Tipifarnib Is Cytotoxic and a Drug Transporter Inhibiting Chemosensitizer in Hodgkin Lymphoma Tumor Cells.

INTRODUCTION: Patients with Hodgkin lymphoma (HL) still suffer from late toxicities and insufficient treatment of relapses. New therapies should therefore be established. Tipifarnib is a farnesyl transferase inhibitor with an excellent toxicity profile and clinical activity in hematologic malignancies. Recently, tipifarnib has also been shown to potentiate the cytotoxicity of anthracyclines in leukemia cells via the inhibition of the multidrug resistance transporter P-glycoprotein. To date, nothing is known about a functional role of drug resistance transporters or the effects of tipifarnib in HL.

METHODS: To test the anti-tumor effects of tipifarnib in HL cell lines, tipifarnib was evaluated in the XTT cytotoxicity assay and the Annexin V binding assay. The combination efficacy of tipifarnib with the anthracycline doxorubicine was monitored using the Chou and Talalay combination index method. Flow cytometry was applied to assess the effects of tipifarnib on drug transporter mediated anthracycline efflux.

RESULTS: First, tipifarnib displayed high single agent toxicity in HL cell lines with an average IC50 of < 0.1 μM. Second, the combination of tipifarnib and doxorubicine was highly synergistic at clinically relevant concentrations (1–3 μM and 0.02–0.2 μM, respectively). Third, measurement of residual doxorubicine after incubation with doxorubicine and tipifarnib indicated a strong inhibition of doxorubicine efflux by tipifarnib suggesting a mechanism for the synergy of the two drugs.

CONCLUSIONS: Since tipifarnib displays high activity in a panel of HL cell lines, the clinical evaluation of tipifarnib in relapsed/refractory patients as single agent is warranted. Interestingly, tipifarnib exhibits a dual targeting mechanism in HL cells: Potent cytotoxicity as single agent and drug transporter dependent chemosensitization leading to a strong synergy with doxorubicine. The synergistic combinations of tipifarnib with doxorubicine correspond to plasma levels of the two drugs in cancer patients. Doxorubicine is one of the most effective but also most toxic drugs in the standard HL polychemotherapies whereas tipifarnib has a very favourable toxicity profile. Consequently, tipifarnib should be evaluated as a combination drug for HL polychemotherapy to save on doxorubicine dose and to lower acute and long-term toxicities. Tipifarnib might also be examined as a chemosensitizer for the combination therapy of patients with refractory disease.