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Experimental Therapeutics, Preclinical Pharmacology

Potentiation of Temozolomide and Topotecan Growth Inhibition and Cytotoxicity by Novel Poly(adenosine Diphosphoribose) Polymerase Inhibitors in a Panel of Human Tumor Cell Lines

Carol A. Delaney, Lan-Z Wang, Suzanne Kyle, Alex W. White, A. Hilary Calvert, Nicola J. Curtin, Barbara W. Durkacz, Zdenek Hostomsky and David R. Newell
Carol A. Delaney
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Lan-Z Wang
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Suzanne Kyle
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Alex W. White
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A. Hilary Calvert
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Nicola J. Curtin
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Barbara W. Durkacz
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Zdenek Hostomsky
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David R. Newell
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DOI:  Published July 2000
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  • Fig. 1.
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    Fig. 1.

    Structures of NU1025 (Ki = 48 nm) (A) and NU1085 (Ki = 6 nm).

  • Fig. 2.
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    Fig. 2.

    Effects on growth of A549 cells of a 72-h exposure to increasing concentrations of TM ± fixed concentrations of NU1025 or NU1085 (A) and TP ± fixed concentrations of NU1025 or NU1085 (B). •, control; ▾, + NU1025 (50 μm); ▿, + NU1025 (200μ m); ▴, + NU1085 (10 μm).

  • Fig. 3.
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    Fig. 3.

    Effect of a 24-h exposure of cells to increasing concentrations of TP or TM, in the presence or absence of NU1025 (200 μm) or NU1085 (10 μm), on clonogenic survival. •, control; ▴, NU1025; □, NU1085.

  • Fig. 4.
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    Fig. 4.

    Comparison of the growth-inhibitory and cytotoxic effects of exposure to NU1025 or NU1085 in LoVo cells. A, effect on growth of a 72-h continuous exposure to NU1025 ▴ or NU1085 ▪; B, effect on survival of a 24-h exposure to NU1025 ▴ or NU1085 ▪.

  • Fig. 5.
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    Fig. 5.

    Effects on growth (A) and clonogenic survival (B) of LoVo cells treated with increasing concentrations of NU1025 alone (•) or in the presence of a fixed concentration (1 mm) of TM (▪).

Tables

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  • Table 1

    Effect of NU1085 and NU1025 on TM-induced growth inhibition in human tumor cell lines

    Cell lineIC50a (μm)
    TMTM + 10 μm NU1085TM + 50 μm NU1025TM + 200 μm NU1025
    A549 (lung)949394 (2.4)b453 (2.1)301 (3.2)
    1223466 (2.6)488 (2.5)373 (3.3)
    CORL23 (lung)855446 (1.9)439 (1.9)427 (2.0)
    984681 (1.4)977 (1.0)719 (1.4)
    H522 (lung)>15001059 (>1.4)837 (>1.8)826 (>1.7)
    1249705 (1.8)524 (2.4)645 (1.9)
    SKOV3 (ovary)>1500639 (>2.3)842 (>1.8)427 (>3.5)
    >1500867 (>1.7)810 (>1.9)339 (>4.4)
    A2780 (ovary)525188 (2.8)231 (2.3)196 (2.7)
    368183 (2.0)203 (1.8)188 (2.0)
    OAW-42 (ovary)568419 (1.4)485 (1.2)364 (1.6)
    714444 (1.6)649 (1.1)405 (1.8)
    HT29 (colon)>1500881 (>1.7)733 (>2.0)415 (>3.6)
    >1500719 (>2.1)623 (>2.4)429 (>3.5)
    LoVo (colon)>1500828 (>1.8)813 (>1.8)474 (>3.2)
    >1500821 (>1.8)572 (>2.6)277 (>5.4)
    >1500929 (>1.6)961 (>1.6)611 (>2.5)
    LS174T (colon)>1500432 (>3.5)749 (>2.0)421 (>3.6)
    1371225 (6.1)363 (3.8)223 (6.1)
    >1500766 (>2.0)1133 (>1.3)609 (>2.5)
    MCF-7 (breast)>1500485 (>3.1)461 (>3.3)429 (>3.5)
    >1500682 (>2.2)990 (>1.5)604 (>2.5)
    T47D (breast)>1500747 (>2.0)956 (>1.6)834 (>1.8)
    >15001547>15001150 (>1.3)
    MDA-231 (breast)>15001211 (>1.2)1401 (>1.1)786 (>1.9)
    14531152 (1.3)1378 (1.1)725 (2.0)
    • a IC50s were calculated from data from individual experiments, using five replicates for all samples.

