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Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment.

Isaacs, John T; Dalrymple, Susan L; Rosen, D Marc; Hammers, Hans; Olsson, Anders and Leanderson, Tomas LU (2014) In Oncotarget 5(18). p.8093-8106
Abstract
Tasquinimod, an orally active quinoline-3-carboxamide, binds with high affinity to HDAC4 and S100A9 in cancer and infiltrating host cells within compromised tumor microenvironment inhibiting adaptive survival pathways needed for an angiogenic response. Clinical trials document that as low as 0.5-1mg tasquinimod/day is therapeutic against castrate resistant metastatic prostate cancer. Tasquinimod is metabolized via cytochrome P4503A4, but ketoconazole at a dose which completely inhibits CYP3A metabolism does not affect tasquinimod's ability to inhibit endothelial "sprouting" in vitro or anti-cancer efficacy against human prostate cancer xenografts in vivo. Tasquinimod's potency is facilitated by its reversible binding (Kd < 35 μM) to the... (More)
Tasquinimod, an orally active quinoline-3-carboxamide, binds with high affinity to HDAC4 and S100A9 in cancer and infiltrating host cells within compromised tumor microenvironment inhibiting adaptive survival pathways needed for an angiogenic response. Clinical trials document that as low as 0.5-1mg tasquinimod/day is therapeutic against castrate resistant metastatic prostate cancer. Tasquinimod is metabolized via cytochrome P4503A4, but ketoconazole at a dose which completely inhibits CYP3A metabolism does not affect tasquinimod's ability to inhibit endothelial "sprouting" in vitro or anti-cancer efficacy against human prostate cancer xenografts in vivo. Tasquinimod's potency is facilitated by its reversible binding (Kd < 35 μM) to the IIA subdomain of albumin (Sudlow's site I). As blood vessels within the compromised cancer microenvironment are characterized by a higher degree of leakiness than those in normal tissues, this results in an enhanced uptake of tasquinimod bound to albumin in cancer tissue via a tumor specific process known as the "enhanced permeability and retention" (i.e., EPR) effect. Thus, despite plasma levels of < 1 µM, the EPR effect results in intracellular drug concentrations of 2-3 µM, levels several-fold higher than needed for inhibition of endothelial sprouting (IC50 ~ 0.5 µM) or for inhibition of HDAC4 and S100A9 mediated tumor growth. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Oncotarget
volume
5
issue
18
pages
8093 - 8106
publisher
Impact Journals, LLC
external identifiers
  • pmid:25193858
  • wos:000348030900011
  • scopus:84907997102
ISSN
1949-2553
language
English
LU publication?
yes
id
d0c647a4-98c2-498a-b040-28454788c1f6 (old id 4692178)
alternative location
http://www.ncbi.nlm.nih.gov/pubmed/25193858?dopt=Abstract
http://www.impactjournals.com/oncotarget/index.php?journal=oncotarget&page=article&op=view&path[]=2378
date added to LUP
2014-10-02 19:44:13
date last changed
2017-04-23 03:46:48
@article{d0c647a4-98c2-498a-b040-28454788c1f6,
  abstract     = {Tasquinimod, an orally active quinoline-3-carboxamide, binds with high affinity to HDAC4 and S100A9 in cancer and infiltrating host cells within compromised tumor microenvironment inhibiting adaptive survival pathways needed for an angiogenic response. Clinical trials document that as low as 0.5-1mg tasquinimod/day is therapeutic against castrate resistant metastatic prostate cancer. Tasquinimod is metabolized via cytochrome P4503A4, but ketoconazole at a dose which completely inhibits CYP3A metabolism does not affect tasquinimod's ability to inhibit endothelial "sprouting" in vitro or anti-cancer efficacy against human prostate cancer xenografts in vivo. Tasquinimod's potency is facilitated by its reversible binding (Kd &lt; 35 μM) to the IIA subdomain of albumin (Sudlow's site I). As blood vessels within the compromised cancer microenvironment are characterized by a higher degree of leakiness than those in normal tissues, this results in an enhanced uptake of tasquinimod bound to albumin in cancer tissue via a tumor specific process known as the "enhanced permeability and retention" (i.e., EPR) effect. Thus, despite plasma levels of &lt; 1 µM, the EPR effect results in intracellular drug concentrations of 2-3 µM, levels several-fold higher than needed for inhibition of endothelial sprouting (IC50 ~ 0.5 µM) or for inhibition of HDAC4 and S100A9 mediated tumor growth.},
  author       = {Isaacs, John T and Dalrymple, Susan L and Rosen, D Marc and Hammers, Hans and Olsson, Anders and Leanderson, Tomas},
  issn         = {1949-2553},
  language     = {eng},
  number       = {18},
  pages        = {8093--8106},
  publisher    = {Impact Journals, LLC},
  series       = {Oncotarget},
  title        = {Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment.},
  volume       = {5},
  year         = {2014},
}