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Blood, Vol. 113, Issue 20, 4841-4852, May 14, 2009
Active oral regimen for elderly adults with newly diagnosed acute myelogenous leukemia: a preclinical and phase 1 trial of the farnesyltransferase inhibitor tipifarnib (R115777, Zarnestra) combined with etoposide
Blood Karp et al.
113: 4841
Supplemental materials for: Karp et al
Files in this Data Supplement:
- Table S1. Toxicity scores for “B” cohorts (21-day tipifarnib) (PDF, 11.9 KB)
- Table S2. Logistic regression results, in terms of odds ratios (OR) for toxicity (PDF, 14.4 KB) -
The outcome is the binary variable indicating that a patient had at least a grade 3 toxicity.
- Table S3. Comparison of 158 patients treated with tipifarnib alone and 84 patients Treated with tipifarnib plus etoposide (PDF, 49.3 KB)
- Figure S1. Synergistic effects of etoposide and tipifarnib in Jurkat, DOHH2, and I2.1 cells (JPG, 77.3 KB)
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(A) after Jurkat cells were treated for 24 h with diluent, 1 µM etoposide, 1 µM tipifarnib, or the combination, binding of APC-conjugated annexin V was assessed by flow microfluorimetry. (B) Jurkat cells were treated with the indicated concentration of etoposide in the absence or presence of 1 µM tipifarnib. (C) combination index calculated from the data shown in panel B and additional data from the same experiment. (D) after Jurkat cells were treated for 24 h with diluent, 1 µM etoposide, 1 µM tipifarnib, or the combination in the absence or presence of the broad spectrum caspase inhibitor N-(2-quinolyl)valylaspartyl-(2,6-difluorophenoxy)methyl ketone (QVDOPhe, 5 µM), whole cell lysates were subjected to SDS-PAGE, transferred to nitrocellulose, and probed with antibodies to the indicated antigens. Arrowheads indicate caspase-generated cleavage fragments.76 Heat shock protein 90 (HSP90) served as a loading control. (E) DoHH2 cells were treated with the indicated concentration of etoposide in the absence or presence of 1 µM tipifarnib. (F) combination index calculated from the data shown in panel E and the tipifarnib dose-response curve from the same experiment. (G) After Jurkat or I2.1 cells were treated for 5 h with diluent, 50 ng/ml CH-11 agonistic anti-Fas antibody or 37.5 ng/ml TRAIL, annexin V binding was assayed as illustrated in panel A. Error bars, ± 1 standard deviation of 3–6 independent experiments. Inset in (G) Aliquots containing 50 µg of cellular protein from parental Jurkat cells (lane 1) or I2.1 cells (lane 2) were subjected to immunoblotting for FADD or, as a loading control, actin. (H) I2.1 cells were treated with the indicated concentration of etoposide in the absence or presence of 1 µM tipifarnib. (I) combination index calculated from the data shown in panel H and the tipifarnib dose-response curve from the same experiment.
- Figure S2. Lack of effects of tipifarnib on Bcl-2 family members, cyclin B1, or mitogen-activated protein kinase pathway signaling (JPG, 40.5 KB)
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(A) After HL-60 cells were treated with 0, 62.5, 125, 250, 500, or 1000 nM tipifarnib for 72 h, aliquots containing 50 µg of total cellular protein were subjected to SDS-polyacrylamide gel electrophoresis followed by immunoblotting with reagents that recognize the indicated Bcl-2 family member or XIAP. Actin served as a loading control. (B) after HL-60 cells were treated with 0, 62.5, 125, 250, 500, or 1000 nM tipifarnib for 24 h (lanes 1–6, respectively), aliquots containing 50 µg of total cellular protein were subjected to immunoblotting with the indicated anti-cyclin B1 or phospho-epitope–specific antisera. Probing of the same blots with antisera that do not distinguish between phosphorylated and unphosphorylated polypeptides served as a loading control.
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