In vitro antiproliferative activity of the farnesyltransferase inhibitor R115777 in hematopoietic progenitors from patients with myelofibrosis with myeloid metaplasia.
R115777 is an orally bioavailable farnesyltransferase inhibitor (FTI) that has displayed encouraging activity in patients with acute myeloid leukemia. To determine whether R115777 might exert similar activity in myelofibrosis with myeloid metaplasia (MMM), we evaluated its effects on circulating myeloid progenitor cells from patients with MMM (n=25) using in vitro colony-forming assays. The median R115777 concentrations that inhibited colony formation by 50% were 34 and 2.7 nM for myeloid and megakaryocytic colonies from MMM patients, respectively. Progenitors from normal controls and patients with other myeloproliferative disorders demonstrated similar sensitivity. Since the ras polypeptides are one putative target of FTIs, the potential role of ras effectors was examined by incubating parallel progenitor assays with the phosphatidyl-inositol-3 (PI-3) kinase inhibitor LY294002 and the mitogen-activated protein kinase 1 inhibitor PD98059. MMM progenitor colonies (n=7) were highly sensitive to LY294002 but not to PD98059, implying that the PI-3 kinase pathway may be critical for survival and proliferation of these cells. In addition to indicating that MMM progenitors are sensitive to clinically achievable R115777 concentrations in vitro, these results provide a potential explanation for the thrombocytopenia observed with R115777 during the treatment of other hematologic malignancies.
Mesa
R A
RA
Division of Hematology and Internal Medicine, Mayo Clinic, Rochester, MN 55905, USA.
Tefferi
A
A
Gray
L A
LA
Reeder
T
T
Schroeder
G
G
Kaufmann
S H
SH
D000328:Adult; D000368:Aged; D019883:Alkyl and Aryl Transferases / Q000037:antagonists & inhibitors*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D003114:Colony-Forming Units Assay; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004906:Erythrocyte Count; D051231:Farnesyltranstransferase; D005260:Female; D005419:Flavonoids / Q000494:pharmacology; D058851:GPI-Linked Proteins; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D006801:Humans; D008297:Male; D008562:Membrane Glycoproteins; D000090204:Mesothelin; D008875:Middle Aged; D009025:Morpholines / Q000494:pharmacology; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011087:Polycythemia Vera / Q000097:blood / Q000188:drug therapy / Q000473:pathology; D055728:Primary Myelofibrosis / Q000097:blood* / Q000188:drug therapy / Q000473:pathology; D011506:Proteins / Q000378:metabolism; D015363:Quinolones / Q000494:pharmacology*; D013920:Thrombocythemia, Essential / Q000097:blood / Q000188:drug therapy / Q000473:pathology
D000970:Antineoplastic Agents; D002867:Chromones; D004791:Enzyme Inhibitors; D005419:Flavonoids; D058851:GPI-Linked Proteins; D008562:Membrane Glycoproteins; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011506:Proteins; D015363:Quinolones; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D019883:Alkyl and Aryl Transferases; D051231:Farnesyltranstransferase; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000090204:Mesothelin; C402769:tipifarnib; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one