title: Farnesyltransferase inhibitor tipifarnib (R115777) preferentially inhibits in vitro autonomous erythropoiesis of polycythemia vera patient cells.
abstract: Polycythemia vera (PV) is an acquired myeloproliferative disorder with primary expansion of the red cell mass leading to an increased risk of thrombosis and less frequently to myelofibrosis and secondary acute leukemia. Standard therapies include cytoreduction with either phlebotomy or chemotherapeutic agents and antithrombotic drugs. Because long-term exposure to cytotoxic chemotherapy may increase the risk of acute transformation, new therapeutic options are needed. Tipifarnib is a nonpeptidomimetic inhibitor of farnesyl transferase that was developed as a potential inhibitor of RAS signaling. In the present study we report that tipifarnib used at pharmacologically achievable concentrations strongly inhibits the erythroid burst-forming unit (BFU-E) autonomous growth that characterizes patients with PV. Moreover, at low tipifarnib concentrations (0.15 muM), the inhibitory effect was preferentially observed in PV BFU-E progenitors and not in normal BFU-E progenitors and was not rescued by erythropoietin (EPO). Thus tipifarnib may specifically target PV stem cells and may be of clinical interest in the treatment of patients with PV.
authors.affiliation: Service Clinique des Maladies du Sang, Hôpital Saint-Louis, 1 avenue Claude Vellefaux, 75475 Paris cedex 10, France.
authors.forename: Jérôme
authors.initials: J
authors.lastname: Larghero
authors.forename: Nathalie
authors.initials: N
authors.lastname: Gervais
authors.forename: Bruno
authors.initials: B
authors.lastname: Cassinat
authors.forename: Jean-Didier
authors.initials: JD
authors.lastname: Rain
authors.forename: Marie-Hélène
authors.initials: MH
authors.lastname: Schlageter
authors.forename: Rose Ann
authors.initials: RA
authors.lastname: Padua
authors.forename: Christine
authors.initials: C
authors.lastname: Chomienne
authors.forename: Philippe
authors.initials: P
authors.lastname: Rousselot
mesh_terms: D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D016022:Case-Control Studies; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D051231:Farnesyltranstransferase; D006801:Humans; D011087:Polycythemia Vera / Q000188:drug therapy / Q000473:pathology*; D015363:Quinolones / Q000494:pharmacology*
chemical_list: D015363:Quinolones; D004921:Erythropoietin; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; C402769:tipifarnib