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Preclinical Antitumor Activity and Pharmacodynamic Studies with the Farnesyl Protein Transferase Inhibitor R115777 in Human Breast Cancer

Lloyd R. Kelland, Vicki Smith, Melanie Valenti, Lisa Patterson, Paul A. Clarke, Simone Detre, Dave End, Angela J. Howes, Mitch Dowsett, Paul Workman and Stephen R. D. Johnston
Lloyd R. Kelland
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Vicki Smith
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Melanie Valenti
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Lisa Patterson
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Paul A. Clarke
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Simone Detre
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Dave End
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Angela J. Howes
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Mitch Dowsett
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Paul Workman
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Stephen R. D. Johnston
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DOI:  Published November 2001
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    Fig. 1.

    In vitro effects of R115777 against MCF-7 human breast cancer cells. A, growth inhibition after 4 days of exposure and assessment of cell number by the SRB assay. Values are mean ± SD (bars); n = 3. B, induction of prelamin A as determined by Western blotting of MCF-7 cells exposed to different concentrations of R115777 for 24 h. Lane 1, 0.2 μm; Lane 2, 0.4 μm; Lane 3, 1.0 μm; Lane 4, 2.0 μm; Lane 5, 4.0 μm; Lane 6, 10 μm. C, induction kinetics for prelamin A following exposure of MCF-7 cells to 2 μm R115777. Lane 1, 1 h; Lane 2, 2 h; Lane 3, 4 h; Lane 4, 8 h; Lane 5, 16 h; Lane 6, 24 h; Lane 7, 48 h; Lane 8, 72 h.

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    Fig. 2.

    Tumor growth curves for MCF-7 cells treated with either drug vehicle (Control; □) or with varying doses of R115777 administered p.o. twice a day for 10 consecutive days (▴, 25 mg/kg; ▾, 50 mg/kg; ♦, 100 mg/kg). Values are mean ± SD (bars); n = 6.

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    Fig. 3.

    Increases in prelamin A as determined by Western blotting of MCF-7 xenografts taken at day 11, one day after the final dose of either vehicle (controls) or R115777 administered p.o. twice daily for 10 consecutive days at dose of 25, 50, and 100 mg/kg. Lanes 1–5 for each group refer to individual tumors/animals. Levels of actin are shown as loading controls.

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    Fig. 4.

    Immunohistochemical analyses of proliferation (based on Ki-67 staining; A), of apoptosis (based on TUNEL staining; B), and of p21 induction (C) in MCF-7 xenografts removed from vehicle-treated (control) or R115777-treated (100 mg/kg administered p.o. twice daily for 10 consecutive days) animals. D, apoptosis as determined by TUNEL staining in either MCF-7 xenografts removed from vehicle-treated (Control) or R115777-treated (25, 50, or 100 mg/kg administered p.o. twice daily for 10 consecutive days) animals. Values are mean ± SD (bars); n = 5 tumors.

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    Fig. 5.

    Increases in prelamin A in patient PBL samples before and after treatment with R115777 (samples collected after patients had received 300 mg twice daily every day for 4 weeks) in Patient 1 (who exhibited a partial response) and Patient 2 (who did not respond). In two patients (nonresponders), there was no detectable prelamin A in either sample.

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November 2001
Volume 7, Issue 11
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Preclinical Antitumor Activity and Pharmacodynamic Studies with the Farnesyl Protein Transferase Inhibitor R115777 in Human Breast Cancer
Lloyd R. Kelland, Vicki Smith, Melanie Valenti, Lisa Patterson, Paul A. Clarke, Simone Detre, Dave End, Angela J. Howes, Mitch Dowsett, Paul Workman and Stephen R. D. Johnston
Clin Cancer Res November 1 2001 (7) (11) 3544-3550;

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Preclinical Antitumor Activity and Pharmacodynamic Studies with the Farnesyl Protein Transferase Inhibitor R115777 in Human Breast Cancer
Lloyd R. Kelland, Vicki Smith, Melanie Valenti, Lisa Patterson, Paul A. Clarke, Simone Detre, Dave End, Angela J. Howes, Mitch Dowsett, Paul Workman and Stephen R. D. Johnston
Clin Cancer Res November 1 2001 (7) (11) 3544-3550;
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