AKR1C3Hypoxiahypoxia-activated prodrugshepatocellular carcinomanitrogen mustardsPR-104sorafenibaldo-keto reductase 1C3HCCPORPR-104 is a clinical stage bioreductive prodrug that is converted in vivo to its cognate alcohol, PR-104A. This dinitrobenzamide mustard is reduced to activated DNA cross-linking...
AKR1C3 is a biomarker of sensitivity to PR-104 in preclinical models of T-cell acute lymphoblastic leukemia. Blood 2015;126:1193-202.Moradi Manesh D, El-Hoss J, Evans K, Richmond J, Toscan CE, Bracken LS, Hedrick A, Sutton R, Marshall GM, Wilson WR, Kurmasheva RT, Billups C, ...
Levels of AKR1C3 protein did not correlate with tumor responsiveness.ConclusionsAs monotherapy, PR-104 demonstrated a high level of activity against both solid tumor and ALL models at its MTD, but the activity was almost completely lost at half the MTD dose for solid tumors. Pharmacokinetic data...
A screen of non-steroidal anti-inflammatory drugs identified naproxen as an effective AKR1C3 inhibitor in human tumor cell cultures and xenografts, suggesting its potential use to ameliorate PR-104 toxicity in patients. However, neither naproxen nor the pan-CYP inhibitor 1-aminobenzotriazole inhibited...
A screen of non-steroidal anti-inflammatory drugs identified naproxen as an effective AKR1C3 inhibitor in human tumor cell cultures and xenografts, suggesting its potential use to ameliorate PR-104 toxicity in patients. However, neither naproxen nor the pan-CYP inhibitor 1-aminobenzotriazole inhibited...
Interestingly, SF had no significant influence on PR-104A cytotoxicity in non-cancerous, immortalized human colonic epithelial cell lines expressing either low or high levels of AKR1C3. In conclusion, the enhanced response of PR-104A after preconditioning with SF was apparent only in cancer cells ...