Figure 2
Figure 2. Results of treatment with tipifarnib. (A) Western blot for HDJ-2 and Rap1 protein prenylation, which are substrates for FTase and geranylgeranyltransferase enzymes, respectively. P = processed (farnesylated) HDJ-2 and (geranylgeranylated) Rap1. U = unprocessed (nonfarnesylated HDJ-2 and nongeranylgeranylated Rap1). Pretreatment (pre-tx; lane 1) and posttreatment (post-tx; lane 2) PBMCs were collected from the patient treated in vivo with tipifarnib for 4 months. U266 multiple myeloma cells cultured in vitro with DMSO (C, lane 3) served as control for processed HDJ-2 and Rap1 proteins. Treatment of U266 cells with the selective GGTase I inhibitor, GGTI-2431 50 μM (G lane 4) and FTI-2153 20 μM (F lane 5) served as controls for migration of the unprocessed proteins. (B) CBC results obtained during the active treatment phase of a clinical trial. Hemaglobin, white blood cell count (WBC), absolute lymphocyte count (ALC), and absolute neutrophil count (ANC) are shown. (C) Results of bone marrow biopsies performed at baseline (pretreatment) and after 4 courses of tipifarnib (posttreatment). Insert shows higher magnification of a cluster of large early erythroid precursors with nucleoli apparent after treatment. (D) Bone marrow aspirates were obtained at the time of biopsy and analyzed for colony formation in vitro and the number of CFU-GM and BFU-E are shown. Bars represent the mean number of colonies in 3 separate plates and the error in these measures is shown. (E) Diagram of the NKR signaling cascade. Activating NKR such as NKG2D, KIR2DS, KIR3DS, NKG2C, NKp44, NKp46, FcRγIII (CD16), TCR, and NKp30 act through 3 adaptor proteins either in a homodimeric or heterodimeric form (DAP12, DAP10, and CD3ζ). These signals lead to Ras and PI3K activation, granule redistribution and cytolysis or resistance to Fas-mediated apoptosis, survival, and expansion. Blockage of this pathway with the farnesyl-transferase inhibitor (FTI) tipifarnib or inhibitors of the adaptor molecules prevents the downstream activation of these effector functions.

Results of treatment with tipifarnib. (A) Western blot for HDJ-2 and Rap1 protein prenylation, which are substrates for FTase and geranylgeranyltransferase enzymes, respectively. P = processed (farnesylated) HDJ-2 and (geranylgeranylated) Rap1. U = unprocessed (nonfarnesylated HDJ-2 and nongeranylgeranylated Rap1). Pretreatment (pre-tx; lane 1) and posttreatment (post-tx; lane 2) PBMCs were collected from the patient treated in vivo with tipifarnib for 4 months. U266 multiple myeloma cells cultured in vitro with DMSO (C, lane 3) served as control for processed HDJ-2 and Rap1 proteins. Treatment of U266 cells with the selective GGTase I inhibitor, GGTI-2431 50 μM (G lane 4) and FTI-2153 20 μM (F lane 5) served as controls for migration of the unprocessed proteins. (B) CBC results obtained during the active treatment phase of a clinical trial. Hemaglobin, white blood cell count (WBC), absolute lymphocyte count (ALC), and absolute neutrophil count (ANC) are shown. (C) Results of bone marrow biopsies performed at baseline (pretreatment) and after 4 courses of tipifarnib (posttreatment). Insert shows higher magnification of a cluster of large early erythroid precursors with nucleoli apparent after treatment. (D) Bone marrow aspirates were obtained at the time of biopsy and analyzed for colony formation in vitro and the number of CFU-GM and BFU-E are shown. Bars represent the mean number of colonies in 3 separate plates and the error in these measures is shown. (E) Diagram of the NKR signaling cascade. Activating NKR such as NKG2D, KIR2DS, KIR3DS, NKG2C, NKp44, NKp46, FcRγIII (CD16), TCR, and NKp30 act through 3 adaptor proteins either in a homodimeric or heterodimeric form (DAP12, DAP10, and CD3ζ). These signals lead to Ras and PI3K activation, granule redistribution and cytolysis or resistance to Fas-mediated apoptosis, survival, and expansion. Blockage of this pathway with the farnesyl-transferase inhibitor (FTI) tipifarnib or inhibitors of the adaptor molecules prevents the downstream activation of these effector functions.

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