The use of Trichomonas vaginalis purine nucleoside phosphorylase to activate fludarabine in the treatment of solid tumors

Parker, William B.; Allan, Paula W.; Waud, William R.; Hong, Jeong S.; Gilbert‐Ross, Melissa; Achyut, Bhagelu R.; Joshi, Deepak; Behbahani, Turang E; Rab, Regina; Ealick, S.E.; Sorscher, Eric J.

doi:10.1007/s00280-019-04018-7

Cited by 8 publications

(14 citation statements)

References 21 publications

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“…NOD‐scid‐gamma (NSG) (female, aged 6–8 weeks) mice were inoculated with 1 × 10 7 328373‐195‐R‐J1‐PDC cells subcutaneously (150 μl/injection) in each flank. Note that tumor mass in studies such as these can be estimated by a conventional caliper measurement using the equation: (length x width squared)/2 = cubic mm and converted to mg assuming unit density 1 . (By this method, a calculated tumor volume of 100 mm 3 represents mass of approximately 100 mg.) Tumors were treated when they reached a size of 100–300 mm 3 .…”

Section: Methodsmentioning

confidence: 99%

“…Therapeutic gene transfer comprises an important experimental approach to treatment of refractory solid tumors. Such strategies have been tested clinically with encouraging results against head and neck squamous cell carcinoma (HNSCC) using a modified Escherichia coli purine nucleoside phosphorylase (PNP) gene and replication deficient adenovirus 1–5 . PNP converts specific nucleosides to highly active purine base molecules that inhibit refractory tumors.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, PNP is active even when a very small fraction of cancer cells (e.g., <2.5% of a tumor mass) express the transgene 3,4,7,8 . This level of bystander cell killing is unprecedented, and the approach is fundamentally distinct from earlier interventions using transgenes such as thymidine kinase or cytosine deaminase 1–5 …”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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.

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Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…Purine nucleoside phosphorylase (E.C. 2.4.2.1, PNP) is a well-known drug target including cancer and immunodeficiency diseases (Pant et al 2021 ; Parker et al 2020 ). PNP can reversibly catalyze phosphorolysis of purine nucleosides to form glycosidic bonds (Holanda et al 2020 ; Stachelska-Wierzchowska and Wierzchowski 2020 ; Timofeev et al 2020 ).…”

Section: Enzymatic Synthesis Of Fluorinated Compoundsmentioning

confidence: 99%

Enzymatic synthesis of fluorinated compounds

Cheng

2021

Appl Microbiol Biotechnol

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Fluorinated compounds are widely used in the fields of molecular imaging, pharmaceuticals, and materials. Fluorinated natural products in nature are rare, and the introduction of fluorine atoms into organic compound molecules can give these compounds new functions and make them have better performance. Therefore, the synthesis of fluorides has attracted more and more attention from biologists and chemists. Even so, achieving selective fluorination is still a huge challenge under mild conditions. In this review, the research progress of enzymatic synthesis of fluorinated compounds is summarized since 2015, including cytochrome P450 enzymes, aldolases, fluoroacetyl coenzyme A thioesterases, lipases, transaminases, reductive aminases, purine nucleoside phosphorylases, polyketide synthases, fluoroacetate dehalogenases, tyrosine phenol-lyases, glycosidases, fluorinases, and multienzyme system. Of all enzyme-catalyzed synthesis methods, the direct formation of the C-F bond by fluorinase is the most effective and promising method. The structure and catalytic mechanism of fluorinase are introduced to understand fluorobiochemistry. Furthermore, the distribution, applications, and future development trends of fluorinated compounds are also outlined. Hopefully, this review will help researchers to understand the significance of enzymatic methods for the synthesis of fluorinated compounds and find or create excellent fluoride synthase in future research. Key points • Fluorinated compounds are distributed in plants and microorganisms, and are used in imaging, medicine, materials science . • Enzyme catalysis is essential for the synthesis of fluorinated compounds . • The loop structure of fluorinase is the key to forming the C-F bond . Supplementary Information The online version contains supplementary material available at 10.1007/s00253-021-11608-0.

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“…Además, se utilizaron PNPs de otras especies como Trichomonas vaginalis, la cual presenta 25 veces más eficiencia catalítica utilizando la fludarabina que la PNP de E. coli, obteniendo una gran eficiencia de regresión tumoral in vivo (23). Incluso se ha utilizado una PNP humana mutada que reconoce derivados de desoxiadenosina y que podría producir menos reacción inmunológica que las enzimas bacterianas utilizadas (24).…”

Section: Sistema Purina Nucleósido Fosforilasa Y 6-metilpurina Desoxirribósido O Fludarabinaunclassified

Suicide gene therapy against cancer

Piñeiro-Silva

2021

Actual. Med.

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Cancers are a large family of diseases with the highest mortality rate worldwide. Conventional therapies such as chemotherapy or radiotherapy are not efficient in all cases and have important side effects. To solve it, suicide gene therapy can be used. This therapy consists on inducing cell death of cancer cells due to the introduction of a gene. There are three types of this therapy: introduction of a gene encoding generally a bacterial enzyme that actives a prodrug, introduction of a gene encoding a toxin or introduction of a proapoptotic gene. The expression of the targeted gene in tumor cells is produced by using tumor-specific promoters and target vectors. Using those three gene suicide therapies many hallmarks in the field were reached, achieving successful clinical trials and products approved to be used in China (gendicine), achieving apoptosis of tumor cells in vitro and in vivo. Furthermore, several improvements on these techniques were developed due to the mutation of the enzymes and toxins, modification of prodrugs and search of new more active enzymes, toxins and genes, between others. Regardless, further research on this area is needed to guarantee the efficiency of this state-of-the-art therapy and its effectiveness.

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The use of Trichomonas vaginalis purine nucleoside phosphorylase to activate fludarabine in the treatment of solid tumors

Cited by 8 publications

References 21 publications

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

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

Enzymatic synthesis of fluorinated compounds

Suicide gene therapy against cancer

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