| Abstract: |
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. © 2002 American Association for Cancer Research. |
| Keywords: |
dose response; antineoplastic agents; antineoplastic agent; mouse; animal; metabolism; animals; mice; drug effect; dose-response relationship, drug; enzyme inhibitor; time; time factors; drug antagonism; mononuclear cell; leukocytes, mononuclear; enzyme inhibitors; dog; dogs; immunoblotting; protein p21; proto-oncogene proteins p21(ras); leukocyte; models, chemical; imidazoles; rap1 protein; imidazole derivative; leukocytes; chemical model; transferase; humans; human; article; alkyl and aryl transferases; hras protein, human; geranylgeranyltransferase type i; geranylgeranyltransferase type-i; l 778,123; p21(ras) farnesyl protein transferase; p21(ras) farnesyl-protein transferase; rap1 gtp-binding proteins
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