Biomedical subjects

P Auvray

Publications and source records attributed to P Auvray.

At least 19 recordsLinked to original sources

PubMed2005

Towards a laser neutron driver.

During the last few years, important experimental investigations have been made concerning the possibility of induced nuclear fission of high-Z elements by electromagnetic interaction (photofission, electron fission, neutron fission). Fast ions, neutrons and fission fragments from such interactions can be used to pump a laser medium, to produce energy from the (232)Th-(233)U nuclear fission cycle. The main aim of the present work is to study a three-step process, in a relatively new experimental scheme, in order to improve the number of both neutrons and fast ions. In the proposed scheme, high-energy particles and photons are produced by high-intensity laser beam interaction with a solid or gas target, which are utilized later on to trigger the nuclear reactions for the production of (photo) neutrons. These neutrons can give rise to fission of (232)Th that leads through a cascade of decays to (233)U --a highly fissionable material. Such a process will enhance, by an important factor, the final neutron flux and the energetic fission fragments. The use of a high intensity pulsed laser beam will control the turn-on and turn-off of the nuclear reactions and allow one to ensure the security of the whole operation. Finally, the produced neutrons are used to accomplish a major population inversion in an appropriate gas medium for the last stage of amplification of a high-contrast ultra-short laser seed pulse.

Journal Article↗

PubMed2002

Study of substrate specificity of human aromatase by site directed mutagenesis.

Human aromatase is responsible for estrogen biosynthesis and is implicated, in particular, in reproduction and estrogen-dependent tumor proliferation. The molecular structure model is largely derived from the X-ray structure of bacterial cytochromes sharing only 15-20% identities with hP-450arom. In the present study, site directed mutagenesis experiments were performed to examine the role of K119, C124, I125, K130, E302, F320, D309, H475, D476, S470, I471 and I474 of aromatase in catalysis and for substrate binding. The catalytic properties of mutants, transfected in 293 cells, were evaluated using androstenedione, testosterone or nor-testosterone as substrates. In addition, inhibition profiles for these mutants with indane or indolizinone derivatives were obtained. Our results, together with computer modeling, show that catalytic properties of mutants vary in accordance with the substrate used, suggesting possible differences in substrates positioning within the active site. In this respect, importance of residues H475, D476 and K130 was discussed. These results allow us to hypothesize that E302 could be involved in the aromatization mechanism with nor-androgens, whereas D309 remains involved in androgen aromatization. This study highlights the flexibility of the substrate-enzyme complex conformation, and thus sheds new light on residues that may be responsible for substrate specificity between species or aromatase isoforms.

Amino Acid Sequence↗

PubMed2000

New aromatase inhibitors. Synthesis and biological activity of aryl-substituted pyrrolizine and indolizine derivatives.

We report herein the design and the synthesis of some aryl-substituted pyrrolizine and indolizine derivatives, on the basis of a hypothetical pharmacophore structure designed to fit the catalytic site of the human cytochrome P450 aromatase. The in vitro biological evaluation of these compounds allowed us to point out two new potent non-steroidal aromatase inhibitors, MR 20494 and MR 20492, with IC50 values in the range of 0.1 microM.

Aromatase Inhibitors↗

PubMed2000

[Preclinical evaluation of aromatase inhibitors antitumor activity].

Aromatase is an enzymatic complex responsible for the conversion of androgens into estrogens; these hormones are important in development, reproduction, but also in the growth of estrogen-dependent cancer. This enzyme is present in 60-70% of the breast cancer. The aromatase inhibitors are important drugs in the breast cancer treatment of postmenopausal women. In order to study their in vivo activity, animal models have been developed, e.g. rat with tumour induced by 7,12-dimethylbenz[a]anthracene, PMSG-primed immature rat or athymic nude mice with aromatase transfected MCF-7 xenograft. In this review, we were interested in preclinical results obtained with both classes: steroidal and nonsteroidal inhibitors. The former group, as substrate analogs formestane or exemestane, are irreversible, selective and long-lasting inhibitors of aromatase. The nonsteroidal molecules, such as letrozole or anastrozole, are reversible inhibitors with high affinity. Finally, knowledge of the enzyme active site, with molecular modeling and site-directed mutagenesis, could be useful to develop new inhibitor families, more specific and potent in vivo.

Aminoglutethimide↗

PubMed1998

PAAn-1b and PAAn-E: two phosphorothioate antisense oligodeoxynucleotides inhibit human aromatase gene expression.

Estrogen-dependent diseases, especially breast cancers, are frequently treated with aromatase inhibitors. Another more recent strategy is the antisense technology. In this study, after predicting aromatase mRNA secondary structure, we describe the design, the efficiency, and the toxicity of two antisense phosphorothioate oligodeoxynucleotides (PAAn-1b and PAAn-E) directed toward aromatase mRNA. Indeed, 2 microM PAAn-1b and PAAn-E encapsulated with 54 microM polyethylenimine inhibit aromatase activity by 71 and 79%, respectively, in transfected 293 cells, with IC50 values of 0.2 and 0.6 microM. The mechanism of inhibition appears to be specific after using sense and scramble oligodeoxynucleotides as controls and largely decreases aromatase mRNA and protein amounts. Moreover, PAAn-1b and PAAn-E are not cytotoxic for 293 cells. This study finally provides a new strategy for aromatase inhibition. It offers new tools for studying aromatase gene expression and its role in cancer for instance, and this could be of help for the therapy of estrogen-dependent diseases.

Actins↗

PubMed1998