Farnesyl Transferase Inhibitors Ftis

The family of Ras proteins are components of multiple cellular pathways essential for cell proliferation, growth, and survival. Addition of the carbon farnesyl group to these cytoplasmic proteins allows them to be transported to the cell membrane, where they are integral to signal transduction pathways. The enzyme farnesyl transferase mediates the farnesylation process. Ras mutations are found in <20% of MDS patients, but are more common in chronic myelomonocytic leukemia (CMMoL). Ras, however, may be activated by other proteins that similarly require farnesylation, and therefore its expression may be controlled by multiple mechanisms. Small molecules that can selectively and competitively inhibit far-nesyl transferase (FTIs) have been developed for clinical use, and two, tipifarnib (R115777) and lonafarnib (SCH66336), have been studied in high-risk MDS.

A phase I trial of R115777 in 21 MDS patients of all subtypes, reported by Kurzrock et al.,15 established the maximum tolerated dose of 600 mg b.i.d. Of note, only two of the six responders had Ras mutations, and no correlation between Ras mutation status and response was detected in this initial study. In a phase II trial by the same group,16 28 MDS patients were given R115777 600 mg twice a day, 4 weeks on, 2 weeks off, to increase exposure to the drug. There were two complete responses, both of which did not possess a Ras mutation. Eleven of 27 patients discontinued treatment due to toxicity, with more than 60% of patients experiencing myelosuppres-sion, fatigue, and nausea. The phase II study therefore concluded that lower doses should be used in future trials. A separate phase II study done in patients with poor-risk AML or MDS using 600 mg b.i.d. every 4-6 weeks yielded responses in 12 of 30 patients (2 CRs and 8 PRs), with stabilization of disease in 12 patients.17

List et al. conducted a phase I study of continuous dosing of lonafarnib (SCH66336) in advanced CML, MDS, CMMoL, or AML.18 Twenty-nine percent of patients showed clinical improvement, and dose-limiting toxicity was diarrhea and hypokalemia at 300 mg b.i.d. In a phase II trial by Feldman et al.,19 67 MDS patients with RAEB/RAEB-T or CMMoL were given lon-afarnib 200 mg b.i.d. and a 29% response was seen. There were two complete responses, and 10 patients showed hematologic improvement. In this study, 26% of patients discontinued therapy due to grade III and IV toxicities. Current phase III trials are being conducted with lower doses of single-agent FTIs for longer periods of time, which may be useful for previously untreated patients and those with minimal residual disease. There is limited data to suggest a synergistic effect with chemotherapy,20 but identifying specific molecular targets within the cell cycle may lead to useful combinations of FTIs and chemotherapeutic agents, each affecting a different stage of the cycle.

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