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

Research output: Contribution to journalArticle

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.

Details

Authors
  • J T Isaacs
  • R Pili
  • D Z Qian
  • S L Dalrymple
  • J B Garrison
  • N Kyprianou
  • A Bjork
  • A Olsson
  • Tomas Leanderson
External organisations
  • Active Biotech Research AB
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Obstetrics, Gynecology and Reproductive Medicine

Keywords

  • anti-angiogenesis, quinolines, prostate cancer
Original languageEnglish
Pages (from-to)1768-1778
JournalThe Prostate
Volume66
Issue number16
Publication statusPublished - 2006
Publication categoryResearch
Peer-reviewedYes
Externally publishedYes