Résumés
Résumé
L’observation selon laquelle la farnésylation est une modification post-traductionnelle nécessaire au pouvoir transformant de l’oncogène ras a conduit à la conception d’inhibiteurs de farnésyl transférase (FTI) afin de contrôler la croissance des tumeurs présentant des mutations de ras. Des études précliniques sur des modèles murins ont précisé l’effet inhibiteur sur la transformation tumorale et ont permis le développement clinique des FTI. Les études récentes de phases I et II confirment leur potentiel anti-tumoral et leur faible toxicité. Paradoxalement, alors que l’intérêt des FTI se précise au niveau clinique, le support moléculaire de leur activité biologique reste encore à définir. En effet, il est maintenant clair que Ras n’est pas la cible unique de l’effet anti-transformant des FTI et que d’autres protéines farnésylées, telle que RhoB, pourraient intervenir. Il reste donc à caractériser ces protéines, ce qui permettrait à la fois de compléter nos connaissances de l’oncogenèse et de définir les paramètres pharmacodynamiques de lé clinique des FTI.
Summary
The fact that proteins such as Ras require farnesylation to induce malignant transformation prompted many investigators to design farnesyl transferase inhibitors (FTI) as novel anticancer drugs. FTIs inhibit the growth of ras transformed cells in vitro and induce tumor regression in ras dependent tumor in vivo. Moreover, FTIs inhibit tumor progression in human tumor xenograft models. Currently, FTIs are undergoing phase I and II trials in various cancer types. They show impressive antitumour efficacy and they lack toxicity. Despite these promising results, the development of such molecules is hindered by the absence of appropriate clinical endpoints and of surrogate biological markers. Indeed, it seems likely that Ras is not the critical target of FTIs and that inhibition of the farnesylation of proteins such as RhoB, might also contribute to the observed antitumour properties. Identification of targets that underlie their biological effect is essential in order to predict and evaluate their efficacy.
Parties annexes
Références
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