Identification of ABR-215050 as lead second generation quinoline-3- carboxamide anti-angiogenic agent for the treatment of prostate cancer

John T. Isaacs, Roberto Pili, David Z. Qian, Susan L. Dalrymple, Jason B. Garrison, Natasha Kyprianou, Anders Björk, Anders Olsson, Tomas Leanderson

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    73 Scopus citations

    Abstract

    BACKGROUND. Linomide, Figure 1, produces robust and consistent in vivo growth inhibition of prostate cancer models via its anti-angiogenic activity and inhibition of autoimmune encephalomyelitis models of multiple sclerosis (MS). MS clinical trials were discontinued because of unacceptable toxicity, due to dose-dependent induction of proinflammation. METHODS. Therefore, linomide analogs were initially screened to determine their in vivo potency to inhibit growth of the Dunning R-3327 AT-1 rat prostate cancer model in rats and their potency to inhibit angiogenesis in a Matrigel assay in mice. RESULTS. Based upon its superior potency (i.e., 30- to 60-fold more potent than linomide) in these assays and its lack of a proinflammation in the Beagle-dog, ABR-215050 (tasquinimod), Figure 1, was characterized for dose-response ability to inhibit the growth of a series of four additional human and rodent prostate cancer models in mice. Pharmacokinetic analysis following oral dosing documented that blood and tumor tissue levels of ABR-215050 as low as 0.5-1 μM are therapeutically effective. This efficacy is correlated with inhibition of angiogenesis in a variety of assays (endothelial capillary tube formation, aortic ring assay, chorioallantoic membrane assay, real-time tumor blood flow and PO2 measurements, tumor blood vessel density, and tumor hypoxic and apoptotic fractions). CONCLUSIONS. Based upon its robust and consistent anti-angiogenic activity and thus tumor growth, ABR-215050 has entered clinical trials for the treatment of prostate cancer.

    Original languageEnglish (US)
    Pages (from-to)1768-1778
    Number of pages11
    JournalProstate
    Volume66
    Issue number16
    DOIs
    StatePublished - Dec 1 2006

    Keywords

    • Anti-angiogenesis
    • Prostate cancer
    • Quinolines

    ASJC Scopus subject areas

    • Oncology
    • Urology

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    Isaacs, J. T., Pili, R., Qian, D. Z., Dalrymple, S. L., Garrison, J. B., Kyprianou, N., Björk, A., Olsson, A., & Leanderson, T. (2006). Identification of ABR-215050 as lead second generation quinoline-3- carboxamide anti-angiogenic agent for the treatment of prostate cancer. Prostate, 66(16), 1768-1778. https://doi.org/10.1002/pros.20509