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Research Area
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Description
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Cancer |
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Biological Activity
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Description
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ABT-751 (E7010) binds to the colchicine site on ?-tubulin and inhibits polymerization of microtubules. |
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Targets
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IC50 |
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In Vitro
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In vitro, ABT-751 shows the selective cytotoxicity with IC50 of 0.6–2.6 μM in neuroblastoma and 0.7–4.6 μM in other solid tumor cell lines. Furthermore, ABT-751 also exhibits a selective effect on dynamic microtubules and spares stable microtubules, accounting for the persistence of acetylated and detyrosinated α-tubulin positive polymerized tubules at the IC90 concentration of ABT-751. [1] |
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In Vivo
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In this Calu-6 xenograft model, ABT-751 as a single agent at 100 and 75 mg/kg/day shows significant antitumor activity, while in combination with cisplatin, ABT-751 shows a dose-dependent enhancement in growth delay. In the HT-29 colon xenograft model, ABT-751 also shows significant antitumor activity as a single agent and produced a dose-dependent enhancement in growth delay In combination with 5-FU. [2] In dogs with lymphoma, ABT-751 exhibits the dose-limiting toxicities that included vomiting, diarrhea, anorexia, or some combination of these with a maximum tolerated dose (MTD) of 350 mg/m2 PO q24h. Furthermore, the mean AUC and Cmax for ABT-751 at the MTD of 350 mg/m2 is 5.55 μg-hour/mL and 0.9 μg/mL, respectively. [3] |
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Clinical Trials
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ABT-751 is currently in Phase II clinical trials in patients with Colorectal Cancer. |
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Features
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ABT-751 is a orally bioavailable tubulin-binding and antimitotic sulfonamide. |
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Protocol
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Cell Assay
[1]
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| Cell Lines |
HOS, HTB-186 Daoy, TC-71, RD, SK-N-AS, SK-N-DZ, LD and KCNR cells |
| Concentrations |
0 to 100 μM |
| Incubation Time |
72 hours |
| Methods |
Cells, in 1640 RPMI media with FBS, are plated in triplicate onto 96 well tissue culture plates in numbers determined optimal for confluent monolayer growth (5,000 cells/well for HOS, HTB-186 Daoy; 10,000 cells/well for TC-71, RD, SK-N-AS, SK-N-DZ, LD; 30,000 cells/well for KCNR), with an automated, multichannel pipette system. Cells are incubated for 24 hours at 37 °C/5% CO2 then exposed to vehicle control (1.25% DMSO/H2O), VCR (0.1–1000 nM), ABT-751 (0.1 nM–100 μM), and in 4 cell lines (SK-N-AS, KCNR, RD, TC-71) combretastatin (0.1–1000 nM) for 72 hours. Cells are fixed with trichloroacetic acid (final concentration 10%) at 4 °C, washed, then dried at room temperature, stained with SRB in 1% acetic acid and dye is then solubilized with Tris base. Optical density measurements are performed at 540 and 405 nm dual wavelengths in a Bio-Tek EL 340 UV plate reader. |
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Animal Study
[2]
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| Animal Models |
Calu-6 NSCLC, HT-29 colon, and HCT-116 cells are injected into athymic mice. |
| Formulation |
ABT-751 is dissolved 4% ethanol/96% dextrose solution (D5W) with 1 eq. 1 N HCl. |
| Doses |
75 or 100 mg/kg/day |
| Administration |
Administered via p.o. |
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