TH-302 – pro

TH-302 is an non-FDA approved cancer treatment that is in clinical development. It is unique in that it is activated under hypoxic.  TH-302 exploits the activation of a nitroazole prodrug by a process that involves a one electron reduction mediated by ubiquitous cellular reductases such as the NADPH cytochrome P450 to generate a radical anion prodrug (RP). In the presence of oxygen (normoxia) the radical anion prodrug reacts rapidly with oxygen to generate the original prodrug and superoxide (SO). Under the low oxygen conditions of the hypoxic zones in tumors, however, the radical anion prodrug undergoes further irreversible reductions to the hydroxylamine (HA) followed by elimination, releasing the active drug and an azole derivative (AZ).

It is a promising drug. In March of 2012. European Commission has granted Orphan Drug Designation for TH-302. An international, randomized, controlled Phase 3 clinical trial was initiated in September 2011, and is being conducted in partnership with the Sarcoma Alliance for Research through Collaboration (SARC). The trial is designed to enroll 450 patients with metastatic or locally advanced unresectable soft tissue sarcoma.

With data from over 500 patients to date, TH-302 is currently being evaluated in a controlled Phase 2 clinical trial in patients with advanced pancreatic cancer. Results of phase I trials have been encouraging. University of Texas at San Antonio initiated a clinical trial of TH-302 in combination with bevacizumab in patients with recurrent high grade astrocytoma including glioblastoma.

Until more information is published and assessed, TH-302 remamns an investigational agent.

J. Thomas Pento (2011). “TH-302″. Drugs of the Future 36 (9): 663–667.

Fanying Meng, James W.  et al, Molecular and Cellular Pharmacology of the Hypoxia-Activated Prodrug TH-302
Mol Cancer Ther March 2012 11; 740

Duan J; Jiao, H; Kaizerman, J; Stanton, T; Evans, JW; Lan, L; Lorente, G; Banica, M et al (2008). “Potent and Highly Selective Hypoxia-Activated Achiral Phosphoramidate Mustards as Anticancer Drugs”. J. Med. Chem. 51 (8): 2412–20.

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