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Molecular Cancer Therapeutics
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Article

MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo

Deepak Sampath, Carolyn M. Discafani, Frank Loganzo, Carl Beyer, Hao Liu, Xingzhi Tan, Sylvia Musto, Tami Annable, Patricia Gallagher, Carol Rios and Lee M. Greenberger
Deepak Sampath
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Carolyn M. Discafani
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Frank Loganzo
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Carl Beyer
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Hao Liu
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Xingzhi Tan
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Sylvia Musto
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Tami Annable
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Patricia Gallagher
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Carol Rios
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Lee M. Greenberger
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DOI:  Published September 2003
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  • Figure 1.
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    Figure 1.

    Chemical structures of PTX, DTX, and MAC-321. Modifications of the baccatin III core structure (denoted as A, B, C, and D) are indicated as R1, R2, and R3.

  • Figure 2.
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    Figure 2.

    In vitro tubulin polymerization assay. Tubulin polymerization assays were conducted at 24°C using 1.5 mg/ml of purified bovine brain MAP-free tubulin in the presence of vehicle control (▴) or the indicated concentrations of DTX (closed symbols) or MAC-321 (open symbols) as shown. Turbidity was measured by absorbance (340 nm) for up to 60 min.

  • Figure 3.
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    Figure 3.

    Immunofluorescence staining of α-tubulin in KB-3-1 cells treated with PTX and MAC-321. Cells were treated for 20 h with vehicle (A), 8 nm vinblastine (B), 1.25 nm MAC-321 (C), 12.5 nm MAC-321 (E), 4 nm PTX (D), or 40 nm PTX (F). After fixation, cells were incubated with an anti-α-tubulin antibody followed by a FITC-conjugated secondary antibody and stained with propidium iodide to visualize DNA. Images were overlaid electronically after cells were examined by fluorescent microscopy for tubulin and propidium iodide staining. Insets in panels A, B, C, and E were electronically enlarged to demonstrate tubulin morphology. Arrowheads in panels B, C, E, and F indicate altered microtubule morphology.

  • Figure 4.
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    Figure 4.

    Expression of MDR1 mRNA and protein in a panel of tumor cell lines. RNA (A) or membrane proteins (B) was prepared from non-selected breast, lung, colon, or ovarian cell lines or from parental (KB-3-1) cell lines selected for resistance to colchicine (KB-8-5) or vinblastine (KB-V1). A, levels of MDR1 mRNA were assessed by real-time RT-PCR. Columns, mean relative expression from two experiments of MDR1 mRNA normalized to β-actin mRNA as described in “Materials and Methods”; bars, SD. Expression is represented on a logarithmic scale with the lowest expressing cell line, NCI-H838, set at 1. B, P-glycoprotein was detected by immunoblotting methods using an anti-MDR1 antibody.

  • Figure 5.
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    Figure 5.

    Accumulation of MAC-321 and PTX in KB-3-1 cells. The intracellular accumulation of MAC-321 in KB-3-1, KB-8-5, and KB-V1 cells was performed as described in “Materials and Methods.” Cells were incubated with [14C]-MAC-321 (104 mCi/mmol) and [14C]-PTX (74 mCi/mmol) at a final concentration of 500 nm (0.051 and 0.039 μCi/ml, respectively) for 2 h at 37°C. Radioactivity in the cell lysates was determined by liquid scintillation counting and was normalized for protein content. Data are reported as mean pmol drug/mg of total protein from triplicate wells.

  • Figure 6.
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    Figure 6.

    Efficacy of MAC-321 in PTX-sensitive xenograft tumor models in vivo by i.v. and p.o. administration. Female nu/nu mice were given injections of 1.5 × 106 Lox melanoma cells, 5 × 106 KB-3-1 cells, or 8 × 106 A375SM melanoma cells. Animals bearing Lox melanoma tumors approximately 100 mg in size were treated i.v. with vehicle or 10–70 mg/kg MAC-321 (A) or 10–200 mg/kg p.o. (B) on day 1. Tumor growth in all cases was determined approximately every 7 days. C and D, animals bearing KB-3-1 or A375SM staged tumors were treated with vehicle, 70 mg/kg MAC-321 p.o., or 70 mg/kg MAC-321 i.v. on day 1. In KB-3-1 xenografts, PTX was given i.v. at 60 mg/kg on day 1 or 20 mg/kg on days 1, 5, 9, and 13 (C). In A375SM xenografts, PTX was dosed i.v. at 60 mg/kg on days 1, 5, and 9 only (D). Statistical significance was determined by Student's two-tailed t test for all doses and test agents compared with the vehicle control group. *, P ≤ 0.01

  • Figure 7.
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    Figure 7.

