The use of Trichomonas vaginalis purine nucleoside phosphorylase to activate fludarabine in the treatment of solid tumors
| Autor: | Disha Joshi, Eric J. Sorscher, Steven E. Ealick, Bhagelu R. Achyut, William B. Parker, Paula W. Allan, Melissa Gilbert-Ross, Turang E. Behbahani, Jeong S. Hong, William R. Waud, Regina Rab |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Cell Genetic Vectors Purine nucleoside phosphorylase Mice Nude Toxicology medicine.disease_cause Article Viral vector 03 medical and health sciences Mice 0302 clinical medicine Cell Line Tumor medicine Escherichia coli Trichomonas vaginalis Animals Humans Pharmacology (medical) Fludarabine Phosphate Pharmacology chemistry.chemical_classification Squamous Cell Carcinoma of Head and Neck Lentivirus Genetic Therapy Glioma Molecular biology Adenosine Fludarabine 030104 developmental biology Enzyme medicine.anatomical_structure Oncology chemistry Purine-Nucleoside Phosphorylase 030220 oncology & carcinogenesis Vidarabine medicine.drug |
| Zdroj: | Cancer Chemother Pharmacol |
| ISSN: | 1432-0843 |
| Popis: | Treatment with fludarabine phosphate (9-β-D-arabinofuranosyl-2-F-adenine 5'-phosphate, F-araAMP) leads to regressions and cures of human tumor xenografts that express Escherichia coli purine nucleoside phosphorylase (EcPNP). This occurs despite the fact that fludarabine (F-araA) is a relatively poor substrate for EcPNP, and is cleaved to liberate 2-fluoroadenine at a rate only 0.3% that of the natural E. coli PNP substrate, adenosine. In this study, we investigated a panel of naturally occurring PNPs to identify more efficient enzymes that may be suitable for metabolizing F-araA as part of experimental cancer therapy. We show that Trichomonas vaginalis PNP (TvPNP) cleaves F-araA with a catalytic efficiency 25-fold greater than the prototypic E. coli enzyme. Cellular extracts from human glioma cells (D54) transduced with lentivirus stably expressing TvPNP (D54/TvPNP) were found to cleave F-araA at a rate similar to extracts from D54 cells expressing EcPNP, although much less enzyme was expressed per cell in the TvPNP transduced condition. As a test of safety and efficacy using TvPNP, human head and neck squamous cell carcinoma (FaDu) xenografts expressing TvPNP were studied in nude mice and shown to exhibit robust tumor regressions, albeit with partial weight loss that resolved post-therapy. F-araAMP was also a very effective treatment for mice bearing D54/TvPNP xenografts in which approximately 10% of tumor cells expressed the enzyme, indicating pronounced ability to kill non-transduced tumor cells (high bystander activity). Moreover, F-araAMP demonstrated activity against D54 tumors injected with an E1, E3 deleted adenoviral vector encoding TvPNP. In that setting, despite higher F-araA cleavage activity using TvPNP, tumor responses were similar to those obtained with EcPNP, indicating factors other than F-Ade production may limit regressions of the D54 murine xenograft model. Our results establish that TvPNP is a favorable enzyme for activating F-araA, and support further studies in combination with F-araAMP for difficult-to-treat human cancers. |
| Databáze: | OpenAIRE |
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