-galactopyranosyl-(1-->2)-O-[beta-D-xylopyranosyl-(1-->3)]-O-beta-D-glucopyranosyl-(1-->4)-beta-D-galactopyranoside} (2), and their O-methyl derivatives (3 and 4), and a new megastigmane glucoside, (6S,7E,9xi)-6,9,10-trihydroxy-4,7-megastigmadien-3-one 10-O-beta-D-glucopyranoside (6), along with one known spirostanol saponin, gitonin (5), and four known megastigmane glucosides were isolated from the aerial parts of Tribulus parvispinus. Their structures were established by detailed spectroscopic analysis. The cytotoxic activities of 1-6 against U937, MCF7, and HepG2 cells were evaluated. Compounds 2 (IC(50) 0.5 microM) and 5 (IC(50) 0.1 microM) showed the highest activity against U937 cells.