Evaluating antitumor activity of Escherichia coli purine nucleoside phosphorylase against head and neck patient‐derived xenografts

Abstract

Abstract Background Purine nucleoside phosphorylase (PNP) gene transfer represents a promising approach to treatment of head and neck malignancies. We tested recombinant adenovirus already in phase I/II clinical testing and leading‐edge patient‐derived xenografts (PDX) as a means to optimize this therapeutic strategy. Methods Our experiments investigated purine base cytotoxicity, PNP enzyme activity following treatment of malignant tissue, tumor mass regression, viral receptor studies, and transduction by tropism‐modified adenovirus. Results Replication deficient vector efficiently transduced PDX cells and mediated significant anticancer effect following treatment with fludarabine phosphate in vivo. Either 6‐methylpurine or 2‐fluoroadenine (toxic molecules generated by the PNP approach) ablated head and neck cancer cell proliferation. High levels of adenovirus‐3 specific receptors were detected in human tumor models, and vector was evaluated that utilizes this pathway. Conclusions Our studies provide the scientific foundation necessary to improve PNP prodrug cleavage and advance a new treatment for head and neck cancer.

Keywords

• gene transfer
• head and neck squamous cell carcinoma
• patient‐derived xenografts
• purine nucleoside phosphorylase
• tropism modified adenovirus