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Departments of Cancer Research [R. B. L., D. L., C. A. B., J. P. D., K. H., K. S. K., S. M., N. E. K.] Drug Metabolism [E. D.,Y. L.] Laboratory Animal Resources [S. L. M.] Clinical Pharmacology [P. J. D., K. E. M., B. W. M., L. W., S-L. Y.] Merck Research Laboratories, West Point, Pennsylvania 19486 and Rahway, New Jersey 07065; University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030 [J. L. A.] Dana-Farber Cancer Institute, Boston, Massachusetts 02115 [C. S. F.] Institute for Drug Development, Cancer Therapy and Research Center, San Antonio, Texas 78245 [E. K. R.] University of Medicine and Dentistry New Jersey-Cancer Institute, New Brunswick, New Jersey 08901 [E. H. R.] Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [S. S.]
Farnesyl:protein transferase (FPTase) inhibitors were developed as anti-Ras drugs, but they fail to inhibit Ki-Ras activity because Ki-Ras can be modified by geranylgeranyl:protein transferase type-I (GGPTase-I). L-778,123, an inhibitor of FPTase and GGPTase-I, was developed in part because it can completely inhibit Ki-Ras prenylation. To support the clinical development of L-778,123, we developed pharmacodynamic assays using peripheral blood mononuclear cells (PBMCs) to measure the inhibition of prenylation of HDJ2 and Rap1A, proteins that are FPTase- and GGPTase-I substrates, respectively. We validated these assays in animal models and show that inhibition of HDJ2 prenylation in mouse PBMCs correlates with the concentration of FPTase inhibitors in blood. In dogs, continuous infusion of L-778,123 inhibited both HDJ2 and Rap1A prenylation in PBMCs, but we did not detect inhibition of Ki-Ras prenylation. We reported previously results from the first L-778,123 Phase I trial that showed a dose-dependent inhibition of HDJ2 farnesylation in PBMCs. In this report, we present additional analysis of patient samples from this trial and a second Phase I trial of L-778,123, and demonstrate the inhibition of both HDJ2 and Rap1A prenylation in PBMC samples. This study represents the first demonstration of GGPTase-I inhibition in humans. However, no inhibition of Ki-Ras prenylation by L-778,123 was detected in patient samples. These results confirm the pharmacologic profile of L-778,123 in humans as a dual inhibitor of FPTase and GGPTase-I, but indicate that the intended target of the drug, Ki-Ras, was not inhibited.
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