Priority Research Papers:
Anti-cancer potency of tasquinimod is enhanced via albumin-binding facilitating increased uptake in the tumor microenvironment
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John T. Isaacs1,2, Susan L. Dalrymple1, D. Marc Rosen1, Hans Hammers1, Anders Olsson3 and Tomas Leanderson3,4
1 The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins ,Baltimore, MD
2 The Brady Urological Institute-Department of Urology, The Johns Hopkins University School of Medicine ,Baltimore, MD
3 Active Biotech, AB Lund, Sweden
4 Immunology group, Lund University, Sweden
John T Isaacs, email:
Keywords: EPR effect, drug uptake, albumin-binding, tasquinimod
Received: July 17, 2014 Accepted: August 20, 2014 Published: August 21, 2014
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.
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