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Antiangiogenic and antitumor activity of LP-261, a novel oral tubulin binding agent, alone and in combination with bevacizumab

  1. Author:
    Gardner, E. R.
    Kelly, M.
    Springman, E.
    Lee, K. J.
    Li, H. Q.
    Moore, W.
    Figg, W. D.
  2. Author Address

    [Li, Haiqing; Figg, William D.] NCI, Med Oncol Branch, Mol Pharmacol Sect, Bethesda, MD 20892 USA. [Gardner, Erin R.] NCI, Clin Pharmacol Program, SAIC Frederick, Frederick, MD 21702 USA. [Kelly, Martha; Springman, Eric; Lee, Kyoung-jin; Moore, William] Ansaris, Blue Bell, PA 19422 USA.;Figg, WD (reprint author), NCI, Med Oncol Branch, Mol Pharmacol Sect, 9000 Rockville Pike,Bldg 10,Room 5A01, Bethesda, MD 20892 USA;wdfigg@helix.nih.gov
    1. Year: 2012
    2. Date: Feb
  1. Journal: Investigational New Drugs
    1. 30
    2. 1
    3. Pages: 90-97
  2. Type of Article: Article
  3. ISSN: 0167-6997
  1. Abstract:

    LP-261 is a novel tubulin targeting anticancer agent that binds at the colchicine site on tubulin, inducing G2/M arrest. Screening in the NCI60 cancer cell lines resulted in a mean GI50 of approximately 100 nM. Here, we report the results of testing in multiple mouse xenograft models and angiogenesis assays, along with bioavailability studies. To determine the antiangiogenic activity of LP-261, both in vitro and ex vivo experiments were performed. Human Umbilical Vein Endothelial cells (HUVECs) were incubated with LP-261 at 50 nM to 10 mu M. LP-261 was also tested in a rat aortic ring assay, from 20 nM to 10 mu M. Multiple mouse xenograft studies were performed to assess in vivo antitumor activity. LP-261 was tested as a single agent in colon adenocarcinoma (SW620) and prostate cancer (LNCaP and PC3) xenografts, evaluating several different dosing schedules. LP-261 was also used in combination with bevacizumab in the SW620 xenograft model. LP-261 also exhibited high oral bioavailability and apparent lack of efflux by intestinal transporters such as ABCB1. LP-261 is a very potent inhibitor of angiogenesis, preventing microvessel outgrowth in the rat aortic ring assay and HUVEC cell proliferation at nanomolar concentrations. Complete inhibition of tumor growth was achieved in the PC3 xenograft model and shown to be schedule dependent. Excellent inhibition of tumor growth in the SW620 model was observed, comparable with paclitaxel. Combining oral, low dose LP-261 with bevacizumab led to significantly improved tumor inhibition. Oral LP-261 is very effective at inhibiting tumor growth in multiple mouse xenograft models and is well tolerated.

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External Sources

  1. DOI: 10.1007/s10637-010-9520-5
  2. WOS: 000299121500009

Library Notes

  1. Fiscal Year: FY2011-2012
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