    Activity of MAC-321 (i.v. and p.o.) in PTX-resistant xenograft tumor models in vivo. Female nu/nu mice were given injections of 6 × 106 DLD-1 colon carcinoma cells, 5 × 106 KB-8-5 cells, or five fragments of MX-1W breast carcinoma. Animals bearing DLD-1 staged tumors were treated i.v. (A) or p.o. (B) with vehicle or at the doses of MAC-321 indicated on the day after reaching approximately 100 mg in size. In addition, DLD-1 xenografts were also treated i.v. with 25 mg/kg of DTX on days 1, 5, and 9. Animals bearing KB-8-5 (C) or MX-1W (D) staged tumors were treated with either vehicle, 70 mg/kg MAC-321 p.o., or 70 mg/kg MAC-321 i.v. on day 1. Sixty milligrams per kilogram PTX were administered i.v. on days 1, 5, and 9 (C and D). *, P ≤ 0.01 and #, P ≤ 0.02 as determined by Student's two-tailed t test.

  • Figure 8.
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    Figure 8.

    Multiple-dose scheduling of MAC-321 in PTX-resistant HCT-15 colon tumor xenografts. Female nu/nu mice were given injections of 7 × 106 HCT-15 colon carcinoma cells and animals bearing staged tumors were treated with vehicle or MAC-321 i.v. on day 1 or on days 1, 7, and 14 at the doses indicated. Tumor growth was measured weekly up to 21 days. *, P ≤ 0.02 as determined by Student's two-tailed t test.

Tables

  • Figures
  • Table 1.

    Cytotoxicity profile of MAC-321 in a panel of PTX-sensitive and -resistant tumor cell linesa

    Cell LineTumor OriginP-glycoprotein ExpressionbIC50 (nm)
    MAC-321PTXDTXVinblastine
    A549NSCLC01.2 ± 0.77.5 ± 1.81.9 ± 0.73.7 ± 0.9
    HCT-116colon03.1 ± 0.78.2 ± 1.45.4 ± 0.82.3 ± 1.5
    NCI-H838NSCLC03.3 ± 0.32.1 ± 0.96.3 ± 0.70.9 ± 0.6
    KB-3-1epidermoid01.3 ± 0.53.9 ± 1.31.1 ± 0.60.8 ± 0.4
    1A9 (A2780 subclone)ovarian01.7 ± 0.65.1 ± 0.91.9 ± 1.01.9 ± 0.2
    Average ± SD2.1 ± 1.005.4 ± 2.503.3 ± 2.401.9 ± 1.20
    MX-1Wbreast+2.6 ± 1.415.4 ± 2.95.78 ± 2.37n.d.
    NCI-H1299NSCLC++5.3 ± 1.837.7 ± 2.312.9 ± 0.986.33 ± 1.24
    DLD-1colon+++1.2 ± 0.932.5 ± 2.414.29 ± 1.1815.38 ± 0.62
    HCT-15colon++++3.3 ± 0.2438.6 ± 1.954.62 ± 0.1915.81 ± 1.97
    Average ± SD3.1 ± 1.70131.0 ± 205.3021.9 ± 22.109.4 ± 7.75
    COLO 205colonn.d.0.6 ± 0.17.0 ± 2.30.6 ± 0.21.3 ± 1.0
    LOXmelanoman.d.4.3 ± 2.417.4 ± 1.46.9 ± 0.62.8 ± 1.7
    Panc-1pancreaticn.d.1.2 ± 0.96.2 ± 1.71.9 ± 1.2n.d.
    AsPc-1pancreaticn.d.1.2 ± 0.32.4 ± 0.31.9 ± 0.7n.d.
    Capan-1pancreaticn.d.1.2 ± 1.02.6 ± 0.81.5 ± 0.9n.d.
    Average ± SD2.7 ± 1.507.1 ± 6.102.6 ± 2.500.8 ± 1.20
    • ↵a Cell toxicity was measured using the SRB protein stain as an assessment of protein content and survival after a 72-h incubation period with MAC-321, PTX, DTX, or vinblastine as described in “Materials and Methods.” IC50 ± SD values are representative of three independent experiments.

