In vitro antiproliferative activity of the farnesyltransferase inhibitor R115777 in hematopoietic progenitors from patients with myelofibrosis with myeloid metaplasia

Abstract

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 ¼ 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 phosphatidylinositol-3 (PI-3) kinase inhibitor LY294002 and the mitogenactivated protein kinase 1 inhibitor PD98059. MMM progenitor colonies (n ¼ 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.

Modern management of myelofibrosis

“…R115777, a farnesyl transferase inhibitor, has shown in vitro antiproliferative activity in the haemopoietic progenitors from IM patients (Mesa et al, 2003b). In a trial including eight patients, this drug provided 25% favourable responses in anaemia and splenomegaly, with the responses being significantly associated with higher VEGF plasma levels at the start of treatment (Cortes et al, 2003b).…”

A phase II trial of tipifarnib in myelofibrosis: primary, post-polycythemia vera and post-essential thrombocythemia

“…Dose-response curves before initiating therapy showed a median IC 50 of 11.8 nM tipifarnib (range: 0.5-200 nM), which is slightly lower than the IC 50 of 34 nM tipifarnib (range: 7.5-74.5 nM) we previously reported in myeloid progenitors from PMF patients. 24 Although progenitors from nine patients (27%) in the current group exhibited a pretreatment IC 50 434 nM, Further analysis indicated that clinical response to tipifarnib was not significantly correlated with baseline myeloid colony growth or ex vivo tipifarnib sensitivity (IC 50 values) (Wilcoxon rank-sum test). When results of the serial ex vivo dose-response curves were examined, circulating progenitors from seven patients demonstrated decreased sensitivity to tipifarnib in vitro (a 450% increase in IC 50 range (78-5120%)), while progenitors from five displayed an increase in tipifarnib in vitro sensitivity (a 450% decrease in IC 50 range (56-89%), Figure 1).…”

“…Paired samples harvested before and during tipifarnib therapy from 20 patients were examined for tipifarnib sensitivity ex vivo using the methodology we have described previously. 24 Briefly, aliquots containing 600 000 PBMCs (2 Â 10 6 /ml) were placed in Methocult (StemCell Technology; Vancouver, BC, Canada) containing diluent or graded drug concentrations (0-100 nM of tipifarnib) and plated as described above. After a 14-day incubation, progenitor colony numbers and subtypes were counted by light microscopy.…”

“…19 This prior study demonstrated that the median tipifarnib concentrations required to inhibit colony formation by 50% were 34 and 2.7 nM for myeloid and megakaryocytic colonies from PMF patients, respectively. These results indicated that PMF progenitors should be sensitive to clinically achievable tipifarnib concentrations, which are 380 (peak) and 120 nM (trough), upon administration of 300 mg tipifarnib twice daily.…”

“…These results indicated that PMF progenitors should be sensitive to clinically achievable tipifarnib concentrations, which are 380 (peak) and 120 nM (trough), upon administration of 300 mg tipifarnib twice daily. 19 Therefore, based upon this in vitro activity as well as the clinical tolerability and efficacy in other myeloid malignancies, we performed a phase II trial of tipifarnib monotherapy in symptomatic patients with either PMF or post-PV/ET MF.…”