    • b Numbers in parentheses, PF50s derived from the individual experiments. Where it was not possible to obtain IC50s for TM alone because of the limited solubility of this drug (i.e., IC50s were not achieved by the highest concentration (1500 μm) of TM used), PF50s were expressed as greater than the value calculated, assuming the IC50 for TM alone to be 1500μ m.

  • Table 2

    Effect of NU1085 and NU1025 on TP-induced growth inhibition in human tumor cell lines

    Cell lineIC50a (nm)
    TPTP + 10 μm NU1085TP + 50 μm NU1025TP + 200 μm NU1025
    A549 (lung)>7552 (>1.4)b68 (>1.1)40 (>1.9)
    7019 (3.7)32 (2.2)17 (4.1)
    8331 (2.7)62 (1.3)51 (1.6)
    CORL23 (lung)6164 (0.9)28 (2.2)41 (1.5)
    6164 (0.9)28 (2.2)25 (2.4)
    H522 (lung)>300122 (>2.4)81 (>3.7)58 (>5.2)
    25191 (2.8)30 (8.4)46 (5.5)
    SKOV3 (ovary)5029 (1.7)25 (2.0)24 (2.1)
    2319 (1.2)16 (1.4)12 (1.9)
    3826 (1.5)26 (1.5)24 (1.6)
    A2780 (ovary)237.8 (2.9)8.5 (2.7)8.5 (2.7)
    227.9 (2.8)8.7 (2.5)8.1 (2.7)
    OAW-42 (ovary)2521 (1.2)20 (1.3)12 (2.7)
    2719 (1.4)16 (1.7)16 (1.7)
    HT29 (colon)6623 (2.8)45 (1.5)38 (1.7)
    >7545 (>1.7)34 (>2.2)37 (>2.0)
    7228 (2.6)28 (2.6)34 (2.1)
    LoVo (colon)23550 (4.7)79 (3.0)52 (4.5)
    29192 (3.2)90 (3.2)71 (4.1)
    LS174T (colon)109 (1.2)8 (1.3)8 (1.3)
    1010 (0.9)8 (1.3)9 (1.2)
    MCF-7 (breast)>30095 (>3.2)168 (>1.8)98 (>3.1)
    >300155 (>1.9)233 (>1.3)149 (>2.0)
    T47D (breast)9229 (3.2)24 (3.8)34 (2.7)
    271229 (1.2)211 (1.3)210 (1.3)
    MDA-231 (breast)>300>300>300>300
    >300>300136 (>2.2)>300
    • a Data were from individual experiments, using five replicates for all samples.

    • b Numbers in parentheses, PF50 values derived from the individual experiments. Where IC50s were not attained by the highest concentration of TP used (300 nm), PF50s were expressed as greater than the value calculated, assuming the IC50 for TP alone to be 300 nm.

  • Table 3

    Comparison of the growth-inhibitory and cytotoxic effects of NU1025 and NU1085 as single agentsa

    Cell lineNU1025 IC50 (μm)NU1025 LC50 (μm)NU1085 IC50 (μm)NU1085 LC50 (μm)
    A549>1000>1000, >1000, >100083 ± 1874 ± 8
    LoVo330 ± 139901, >1000, >100094 ± 1170 ± 24
    OAW-42263 ± 119920 ± 6782 ± 880 ± 20
    • a Data are presented either as the mean of three or more independent experiments ± SD or as the results of individual experiments. IC50s were calculated as described in “Materials and Methods.” LC50s were determined directly from the survival curves, which were plotted point to point.

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July 2000
Volume 6, Issue 7
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Potentiation of Temozolomide and Topotecan Growth Inhibition and Cytotoxicity by Novel Poly(adenosine Diphosphoribose) Polymerase Inhibitors in a Panel of Human Tumor Cell Lines
Carol A. Delaney, Lan-Z Wang, Suzanne Kyle, Alex W. White, A. Hilary Calvert, Nicola J. Curtin, Barbara W. Durkacz, Zdenek Hostomsky and David R. Newell
Clin Cancer Res July 1 2000 (6) (7) 2860-2867;

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Potentiation of Temozolomide and Topotecan Growth Inhibition and Cytotoxicity by Novel Poly(adenosine Diphosphoribose) Polymerase Inhibitors in a Panel of Human Tumor Cell Lines
Carol A. Delaney, Lan-Z Wang, Suzanne Kyle, Alex W. White, A. Hilary Calvert, Nicola J. Curtin, Barbara W. Durkacz, Zdenek Hostomsky and David R. Newell
Clin Cancer Res July 1 2000 (6) (7) 2860-2867;
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