ABT-751 (E7010)

ABT-751(E 7010) is a novel bioavailable tubulin-binding and antimitotic agent [1][2].
Microtubules are major structure of cells. They play an important role in cellular movement, intracellular transport, cell shape, cellular polarity, and the segregation of chromosomes during mitosis[1].
ABT-751 binds to the colchicine site on ß-tubulin and inhibits polymerization of microtubules, which block the G2/M phase of the cell cycle and promote apoptosis [1]. In endothelial cells, ABT-751 caused significant loss of microtubules and endothelial cell retraction within 1 h in a does-dependent and reversible way [2].
In a rat subcutaneous tumor model, ABT-751 (30 mg/kg, intravenously) reduced tumor perfusion in a rapid, transient way. And tumor perfusion decreased by 57% after 1 h [3]. In Calu-6 xenograft model, ABT-751 dosed at 100 and 75 mg/kg/day showed significant antitumor activity. In combination with cisplatin, ABT-751 enhanced the growth delay in a dose-dependent way [1].
References:
[1]. Jorgensen TJ, Tian H, Joseph IB, et al. Chemosensitization and radiosensitization of human lung and colon cancers by antimitotic agent, ABT-751, in athymic murine xenograft models of subcutaneous tumor growth. Cancer Chemother Pharmacol, 2007, 59(6): 725-732.
[2]. Luo Y, Hradil VP, Frost DJ, et al. ABT-751, a novel tubulin-binding agent, decreases tumor perfusion and disrupts tumor vasculature. Anticancer Drugs, 2009, 20(6): 483-492.

The pharmacokinetics and safety of ABT-751, a novel, orally bioavailable sulfonamide antimitotic agent: results of a phase 1 study.[Pubmed:16675578]

Clin Cancer Res. 2006 May 1;12(9):2834-40.

PURPOSE: Microtubules play a critical role in many cellular functions, including cell division and mitosis. ABT-751 is a novel sulfonamide antimitotic that binds to the colchicine site on beta-tubulin that leads to a block in the cell cycle at the G2M phase, resulting in cellular apoptosis. ABT-751 was investigated in this phase 1 trial designed to assess its maximum tolerated dose (MTD), dose-limiting toxicity (DLT), tolerability, and pharmacokinetics. EXPERIMENTAL DESIGN: ABT-751 was administered on a daily (q.d.) or twice daily (b.i.d.) oral schedule for 7 days every 3 weeks to 39 patients with refractory solid tumors. Toxicity was monitored weekly. Plasma and urine ABT-751 and metabolite pharmacokinetics were determined. RESULTS: The MTD for the q.d. schedule was 250 mg/d. DLTs during cycle 1 were abdominal pain, constipation, and fatigue. The MTD on the b.i.d. schedule was 150 mg. Cycle 1 of therapy with the 175 mg b.i.d. schedule was tolerated without DLT. However, six of seven patients reported grade 3 toxicity (ileus, constipation, abdominal pain, or fatigue), which occurred in cycle 2 or 3. ABT-751 was absorbed after oral administration with an overall mean T(max) of about 2 hours. The pharmacokinetics of ABT-751 were dose-proportional and time-independent. There was minimal accumulation of ABT-751 after multiple q.d. and b.i.d. doses. Efficacious concentrations, as determined from preclinical models (0.5-1.5 microg/mL), were achieved in all subjects. ABT-751 metabolism occurred primarily by glucuronidation and sulfation. No complete or partial tumor responses were noted, but one patient had a minor response, and four patients had stable disease lasting at least 6 months. CONCLUSIONS: The MTD and recommended phase 2 doses for ABT-751 were 250 mg q.d. and 150 mg b.i.d. on a 7-day schedule given every 3 weeks, due to subsequent cycle toxicities at 175 mg b.i.d. dosing. Toxicities were abdominal pain, constipation, and neuropathy.

ABT-751(E 7010) is a novel bioavailable tubulin-binding and antimitotic sulfonamide agent with IC50 of about 1.5 and 3.4 μM in neuroblastoma and non-neuroblastoma cell lines, respectively.

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