Identification of ABR-215050 as lead second generation quinoline-3-carboxamide anti-angiogenic agent for the treatment of prostate cancer.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/1136820
- author
- Isaacs, J T ; Pili, R ; Qian, D Z ; Dalrymple, S L ; Garrison, J B ; Kyprianou, N ; Bjork, A ; Olsson, A and Leanderson, Tomas LU
- publishing date
- 2006
- 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 & 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
- 2022-04-20 19:35:54
@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}},
keywords = {{anti-angiogenesis; quinolines; prostate cancer}},
language = {{eng}},
number = {{16}},
pages = {{1768--1778}},
publisher = {{John Wiley & 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}},
}