1. Cytochrome P450 isoforms 1A1, 1B1 AND 2W1 as targets for therapeutic intervention in head and neck cancer
- Author
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Laurence H. Patterson, James McCaul, Sneha Smarakan, Daniela Presa, Klaus Pors, Amir Zaki Abdullah Zubir, Syed Ali Khurram, Maria Sadiq, Paul M. Loadman, Mark Sutherland, Patricia A. Cooper, Goreti Ribeiro Morais, and Steven D. Shnyder
- Subjects
Indoles ,CYP1B1 ,Science ,Antineoplastic Agents ,Cohort Studies ,Mice ,chemistry.chemical_compound ,In vivo ,Cell Line, Tumor ,Cytochrome P-450 CYP1A1 ,Animals ,Humans ,Prodrugs ,Pyrroles ,Cytochrome P450 Family 2 ,Carcinogen ,Duocarmycin ,Multidisciplinary ,biology ,Chemistry ,Cytochrome P450 ,Prodrug ,Xenograft Model Antitumor Assays ,Head and Neck Neoplasms ,Cell culture ,Cytochrome P-450 CYP1B1 ,Cancer research ,biology.protein ,Medicine ,Female ,CYP2W1 ,Heterocyclic Compounds, 3-Ring - Abstract
Epidemiological studies have shown that head and neck cancer (HNC) is a complex multistage process that in part involves exposure to a combination of carcinogens and the capacity of certain drug-metabolising enzymes including cytochrome P450 (CYP) to detoxify or activate such carcinogens. In this study, CYP1A1, CYP1B1 and CYP2W1 expression in HNC was correlated with potential as target for duocarmycin prodrug activation and selective therapy. In the HNC cell lines, elevated expression was shown at the gene level for CYP1A1 and CYP1B1 whereas CYP2W1 was hardly detected. However, CYP2W1 was expressed in FaDu and Detroit-562 xenografts and in a cohort of human HNC samples. Functional activity was measured in Fadu and Detroit-562 cells using P450-Glo™ assay. Antiproliferative results of duocarmycin prodrugs ICT2700 and ICT2706 revealed FaDu and Detroit-562 as the most sensitive HNC cell lines. Administration of ICT2700 in vivo using a single dose of ICT2700 (150 mg/kg) showed preferential inhibition of small tumour growth (mean size of 60 mm3) in mice bearing FaDu xenografts. Significantly, our findings suggest a potential targeted therapeutic approach to manage HNCs by exploiting intratumoural CYP expression for metabolic activation of duocarmycin-based prodrugs such as ICT2700.
- Published
- 2021