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Dose-ranging pharmacodynamic study of tipifarnib (R115777) in patients with relapsed and refractory hematologic
Todd M Zimmerman1, Helena Harlin, Olatoyosi M Odenike
1Department of Medicine, Section of Hematology/Oncology, University of Chicago, Chicago, IL, USA. tzimmerm@medicine.bsd.uchicago.edu
Purpose:
Tipifarnib, an orally bioavailable inhibitor of farnesyl transferase, has activity in hematologic malignancies, but the dose required to achieve the proposed biologic end point, inhibition of farnesylation, is unknown.
Patients And Methods:
The impact on post-translational farnesylation was assessed in 42 patients with refractory hematologic malignancies and bone marrow involvement. Tipifarnib was taken orally for 21 days of a 28-day cycle. For cycle 1, patients were randomly assigned to one of four dose levels: 100 mg bid, 200 mg bid, 300 mg bid, and 600 mg bid. In cycle 1, peripheral blood and bone marrow mononuclear cells were analyzed for inhibition of HDJ2 prenylation by Western blot analysis at baseline and on day 21.
Results:
Twenty-three patients were assessable for analysis of HDJ2 prenylation before and after therapy. Inhibition of farnesylation was noted at all dose levels, although the highest level of inhibition was noted at the 300-mg-bid dose. The inhibition of farnesylation in the peripheral blood correlated with the inhibition in the bone marrow (r = 0.62). Of the 26 patients assessable for clinical activity after cycle 1, three patients had a significant decrease in total blasts count (acute myeloid leukemia in two patients, and chronic myelogenous leukemia in one patient). The inhibition of farnesylation was greater in the three responders than the nonresponders (P = .03).
Conclusion:
Farnesylation as measured by HDJ2 analysis was inhibited at all dose levels administered. Clinical activity may correlate with the degree of farnesylation inhibition, rather than dose of tipifarnib, and escalation beyond 300 mg bid might not result in additional clinical activity.
Insights
Tipifarnib inhibits farnesylation in hematologic malignancies at all doses tested. The 300 mg bid dose showed the highest inhibition, suggesting clinical activity may depend on farnesylation inhibition, not just tipifarnib dose.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Tipifarnib is an oral farnesyl transferase inhibitor with known activity in hematologic malignancies.
- The optimal dose to achieve biologic endpoints, specifically farnesylation inhibition, remains undetermined.
Purpose of the Study:
- To determine the dose of tipifarnib required to inhibit farnesylation in patients with hematologic malignancies.
- To assess the correlation between farnesylation inhibition and clinical activity.
Main Methods:
- A phase I/II study involving 42 patients with refractory hematologic malignancies.
- Patients received oral tipifarnib at doses of 100, 200, 300, or 600 mg twice daily (bid) for 21 days.
- Peripheral blood and bone marrow mononuclear cells were analyzed for HDJ2 prenylation inhibition via Western blot.
Main Results:
- Farnesylation inhibition was observed at all tested tipifarnib doses, with maximal inhibition at 300 mg bid.
- Inhibition in peripheral blood correlated with bone marrow inhibition (r = 0.62).
- Three of 26 assessable patients showed clinical activity (blast count reduction), and these responders had greater farnesylation inhibition (P = .03).
Conclusions:
- Tipifarnib effectively inhibits farnesylation in hematologic malignancies at all evaluated doses.
- Clinical activity appears to correlate with the degree of farnesylation inhibition, not solely the tipifarnib dose.
- Dose escalation beyond 300 mg bid may not yield additional clinical benefit.
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