[Inhibitors of aurora kinases]. / Les inhibiteurs des kinases Aurora.

Aurora kinases (A, B and C) are proteins expressed only in cells which divide actively and their increase is a factor of bad prognosis in cancer. They regulate the maturation of centrosomes, the separation and the condensation of chromosomes, mitotic checkpoint and cytokinesis. The inhibition of aurora kinases, by powerful and selective inhibitors, is due to the formation of abnormal cells which are eliminated by apoptosis. The purpose of this article is to present the role, the antitumor activity and the tolerability of these inhibitors. They can be administered orally or intravenously, on weekly or monthly schedules. In our knowledge, twelve molecules are evaluated at the present time and will be discussed only the most advanced namely: VX-680, ZM 447439, MLN 8054, AZD 1152, PHA 739358, SU 6668 and AT 9283. The main indications are breast, colon, lung, pancreas and bladder cancers as well as hematologic tumors such as leukemia (ALL, AML, CML) and lymphoma. These inhibitors can be associated with other chemotherapies. They seem well tolerated; the reported side effects are digestive disorders (diarrhea), fever, asthenia, alopecia, slumber, neutropenia, myelosuppression and disturbance of the biological markers.

Comparison of the in vitro efficacies of moxifloxacin and amoxicillin against Listeria monocytogenes.

Listeria monocytogenes is a facultative intracellular bacterium that causes severe infections associated with a high mortality rate. Moxifloxacin presents extended activity against gram-positive bacteria and has recently been suggested to be a potential alternative in the treatment of listeriosis. We evaluated the in vitro efficacy of moxifloxacin against L. monocytogenes using a combination of epidemiological and experimental approaches. The median MIC of moxifloxacin for a large collection of L. monocytogenes strains of various origins (human, food, and environment) was 0.5 microg/ml (MIC range, 0.064 to 1 microg/ml). No differences were observed, irrespective of the origin of the strains. Moreover, no cross-resistance with fluoroquinolones was detected in strains that have been reported to be resistant to ciprofloxacin. The in vitro activities of moxifloxacin and amoxicillin were compared by time-kill curve and inhibition of intracellular growth experiments by using a model of bone marrow-derived mouse macrophages infected by L. monocytogenes EGDe. Both moxifloxacin and amoxicillin were bactericidal in broth against extracellular forms of L. monocytogenes. However, moxifloxacin acted much more rapidly, beginning to exert its effects in the first 3 h and achieving complete broth sterilization within 24 h of incubation. Moxifloxacin has a rapid bactericidal effect against intracellular reservoirs of bacteria, whereas amoxicillin is only bacteriostatic and appears to prevent cellular lysis and the subsequent bacterial spreading to adjacent cells. No resistant bacteria were selected during the in vitro experiments. Taken together, our results suggest that moxifloxacin is an interesting alternative to the reference treatment, combining rapid and bactericidal activity, even against intracellular bacteria.

Urinary 19-norandrosterone purification by immunoaffinity chromatography: application to gas chromatography/combustion/isotope ratio mass spectrometric analysis.

The detection of exogenous 19-norandrosterone (19-NA) in urines was investigated by using gas chromatography/combustion/isotope ratio mass spectrometry (GC/C/IRMS). 19-NA is, for the first time to our knowledge, isolated from urinary matrix by specific immunoaffinity chromatography (IAC) before analysis. The sample preparation consisted of a preliminary purification of urine by solid-phase extraction after hydrolysis by beta-glucuronidase. Unconjugated 19-NA was thus isolated by IAC and directly analysed by GC/C/IRMS. Optimisation of IAC purification was achieved and the reliability of the technique for anti-doping control is discussed.

A direct sensitized fluorimetric determination of 5,10,15,20-tetra(m-hydroxyphenyl)chlorin [m-THPC (Foscan)] in human plasma using a cyclodextrin inclusion complex.

The 5,10,15,20-tetra(m-hydroxyphenyl)chlorin (m-THPC) (Foscan) is a photosensitizer used in the photodynamic therapy (PDT) of cancers which is currently under clinical trial. The formation of a m-THPC inclusion complex with dimethyl-beta-cyclodextrin (Me-beta-CD) in solution was demonstrated on the basis of circular dichroism experiments. A 1:2 complex stoichiometry was found and an inclusion constant beta 2 = 2.8(+/- 0.4) x 10(10) M-2 was determined. The formation of such a complex was shown to enhance the m-THPC fluorescence intensity. It could be exploited to improve the sensitivity of the direct m-THPC detection in human plasma. Optimization of the operating conditions shows that the best results were obtained by the addition of 100 microL of a concentrated Me-beta-CD solution (3.2 x 10(-2) M) to 1 mL plasma samples. Compared to the standard conditions, a 90% increase in sensitivity was obtained. The proposed analytical method which showed a linear response function [0-300 ng mL-1 (440 pM)] and a low limit of detection [1.5 ng mL-1 (2 pM) (S/N = 3)] appears, especially due to the absence of metabolism, a simple and specific method suitable for pharmacokinetics studies in patients.

Importance of the ionization states of m-THPC for its HPLC fluorescence detection.

An original, rapid and sensitive high-performance liquid chromatographic (HPLC) method has been developed for the detection of 5, 10, 15, 20 tetra-meso-hydroxyphenylchlorine (m-THPC), a photosensitizer used in the photodynamic therapy (PDT) of cancers. Chromatographic separation was carried out on a C(8) Zorbax column (80 x 4 mm, 5 microm). The mobile phase was an ethanol/aqueous sulphuric acid, pH 2.0 (65/35 v/v), in an isocratic mode yielding to rapid analysis (3.1 min) with narrow peaks. As the fluorescence intensity was found to be highly pH-dependent and to increase with pH values, a post-column device prior to the fluorescence detection (lambda(exc) = 423 nm, lambda(em) = 650 nm) was used to allow the addition of a 0.05 mol/L Na(2)HPO(4) solution to the mobile phase. Compared to standard conditions, a 300% increase of the fluorescence intensity was obtained for optimized operating conditions using experimental design. The validation of this analytical method showed that the response function was linear for concentrations up to 1000 microg/L (1.47 x 10(-6) mol/L) with a detection limit of 188 pg (S/N = 3).