The Farnesyl Protein Transferase Inhibitor Lonafarnib (SCH66336) Is an Inhibitor of Multidrug Resistance Proteins 1 and 2

Abstract

Clinical studies indicate that the farnesyl protein transferase inhibitor SCH66336 (lonafarnib), an anticancer agent developed to antagonize oncogenic Ras, is generally well tolerated. Lonafarnib has also demonstrated therapeutic synergy with coadministered taxanes, vincristine, cisplatin, cyclophosphamide, 5-fluorouracil (5-FU) and Gleevec. Lonafarnib has recently been shown, in addition, to be a potent inhibitor of the transmembrane efflux transporter P-glycoprotein (P-gp), which confers cellular resistance to the substrates vincristine, taxol and paclitaxel. Treatment with lonafarnib would therefore be predicted to be synergistic with these coadministered cancer therapeutics that are substrates of P-gp. However, cisplatin, 5-FU and cyclophosphamide are not P-gp substrates, yet cisplatin, 5-FU and possibly cyclophosphamide are purported substrates for multidrug resistance proteins (MRPs) 1 and 2 (known to cause chemotherapy resistance). Lonafarnib is shown here to inhibit the function of MRP1 and MRP2 with a potency similar to that of cyclosporin A and may therefore cause the observed synergy with cisplatin and other agents by inhibiting these MRPs. Coadministration of lonafarnib could thus reduce chemotherapy dosage and hence produce lower exposure to normal cells and less undesired toxicity.

The farnesyl transferase inhibitor, tipifarnib, is a potent inhibitor of the MDR1 gene product, P-glycoprotein, and demonstrates significant cytotoxic synergism against human leukemia cell lines

“…In this study, we initially wanted to determine whether tipifarnib had Pgp-inhibiting properties similar to lonafarnib, another FTI with a similar dual mechanism of action. 12 In CCRF-CEM cells, tipifarnib demonstrated half-maximum inhibition (IC 50 ), when compared to verapamil, of Pgp-mediated DNR efflux as concentrations less than 1 mM. At clinically relevant concentrations of DNR (0.2 mM), the IC 50 of tipifarnib was less than 3 mM.…”

“…Intrinsic drug resistance is thought to be a major factor in the resistance of leukemia blasts to chemotherapy. 12 Thus, we assessed the combinatorial effects of tipifarnib plus DNR on cell proliferation, apoptosis, FT inhibition and phosphorylation of ERK1/2 in two human leukemia cell lines which overexpress Pgp.…”

“…Tipifarnib (Zarnestrat, R115777, Johnson & Johnson Pharmaceutical Research & Development, LLC, Raritan, NJ, USA) is an imidazole-containing heterocyclic FTI, which inhibits the growth of several tumor cell lines, including those that contain either the wild-type or mutant Ras gene. [10][11][12] Tipifarnib has demonstrated anti-proliferative effects on cultured AML cells and HL-60 leukemia cells, leading to clinical evaluation in patients with acute leukemia (Lancet JE et al Blood 1999; 94: 149, abstract).…”

“…The MTT assay was performed as described previously. 12 Cells were plated in triplicate at 5-7.5 Â 10 3 cells/ well in 96-well plates. The cells were then incubated at 371C for 24 h. Cells were then exposed to DNR alone (0.02, 0.2 or 2.0 mM), tipifarnib alone (0.5, 2.0, and 4.0 mM) and all possible combinations using the aforementioned drug concentrations.…”

A phase I safety, pharmacological, and biological study of the farnesyl protein transferase inhibitor, lonafarnib (SCH 663366), in combination with cisplatin and gemcitabine in patients with advanced solid tumors

“…Phase I studies of lonafarnib monotherapy in patients with advanced malignancies demonstrated dose limiting toxicities (DLTs) of diarrhea, nausea, vomiting, anorexia, reversible renal insufficiency secondary to dehydration, neutropenia, thrombocytopenia, and fatigue on the 300 and 400 mg BID Pre-clinical and clinical data support combining lonafarnib with cisplatin and gemcitabine. Lonafarnib is additive to synergistic with chemotherapy due to its cytostatic, proapoptotic, and glycoprotein inhibitory properties [46]. Lonafarnib synergistically enhanced cisplatin chemosensitivity in melanoma, NSCLC, and glioblastoma cell lines [3,42].…”