Beam me up: A novel mass spectrometric ionization technique based on rapid evaporation of biological tissues (see picture) can be used to analyze vital tissues during surgical intervention as well as for processed tissue specimens. A tissue identification system based on principal‐component analysis was developed. The method differentiates malignant tumor cells from the surrounding healthy tissue.
Background and purpose: ABC multidrug transporters (MDR-ABC proteins) cause multiple drug resistance in cancer and may be involved in the decreased anti-cancer efficiency and modified pharmacological properties of novel specifically targeted agents. It has been documented that ABCB1 and ABCG2 interact with several first-generation, small-molecule, tyrosine kinase inhibitors (TKIs), including the Bcr-Abl fusion kinase inhibitor imatinib, used for the treatment of chronic myeloid leukaemia. Here, we have investigated the specific interaction of these transporters with nilotinib, dasatinib and bosutinib, three clinically used, second-generation inhibitors of the Bcr-Abl tyrosine kinase activity. Experimental approach: MDR-ABC transporter function was screened in both membrane-and cell-based (K562 cells) systems. Cytotoxicity measurements in Bcr-Abl-positive model cells were coupled with direct determination of intracellular TKI concentrations by high-pressure liquid chromatography-mass spectrometry and analysis of the pattern of Bcr-Abl phosphorylation. Transporter function in membranes was assessed by ATPase activity. Key results: Nilotinib and dasatinib were high-affinity substrates of ABCG2, and this protein mediated an effective resistance in cancer cells against these compounds. Nilotinib and dasatinib also interacted with ABCB1, but this transporter provided resistance only against dasatinib. Neither ABCB1 nor ABCG2 induced resistance to bosutinib. At relatively higher concentrations, however, each TKI inhibited both transporters. Conclusions and implications: A combination of in vitro assays may provide valuable preclinical information for the applicability of novel targeted anti-cancer TKIs, even in multidrug-resistant cancer. The pattern of MDR-ABC transporter-TKI interactions may also help to understand the general pharmacokinetics and toxicities of new TKIs.
A novel, solid phase extraction (SPE)-based sample preparation method was developed for desorption electrospray ionization (DESI) mass spectrometry. Conventional SPE sample preparation was followed by a custom elution procedure. The eluate was evaporated from the closing frit of the cartridge using a gas jet. Thus the analyte was concentrated on the surface of the frit, which is ideal for DESI analysis. Application of the above SPE protocol allowed the concentration of the analyte content of up to 1 L liquid sample into a 1 mm diameter circular spot. The sample preparation procedure can improve the overall sensitivity of the method by up to 6 orders of magnitude if the sample volume is sufficient. The device has been tested using aqueous solutions of Rhodamine 116; the limit of detection was comparable to the LOD of electrospray analysis. Methodology was tested for drug monitoring applications in human serum. Levels of Cyclosporine A were determined using a 0.1 mL serum sample. Dynamic range of the method exceeded 3 orders of magnitude; the detection limit was below the therapeutic serum concentration of the drug.
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