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, Zheng (David) Qian, Susan L. Dalrymple, Jason B. Garrison, Natasha Kyprianou, Anders Björk, Anders Olsson, Tomas Leanderson

Research output: Contribution to journalArticle

70 Citations (Scopus)

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
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Growth
Multiple Sclerosis
Neoplasms
Clinical Trials
Vascular Tissue Neoplasms
Encephalomyelitis
Chorioallantoic Membrane
Rodentia
Pharmacokinetics
Dogs
tasquinimod
quinoline-3-carboxamide
roquinimex

Keywords

  • Anti-angiogenesis
  • Prostate cancer
  • Quinolines

ASJC Scopus subject areas

  • Urology

Cite this

Identification of ABR-215050 as lead second generation quinoline-3- carboxamide anti-angiogenic agent for the treatment of prostate cancer. / Isaacs, John T.; Pili, Roberto; Qian, Zheng (David); Dalrymple, Susan L.; Garrison, Jason B.; Kyprianou, Natasha; Björk, Anders; Olsson, Anders; Leanderson, Tomas.

In: Prostate, Vol. 66, No. 16, 01.12.2006, p. 1768-1778.

Research output: Contribution to journalArticle

Isaacs, JT, Pili, R, Qian, ZD, Dalrymple, SL, Garrison, JB, 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, vol. 66, no. 16, pp. 1768-1778. https://doi.org/10.1002/pros.20509
Isaacs, John T. ; Pili, Roberto ; Qian, Zheng (David) ; Dalrymple, Susan L. ; Garrison, Jason B. ; Kyprianou, Natasha ; Björk, Anders ; Olsson, Anders ; Leanderson, Tomas. / Identification of ABR-215050 as lead second generation quinoline-3- carboxamide anti-angiogenic agent for the treatment of prostate cancer. In: Prostate. 2006 ; Vol. 66, No. 16. pp. 1768-1778.
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AU - Pili, Roberto

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AU - Dalrymple, Susan L.

AU - Garrison, Jason B.

AU - Kyprianou, Natasha

AU - Björk, Anders

AU - Olsson, Anders

AU - Leanderson, Tomas

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N2 - 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.

AB - 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.

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