Article Figures & Data
Figures
- Figure 1.
Structures of dipyridamole and novel pyrimidopyrimidine nucleoside transport inhibitors.
- Figure 2.
Inhibition of thymidine transport and reversal of pemetrexed-induced growth inhibition. A, inhibition of thymidine transport by nucleoside transport inhibitors (1 μmol/L) into L1210 cells in the presence (white columns) and absence (black columns) of AGP (5 mg/mL). Columns, mean of three independent experiments; bars, SD. B, growth of COR-L23 cells exposed to 200 nmol/L pemetrexed (PTX) alone (black column) or in combination with 1 μmol/L thymidine (TdR) + 10 μmol/L hypoxanthine (HPX; white column) or in combination with thymidine + hypoxanthine and the inhibitors (hatched columns) relative to untreated cells for three cell doubling times. Columns, mean of three independent experiments; bars, SD.
- Figure 3.
Pharmacokinetics and pharmacodynamics of the nucleoside transport inhibitors. A, plasma drug levels in BALB/c mice following i.p. administration of 10 mg/kg NU3150 (○), NU3151 (▵), and NU3153 (•). Points, mean of three animals per time point for each drug; bars, SD. B, concentrations of NU3153 in the plasma (white columns) and COR-L23 tumor (black columns) and the incorporation of thymidine into COR-L23 tumor xenografts (dotted columns) at 4, 8, 16, and 24 h after administration of 10 mg/kg NU3153 at 8 hourly intervals. Arrows, administration of drug. Columns, mean of data from three animals per time point for each drug; bars, SD. C, in vitro breakdown of NU3166 to NU3153 in fresh mouse plasma. Data are from a single representative experiment showing degradation of NU3166 (triangles, solid line) and formation of NU3153 (circles, dashed line) over time.
- Figure 4.
Pharmacokinetics, pharmacodynamics, and efficacy of NU3166. A, plasma drug levels of NU3153 (circles) and NU3166 (triangles) in BALB/c mice following i.p. (solid symbols, lines) and i.v. (open symbols, dashed lines) administration of 12 mg/kg NU3166. Points, mean from three animals per time point for each drug; bars, SD. B, plasma drug levels of NU3153 (circles, dashed line) and NU3166 (triangles, solid line) in BALB/c mice following i.p. administration of 120 mg/kg NU3166. Points, mean from three animals per time point; bars, SD. C, concentrations of NU3153 in the plasma (white columns) and tumor (black columns) and the incorporation of thymidine into tumor xenografts (dotted columns) at intervals following either a single dose (1×) or two doses at 24-h intervals (2×) of 120 mg/kg NU3166 administered i.p. Columns, mean from three animals per time point; bars, SD. D, effects of NU3153 on pemetrexed efficacy in vivo. Growth of COR-L23 tumor xenografts, following daily treatment with vehicle control alone (•), NU3166 alone given weekly on 2 d (120 mg/kg, days 0 and 1, 6 and 7, and 13 and 14; ○), pemetrexed alone given weekly (1,000 mg/kg, days 0, 6, and 13; ▴), or NU3166 weekly on 2 d (120 mg/kg) and pemetrexed weekly (1,000 mg/kg; ▵). For all experiments, tumor size is presented as the median tumor volume of surviving mice, measured relative to tumor volumes on day 0 (based on five animals per group). Inset, time to RTV 5 for individual mice. Horizontal bar, mean.
Tables
- Table 1.
Inhibition of thymidine transport and incorporation in L1210 and COR-L23 cells
Inhibition of Thymidine transport (L1210) Thymidine incorporation (L1210) Thymidine incorporation (COR-L23) Dipyridamole, 1 μmol/L 80 ± 8% 96 ± 4% 96 ± 1% Dipyridamole IC50 126 ± 54 nmol/L 15 ± 4 nmol/L NU3108, 1 μmol/L 83 ± 8% 88% 90 ± 1% NU3108 IC50 93 nmol/L 26 ± 5 nmol/L NU3144, 1 μmol/L 98 ± 6% 97% 94% NU3144 IC50 <10 nmol/L 59 nmol/L NU3150, 1 μmol/L 93 ± 8% 100% 96% NU3150 IC50 36.4 nmol/L 60 nmol/L NU3151, 1 μmol/L 73 ± 6% 100% 93% NU3151 IC50 41.4 nmol/L 67 nmol/L NU3153, 1 μmol/L 96 ± 12% 93 ± 4% 96 ± 2% NU3153 IC50 <10, 43, 8 nmol/L 8 ± 1 nmol/L NOTE: Data are the mean ± SD of three or more independent experiments or individual experiments. The IC50 is the concentration required to inhibit thymidine incorporation by 50% of control.
- Table 2.
Plasma pharmacokinetic parameters for NU3166 and NU3153 following either a single dose of NU3153 at 10 mg/kg i.p., NU3166 at 12 mg/kg i.p. or i.v., or 120 mg/kg i.p.
Drug and dose NU3153, 10 mg/kg i.p. NU3166, 12 mg/kg (≡10 mg/kg NU3153) i.p. NU3166, 12 mg/kg (≡10 mg/kg NU3153) i.v. NU3166, 120 mg/kg (≡100 mg/kg NU3153) i.p. Compound detected NU3153 NU3166 NU3153 NU3166 NU3153 NU3166 NU3153 AUC (μg/mL.min) 334 82 378 95 728 587 6,933 Clearance (mL/min/kg) 4.8 122 27 106 14 170 14 Half-life (min) 1259 97 120 95 84 307 634 Cmax (μmol/L) 1.5 0.9 1.6 4.6 6.2 3.0 7.9 Tmax (min) 120 15 90 5 10 5 240 Time above 1 μmol/L (min) >345<1,440 n/a 210 15 >240<360 120 >1,440 Vdss (L/kg) 0.15 11 3.5 6.2 1.4 46 5.5
Supplementary Materials, Thomas et al
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Volume 8, Issue 7
