C. Monneret

Une nouvelle thérapie ciblée avec le bortézomib, médicament oncologique de l’année 2004

Resume Pour degrader les proteines, les cellules eucaryotes disposent de deux systemes principaux de degradation que sont le systeme des proteases lysosomales et le systeme du proteasome, ubiquitine et ATP-dependant. Cette derniere voie de degradation joue un role important dans la croissance des cellules tumorales et dans la formation de metastases en degradant par exemple la proteine p53, un suppreur de tumeurs, les inhibiteurs de kinases dependantes de cycline telle que les proteines p21 et p27, ou en activant le facteur de transcription NFκB aux fonctions anti-apoptotiques. Parmi les inhibiteurs de ce systeme de degradation connus a ce jour c’est un dipeptide borone, le PS341 ou bortezomid qui a recu une autorisation de mise sur le marche sous le nom de Velcade ® , mi-2003 aux USA puis en avril 2004 en Europe pour le traitement du myelome multiple chez les malades ayant deja recu deux traitements anterieurs infructueux. Cette meme annee 2004, le prix Nobel de chimie a ete attribue a trois chercheurs ayant contribue a la decouverte de ce systeme de degradation controlee des proteines.

Actualités thérapeutiques : l’abiratérone, le bélatacept, le vandétanib et la fidaxomycine ☆

Among the 35 new molecular entities approved by the FDA in 2011, 17 were particularly notable for their significant contributions to the health of patients, including abiraterone acetate, vandetanib, belatacept and fidaxomicin. Thus, abiraterone acetate, namely Zytiga®, was included as the first in a new class of drugs to treat late-stage prostate cancer. The ability of Zytiga® to prolong survival in these patients was considered as significant because they have few other treatments options and the benefits of Zytiga® outweighed the risks of reported side-effects. Vandetanib, namely Caprelsa®, was also considered as a relevant drug since it represents the first drug approved to treat particularly aggressive medullary thyroid cancer, an orphan disease. Despite huge progress in transplantation, renal transplantation remains a serious problem since patients treated with the calcineurin inhibitors cyclosporine and tacrolimus are at high risk of developing renal injury. With longer follow-up, the novel immunosuppressant belatacept continued to show better renal function compared with a cyclosporine-based regimen, as well as a consistent safety profile and comparable efficacy. It was approved by the Food and Drug Administration in June 2011 for the prophylaxis of organ rejection in adult recipients of a kidney transplant acting by a selective T-cell costimulation blocker given as an infusion. Clostridium difficile is currently the most important cause of infectious diarrhea in the United States. Fidaxomicin, a macrolide antibiotic, was recently approved for treatment of these infections (CDIs). It could be an alternative treatment for infection with C. difficile, with similar efficacy and safety to vancomycin. Fidaxomicin has minimal activity against Bacteroides species, which may be advantageous in maintaining colonization resistance and protecting the gastrointestinal tract from colonization by C. difficile.

Prodrogues glucuronylées du paclitaxel (Taxol®) activables au niveau des tumeurs

Three glucuronyl prodrugs of paclitaxel have been synthesized in order to be activated by the B-glucuronidase present within the necrotic areas of tumors. As three compartments containing prodrugs, they include a specifier, a self immolative spacer and the drug. In vitro testing clearly indicates that the two former prodrugs are stable and are more or less detoxified. As expected, in the presence of E. coli B-glucuronidase, the glycosidic linkage is hydrolyzed with a rate depending on the nature of the spacer but, once this hydrolysis has occurred, the self immolative spacer is soon eliminated leading to the liberation of the paclitaxel.