ABT-751 (E7010)

2 years -80 in solvent

Administered via p.o.

HOS, HTB-186 Daoy, TC-71, RD, SK-N-AS, SK-N-DZ, LD and KCNR cells

0 to 100 uM

ABT-751 is dissolved 4% ethanol/96% dextrose solution (D5W) with 1 eq. 1 N HCl.

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 ug-hour/mL and 0.9 ug/mL, respectively. [3]

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 uM), 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.

ABT-751 (E7010) binds to the colchicine site on β-tubulin and inhibits polymerization of microtubules, not a substrate for the MDR transporter and is active against cell lines resistant to vincristine, doxorubicin, and cisplatin. Phase 1/2.

ABT-751 is a orally bioavailable tubulin-binding and antimitotic sulfonamide.