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Blood, 1 December 2003, Vol. 102, No. 12, pp. 3880-3889.
Prepublished online as a Blood First Edition Paper on August 14, 2003; DOI 10.1182/blood-2003-02-0633.
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REVIEW IN TRANSLATIONAL HEMATOLOGY
Farnesyltransferase inhibitors in hematologic malignancies: new horizons in therapy
Jeffrey E. Lancet, and
Judith E. Karp
From the James P. Wilmot Cancer Center, University of Rochester, Rochester, NY; and The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD.
Farnesyltransferase inhibitors (FTIs) are small-molecule inhibitors that selectively inhibit farnesylation of a number of intracellular substrate proteins such as Ras. Preclinical work has revealed their ability to effectively inhibit tumor growth across a wide range of malignant phenotypes. Many hematologic malignancies appear to be reasonable disease targets, in that they express relevant biologic targets, such as Ras, mitogen-activated protein kinase (MAPK), AKT, and others that may depend on farnesyl protein transferase (FTase) activity to promote proliferation and survival. A host of phase 1 trials have been recently launched to assess the applicability of FTIs in hematologic malignancies, many of which demonstrate effective enzyme target inhibition, low toxicity, and some clinical responses. As a result, phase 2 trials have been initiated in a variety of hematologic malignancies and disease settings to further validate clinical activity and to identify downstream signal transduction targets that may be modified by these agents. It is anticipated that these studies will serve to define the optimal roles of FTIs in patients with hematologic malignancies and provide insight into effective methods by which to combine FTIs with other agents.
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