Farnesyltransferase inhibitors

The ras oncogene is positioned at the crossroads of cellular signaling pathways, and its role in the neo-plastic process is well appreciated.34 35 Mutations in codons 12, 13, or 62 of ras significantly affect its physiological role and result in a permanently activated state, causing dysregulated proliferation. CMML is the hematologic malignancy with the highest frequency of ras mutations; in the largest reported cohort of patients, the prevalence of the N-ras and K-ras mutations was 38%,4 and the presence of the mutation appeared to negatively influence patients' prognosis and response to therapy.36 These findings made CMML an attractive target for treatment that blocks ras activity by inhibiting the enzyme farnesyltransferase, which is essential for posttranslational ras modification and attainment of its functional state.34 35

Of several farnesyltransferase inhibitors being investigated, tipifarnib (R115777, Zarnestra) and lonafarnib (SH66366, Sarasar) were explored in studies that included a limited number of patients with CMML. In a phase I study, an oral preparation of tipifarnib was administered to 10 patients; two showed a PR and one exhibited an HI, although those responses were tran-sient.37 38 In a phase I/II study, tipifarnib was given to patients with MPD, including seven patients with aCML and two with CMML.39 At an initial oral dosage of 300 mg twice daily for 21 days every 4 weeks, clinical responses were noted in three of the seven patients with aCML and none of the patients with CMML.39 Finally, in the phase II study, lonafarnib, administered orally at 200-300 mg daily until disease progressed or unacceptable toxicity occurred, was investigated in 35 patients with CMML.40 Among the 25 patients evaluable for response, one achieved a CR and seven exhibited HI, mostly in a single lineage; one patient became independent of red blood cell transfusions.40

Orally administered farnesyltransferase inhibitors represent a new category of "targeting" agents; they are only in the early stages of clinical investigations in CMML. However, because the responses to treatment in the malignancies investigated so far, including CMML, do not appear to be influenced by the ras mutational status, and because the responses have correlated poorly with the degree of inhibition of farne-syltransferase,37 38 processes other than farnesylation may be targeted by these agents. Their role as single agents in the treatment of CMML remains uncertain.

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