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

DOI: Published July 2000

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Fig. 1.
Structures of NU1025 (K_i = 48 nm) (A) and NU1085 (K_i = 6 nm).
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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).
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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.
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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 ▪.
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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 (▪).

Table 1

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

^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

^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 agents^{^a}

Cell line	NU1025 IC₅₀ (μm)	NU1025 LC₅₀ (μm)	NU1085 IC₅₀ (μm)	NU1085 LC₅₀ (μm)
A549	>1000	>1000, >1000, >1000	83 ± 18	74 ± 8
LoVo	330 ± 139	901, >1000, >1000	94 ± 11	70 ± 24
OAW-42	263 ± 119	920 ± 67	82 ± 8	80 ± 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.