ArticleCancer biology & therapy2015
Pre-clinical activity of PR-104 as monotherapy and in combination with sorafenib in hepatocellular carcinoma.
Article in Cancer biology & therapy, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers, 1 of them a synthesis that pooled it.
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Who cites it
18 citing papers in PubMed, 1 synthesis or guideline pooled it, 36 citations in OpenAlex.
- Targeting Hypoxia: Hypoxia-Activated Prodrugs in Cancer Therapy.Frontiers in oncology · 2021Pooled it
- Tumour hypoxia in clinical oncology: imaging, therapeutic strategies, and translational challenges.Clinical and translational radiation oncology · 2027Review
- PISTOL MRI allows noninvasive assessment of changes in tumor oxygenation post hypoxia targeted therapy.Scientific reports · 2025Article
- AKR1C3 promotes progression and mediates therapeutic resistance by inducing epithelial-mesenchymal transition and angiogenesis in small cell lung cancer.Translational oncology · 2024Article
- Hypoxia as a Target for Combination with Transarterial Chemoembolization in Hepatocellular Carcinoma.Pharmaceuticals (Basel, Switzerland) · 2024Review
- Exploring the Molecular Mechanisms of Huaier on Modulating Metabolic Reprogramming of Hepatocellular Carcinoma: A Study based on Network Pharmacology, Molecular Docking and Bioinformatics.Current pharmaceutical design · 2024Article
- Review
- TheFrontiers in oncology · 2022Article
- Tissue Pharmacokinetic Properties and Bystander Potential of Hypoxia-Activated Prodrug CP-506 by Agent-Based Modelling.Frontiers in pharmacology · 2022Article
- Selectively Targeting Tumor Hypoxia With the Hypoxia-Activated Prodrug CP-506.Molecular cancer therapeutics · 2021Article
- Characterizing Endocrine Status, Tumor Hypoxia and Immunogenicity for Therapy Success in Epithelial Ovarian Cancer.Frontiers in endocrinology · 2021Review
- AKR1C1-3, notably AKR1C3, are distinct biomarkers for liver cancer diagnosis and prognosis: Database mining in malignancies.Oncology letters · 2019Article
- Hypoxia-activated prodrugs and (lack of) clinical progress: The need for hypoxia-based biomarker patient selection in phase III clinical trials.Clinical and translational radiation oncology · 2019Article
- Intravital Imaging to Monitor Therapeutic Response in Moving Hypoxic Regions Resistant to PI3K Pathway Targeting in Pancreatic Cancer.Cell reports · 2018Article
- Molecular Pathways: Hypoxia-Activated Prodrugs in Cancer Therapy.Clinical cancer research : an official journal of the American Association for Cancer Research · 2017Review
- Synthesis and Biological Evaluation of Benzocyclooctene-based and Indene-based Anticancer Agents that Function as Inhibitors of Tubulin Polymerization.MedChemComm · 2016Article
- Targeting the hypoxic fraction of tumours using hypoxia-activated prodrugs.Cancer chemotherapy and pharmacology · 2016Review
- Hypoxia-Targeted Drug Q6 Induces G2-M Arrest and Apoptosis via Poisoning Topoisomerase II under Hypoxia.PloS one · 2015Article
Corrections and comments
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Authors and funding
8 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
PR-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 metabolites (hydroxylamine PR-104H and amine PR-104M) under hypoxia by one-electron reductases and independently of hypoxia by the 2-electron reductase aldo-keto reductase 1C3 (AKR1C3). High expression of AKR1C3, along with extensive hypoxia, suggested the potential of PR-104 for treatment of hepatocellular carcinoma (HCC). However, a phase IB trial with sorafenib demonstrated significant toxicity that was ascribed in part to reduced PR-104A clearance, likely reflecting compromised glucuronidation in patients with advanced HCC. Here, we evaluate the activity of PR-104 in HCC xenografts (HepG2, PLC/PRF/5, SNU-398, Hep3B) in mice, which do not significantly glucuronidate PR-104A. Cell line differences in sensitivity to PR-104A in vitro under aerobic conditions could be accounted for by differences in both expression of AKR1C3 (high in HepG2 and PLC/PRF/5) and sensitivity to the major active metabolite PR-104H, to which PLC/PRF/5 was relatively resistant, while hypoxic selectivity of PR-104A cytotoxicity and reductive metabolism was greatest in the low-AKR1C3 SNU-398 and Hep3B lines. Expression of AKR1C3 in HepG2 and PLC/PRF/5 xenografts was in the range seen in 21 human HCC specimens. PR-104 monotherapy elicited significant reductions in growth of Hep3B and HepG2 xenografts, and the combination with sorafenib was significantly active in all 4 xenograft models. The results suggest that better-tolerated analogs of PR-104, without a glucuronidation liability, may have the potential to exploit AKR1C3 and/or hypoxia in HCC in humans.
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