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

Isaacs, J T ; Pili, R ; Qian, D Z ; Dalrymple, S L ; Garrison, J B ; Kyprianou, N ; Bjork, A ; Olsson, A and Leanderson, Tomas LU (2006) In The Prostate 66(16). p.1768-1778
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... (More)
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. (Less)
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author
; ; ; ; ; ; ; and
publishing date
type
Contribution to journal
publication status
published
subject
keywords
anti-angiogenesis, quinolines, prostate cancer
in
The Prostate
volume
66
issue
16
pages
1768 - 1778
publisher
John Wiley and Sons Inc.
external identifiers
  • scopus:33845394305
  • pmid:16955399
ISSN
0270-4137
DOI
10.1002/pros.20509
language
English
LU publication?
no
id
4447ff61-12a6-4643-9538-f43eb432eee1 (old id 1136820)
date added to LUP
2016-04-01 11:38:18
date last changed
2020-09-23 02:38:35
@article{4447ff61-12a6-4643-9538-f43eb432eee1,
  abstract     = {BACKGROUND<br/><br>
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.<br/><br>
<br/><br>
METHODS<br/><br>
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.<br/><br>
<br/><br>
RESULTS<br/><br>
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).<br/><br>
<br/><br>
CONCLUSIONS<br/><br>
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.},
  author       = {Isaacs, J T and Pili, R and Qian, D Z and Dalrymple, S L and Garrison, J B and Kyprianou, N and Bjork, A and Olsson, A and Leanderson, Tomas},
  issn         = {0270-4137},
  language     = {eng},
  number       = {16},
  pages        = {1768--1778},
  publisher    = {John Wiley and Sons Inc.},
  series       = {The Prostate},
  title        = {Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer.},
  url          = {http://dx.doi.org/10.1002/pros.20509},
  doi          = {10.1002/pros.20509},
  volume       = {66},
  year         = {2006},
}