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Molecular Cancer Therapeutics
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Preclinical Development

TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells

Daniel P. Fitzgerald, David L. Emerson, Yongzhen Qian, Talha Anwar, David J. Liewehr, Seth M. Steinberg, Sandra Silberman, Diane Palmieri and Patricia S. Steeg
Daniel P. Fitzgerald
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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David L. Emerson
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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Yongzhen Qian
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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Talha Anwar
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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David J. Liewehr
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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Seth M. Steinberg
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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Sandra Silberman
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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Diane Palmieri
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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Patricia S. Steeg
Authors' Affiliations: 1Women's Cancers Section, Laboratory of Molecular Pharmacology, 2Biostatistics and Data Management Section, National Cancer Institute, Bethesda, Maryland; 3Bolder Biopath, Inc., Boulder, Colorado; 4Laboratory Animal Sciences Program, Science Applications International Corporation, National Cancer Institute, Frederick, Maryland; and 5Quintiles, Inc. Durham, North Carolina
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DOI: 10.1158/1535-7163.MCT-12-0061 Published September 2012
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    Figure 1.

    TPI-287 is a cytotoxic microtubule-stabilizing agent. A, chemical structures of TPI-287, paclitaxel, docetaxel, and ixabepilone. B, comparison of the cytotoxic activities of TPI-287 and other microtubule-stabilizing agents. Adherent 231-BR breast cancer cells were exposed to the indicated doses of TPI-287, paclitaxel, docetaxel, or ixabepilone and cultured for 72 hours. Relative numbers of viable cells were determined by an MTT assay, and values normalized to the number of viable cells at the experimental endpoint in the absence of drug.

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    Figure 2.

    Brain permeability of TPI-287 in rats (A) and mice (B). The mean levels of TPI-287 in the blood (open circles) and brain (black symbols) were quantified over a period of 96 hours following a single i.v. injection of 20 mg/kg. CSF levels at a single point in the rat are shown in the black square in A.

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    Figure 3.

    Effect of microtubule-stabilizing drugs on 231-BR primary tumor growth in the mammary fat pad. A, mice were inoculated with 231-BR breast cancer cells into the mammary fat pad. Arrows illustrate the every 4 days ×3 dose schedule for paclitaxel, TPI-287, or vehicle, starting on day 37 postinjection, beginning when the tumors reached a mean volume of 200 mm3. B, tumor volumes were measured by caliper measurement. Final tumor measurements were taken 3 days after the last dose (day 48). Ancova on log10(y) transformed data was used to compare slopes on days 41 to 48. The estimated tumor growth slope for the vehicle treatment was significantly higher than that for paclitaxel and TPI-287 (both P < 0.0001). Paclitaxel and TPI-287 tumor growth slopes were not significantly different (P = 0.26).

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    Figure 4.

    Effects of approved microtubule-stabilizing drugs in an experimental brain metastasis model of breast cancer. A, mice were inoculated by intracardiac injection of 231-BR breast cancer cells and were subsequently randomized to receive weekly treatments (administered i.v.) with the following: vehicle control (5% ethanol:5% cremophor:90% saline), nab paclitaxel (6 mg/kg), or paclitaxel (6 mg/kg). An additional group of mice received no treatment; the no treatment and vehicle control groups were combined. Following 28 days, serial sections of mouse brain were examined histologically and the number of large brain metastases (>300 μm) and micrometastases (smaller) determined. Graphs indicate the mean number of large brain metastases and micrometastases counted per brain section. n = 7 mice for no drug, n = 15 for vehicle, n = 17 for nab paclitaxel, and n = 14 for paclitaxel for combined data from 2 independent experiments. B, number of large brain metastases formed by 231-BR cells after 27 days in untreated mice (no drug, control) or following weekly treatments with ixabepilone (5 mg/kg ×2, 2.5 mg/kg ×2). n = 10 mice for control and n = 8 for ixabepilone. All data not significantly different from vehicle arms.

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    Figure 5.

    TPI-287, but not paclitaxel, prevented the formation of large 231-BR brain metastases. A, experimental schema in which mice were inoculated with 231-BR tumor cells in the left cardiac ventricle. Mice were randomized to receive an every 4 days ×3 schedule of 18 mg/kg paclitaxel or TPI-287, delivered either early (days 3, 7, and 11 postinoculation) or late (days 18, 22, and 26 postinoculation). B, number of large brain metastases (>300 μmol/L) in mice 28 days postinoculation of 231-BR cells following the treatments described in A. C, number of brain micrometastases (<300 μmol/L) in mice 28 days postinoculation of 231-BR cells. n = 17 for vehicle, n = 13 for TPI-287 early, n = 9 for TPI-287 late, n = 8 for paclitaxel early, and n = 7 for paclitaxel late for the results in B and C. D, immunoflourescence for Ki67 was used to determine proliferation rate in brain metastases on day 28, 48 hours after the final treatment with paclitaxel (late schedule) or TPI-287 (late schedule). Each dot represents the percentage of Ki67-positive 231-BR cells counted in a mouse brain, P = 0.0002 in a comparison of TPI-287 and vehicle-treated groups. E, mean (±SEM) animal weight differences from baseline (day 0) through the experiment described in A.

Tables

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  • Table 1.

    Microtubule polymerization kinetics with TPI-287 and taxanes, in vitro

    CompoundMean ± SEM ED50a, μmol/LED50 compound/ED50 paclitaxel
    TPI-2871.58 ± 0.460.53
    Paclitaxel2.97 ± 0.501.00
    Docetaxel3.18 ± 0.451.07
    • ↵aThe ED50 is the amount of drug required to reduce the time required to reach Vmax of tubulin polymerization in the standard reaction mixture as described in the kit instructions. Each value is the mean of 4 reaction wells ± the SEM.

Additional Files

  • Figures
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  • Supplementary Data

    Files in this Data Supplement:

    • Supplementary Figures 1 & 2 - PDF file, 785KB, High dose TPI-287 inhibited proliferation and increased acetylated tubulin in primary tumors while low dose TPI-287 had no effect on brain metastasis prevention.
    • Supplementary Tables 1 - 3 - PDF file, 74KB, Pharmacokinetics for TPI-287 in rodents.
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Molecular Cancer Therapeutics: 11 (9)
September 2012
Volume 11, Issue 9
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TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells
Daniel P. Fitzgerald, David L. Emerson, Yongzhen Qian, Talha Anwar, David J. Liewehr, Seth M. Steinberg, Sandra Silberman, Diane Palmieri and Patricia S. Steeg
Mol Cancer Ther September 1 2012 (11) (9) 1959-1967; DOI: 10.1158/1535-7163.MCT-12-0061

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TPI-287, a New Taxane Family Member, Reduces the Brain Metastatic Colonization of Breast Cancer Cells
Daniel P. Fitzgerald, David L. Emerson, Yongzhen Qian, Talha Anwar, David J. Liewehr, Seth M. Steinberg, Sandra Silberman, Diane Palmieri and Patricia S. Steeg
Mol Cancer Ther September 1 2012 (11) (9) 1959-1967; DOI: 10.1158/1535-7163.MCT-12-0061
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