title: Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer.
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 microM 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 PO(2) 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.
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. isaacjo@jhmi.edu
authors.forename: John T
authors.initials: JT
authors.lastname: Isaacs
authors.forename: Roberto
authors.initials: R
authors.lastname: Pili
authors.forename: David Z
authors.initials: DZ
authors.lastname: Qian
authors.forename: Susan L
authors.initials: SL
authors.lastname: Dalrymple
authors.forename: Jason B
authors.initials: JB
authors.lastname: Garrison
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
authors.forename: Anders
authors.initials: A
authors.lastname: Björk
authors.forename: Anders
authors.initials: A
authors.lastname: Olsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Leanderson
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D004285:Dogs; D006801:Humans; D006912:Hydroxyquinolines / Q000494:pharmacology; D008297:Male; D051379:Mice; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D011471:Prostatic Neoplasms / Q000098:blood supply* / Q000188:drug therapy* / Q000473:pathology; D011804:Quinolines / Q000494:pharmacology*; D015363:Quinolones; D051381:Rats; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D006912:Hydroxyquinolines; D011804:Quinolines; D015363:Quinolones; C045282:roquinimex; C516109:tasquinimod