    • ↵b P-glycoprotein expression was determined by Western blotting and quantitative real-time RT-PCR using MDR-specific antibodies and probes, respectively, as described in “Materials and Methods.” Scoring code based on Western blotting: 0, not detected; + to ++++, low to high expression; n.d., not determined.

  • Table 2.

    Resensitization of MAC-321 in PTX-resistant cell lines with MDR inhibitorsa

    CompoundIC50 (nm)
    KB-3-1KB-8-5KB-V1
    PTX2.2 ± 0.341.9 ± 5.53100.0 ± 141.4
    PTX + CL-329,7532.2 ± 0.11.3 ± 0.76.0 ± 1.4
    MAC-3210.6 ± 0.040.8 ± 0.164.6 ± 2.1
    MAC-321 + CL-329,7530.5 ± 0.10.5 ± 0.10.8 ± 0.1
    • ↵a PTX-resistant KB-8-5 and KB-V1 cells and their KB-3-1 parental counterpart lines were grown in the presence of PTX or MAC-321 alone or in combination with 5 μm of the MDR reversal agent, CL-329,753 for 3 days. Growth was assessed by SRB staining as described in “Materials and Methods.” Data are reported as average IC50 ± SD for three experiments as described above.

  • Table 3.

    Cytotoxicity profile of MAC-321 versus standard chemotherapeutics in PTX- and Epo-resistant cell lines that contain mutations in the taxane-binding site of β-tubulina

    CompoundIC50 (nm)*
    Relative Resistanceb
    1A91A9 PTX101A9 PTX221A9 EpoA81A9 PTX101A9 PTX22EpoA8
    MAC -3211.6 ± 0.65.4 ± 2.78 ± 1.42.6 ± 1.63.45.01.6
    PTX5.1 ± 1.026.6 ± 16.389.2 ± 55.620.9 ± 10.85.217.54.1
    DTX1.8 ± 0.67.5 ± 0.37.9 ± 0.22.2 ± 1.24.24.41.2
    EpoA1.8 ± 0.516.0 ± 49.04.1 ± 3.331.8 ± 14.08.92.317.7
    Compound
    IC50 (nm)**
    Relative Resistanceb
    A549
    A549.EpoB40
    A549.EpoB40
    MAC-3211.1 ± 0.611.3 ± 1.210.7
    PTX7.5 ± 1.3156.9 ± 16.920.8
    DTX1.9 ± 0.731.8 ± 1.616.6
    EpoB1.0 ± 0.191.5 ± 3.995.3
    • ↵a Parental cells and their resistant cell counterpart were grown in the presence of the indicated agents for 3 days and growth assessed by SRB staining (*) or ATP-binding (**) as described in “Materials and Methods.” Data are reported as average IC50 ± SD.

    • ↵b Average relative resistance is defined as the ratio of the IC50 of the resistant cell model to that of the respective sensitive/parental cell counterpart.

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Molecular Cancer Therapeutics: 2 (9)
September 2003
Volume 2, Issue 9
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MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo
Deepak Sampath, Carolyn M. Discafani, Frank Loganzo, Carl Beyer, Hao Liu, Xingzhi Tan, Sylvia Musto, Tami Annable, Patricia Gallagher, Carol Rios and Lee M. Greenberger
Mol Cancer Ther September 1 2003 (2) (9) 873-884;

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MAC-321, a novel taxane with greater efficacy than paclitaxel and docetaxel in vitro and in vivo
Deepak Sampath, Carolyn M. Discafani, Frank Loganzo, Carl Beyer, Hao Liu, Xingzhi Tan, Sylvia Musto, Tami Annable, Patricia Gallagher, Carol Rios and Lee M. Greenberger
Mol Cancer Ther September 1 2003 (2) (9) 873-884;
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