Use of E. coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors

Parker, William B.; Sorscher, Eric J.

doi:10.2174/1381612823666171109101851

Cited by 6 publications

(33 citation statements)

References 115 publications

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“…Vinyl chloride, a known chemical mutagen and carcinogen, acts as a modifier of nucleobases, in particular, of adenine and guanine moieties [14,15], which upon this chemical modification change the respective coding properties, leading to the mutagenic effect [33,34]. In addition some of the bases modified in this way exhibit additionally marked fluorescence [1][2][3][4], which make them good candidates for fluorescent probes in enzymological research.…”

Section: Fluorescent Isomers Of the Etheno-2-aminopurinementioning

confidence: 99%

“…It belongs to a group of enzymes involved in the purine salvage pathway, present in the majority of higher organisms [12], which is the only source of these indispensable building blocks of DNA and RNA for microorganisms lacking de novo purine nucleoside synthesis. PNP is responsible for the regulation of the nucleoside concentrations within the living cells, and it is a target of various types of pharmaceutical interventions [12,13], including gene therapy of some inherited immunological deficiencies [14] and gene therapy of solid tumors [15]. Additionally, PNP's from various sources are utilized as biocatalysts in chemo-enzymatic syntheses of various nucleoside analogs of pharmaceutical and/or analytical significance [16][17][18][19][20].…”

Section: Introductionmentioning

confidence: 99%

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Tricyclic Nucleobase Analogs and Their Ribosides as Substrates and Inhibitors of Purine-Nucleoside Phosphorylases III. Aminopurine Derivatives

Stachelska-Wierzchowska

Wierzchowski

Górka

et al. 2020

Molecules

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Etheno-derivatives of 2-aminopurine, 2-aminopurine riboside, and 7-deazaadenosine (tubercidine) were prepared and purified using standard methods. 2-Aminopurine reacted with aqueous chloroacetaldehyde to give two products, both exhibiting substrate activity towards bacterial (E. coli) purine-nucleoside phosphorylase (PNP) in the reverse (synthetic) pathway. The major product of the chemical synthesis, identified as 1,N2-etheno-2-aminopurine, reacted slowly, while the second, minor, but highly fluorescent product, reacted rapidly. NMR analysis allowed identification of the minor product as N2,3-etheno-2-aminopurine, and its ribosylation product as N2,3-etheno-2-aminopurine-N2-β-d-riboside. Ribosylation of 1,N2-etheno-2-aminopurine led to analogous N2-β-d-riboside of this base. Both enzymatically produced ribosides were readily phosphorolysed by bacterial PNP to the respective bases. The reaction of 2-aminopurine-N9-β -d-riboside with chloroacetaldehyde gave one major product, clearly distinct from that obtained from the enzymatic synthesis, which was not a substrate for PNP. A tri-cyclic 7-deazaadenosine (tubercidine) derivative was prepared in an analogous way and shown to be an effective inhibitor of the E. coli, but not of the mammalian enzyme. Fluorescent complexes of amino-purine analogs with E. coli PNP were observed.

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Section: Fluorescent Isomers Of the Etheno-2-aminopurinementioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Tricyclic Nucleobase Analogs and Their Ribosides as Substrates and Inhibitors of Purine-Nucleoside Phosphorylases III. Aminopurine Derivatives

Stachelska-Wierzchowska

Wierzchowski

Górka

et al. 2020

Molecules

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“…The toxic purine base analogues generated by ePNP readily diffuse across cell membrane, therefore killing not only the tumour cell in which they are generated, but also many surrounding tumour cells that do not express ePNP (bystander effect). The first prodrug used with ePNP was 9-β- d -[2-deoxyribofuranosyl]-6-methylpurine (MeP-dR), which, being a poor substrate for human salvage enzymes, such as dCK and hPNP, is not cytotoxic to human cells [123]. Therefore, its toxicity is exerted in tumour cells, where ePNP GDEPT is directed: in fact, 6-methylpurine (MeP), the product of MeP-dR phosphorolysis, is activated to the cytotoxic compound by cellular HPRT and/or APRT activities (see Section 6) and then incorporated both in RNA and DNA.…”

Section: Purine Nucleoside Phosphorylasementioning

confidence: 99%

“…With F-araAde being an insoluble compound, it is administered as F-araAde-5′-monophosphate (F-araAMP), which must be dephosphorylated by plasma phosphatases, before entering the cell (Figure 4). An important feature of the ePNP GDEPT is its inhibition of protein and RNA/DNA synthesis, making it a good therapeutic approach for solid tumours, which exhibit a high fraction of non-replicating cells [123,124,125]. The ePNP/F-araAMP GDEPT in combination with docetaxel was used against multidrug-resistant ovarian cancer cells [126] and castration-resistant prostate cancer cells [127].…”

Section: Purine Nucleoside Phosphorylasementioning

confidence: 99%

Purine-Metabolising Enzymes and Apoptosis in Cancer

Camici¹,

Garcia‐Gil

Pesi³

et al. 2019

Cancers

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The enzymes of both de novo and salvage pathways for purine nucleotide synthesis are regulated to meet the demand of nucleic acid precursors during proliferation. Among them, the salvage pathway enzymes seem to play the key role in replenishing the purine pool in dividing and tumour cells that require a greater amount of nucleotides. An imbalance in the purine pools is fundamental not only for preventing cell proliferation, but also, in many cases, to promote apoptosis. It is known that tumour cells harbour several mutations that might lead to defective apoptosis-inducing pathways, and this is probably at the basis of the initial expansion of the population of neoplastic cells. Therefore, knowledge of the molecular mechanisms that lead to apoptosis of tumoural cells is key to predicting the possible success of a drug treatment and planning more effective and focused therapies. In this review, we describe how the modulation of enzymes involved in purine metabolism in tumour cells may affect the apoptotic programme. The enzymes discussed are: ectosolic and cytosolic 5′-nucleotidases, purine nucleoside phosphorylase, adenosine deaminase, hypoxanthine-guanine phosphoribosyltransferase, and inosine-5′-monophosphate dehydrogenase, as well as recently described enzymes particularly expressed in tumour cells, such as deoxynucleoside triphosphate triphosphohydrolase and 7,8-dihydro-8-oxoguanine triphosphatase.

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“…However, getting a reasonable concentration of exogenous enzymes in tumor tissues is the major bottleneck of DEPT therapies. In this context, two different DEPT strategies can be distinguished: (i) the delivery of genes which encode prodrug-activating enzymes into the tumor cells (gene-directed enzyme prodrug therapy, GDEPT), using virus or non-virus carriers [ 5 , 6 ] and (ii) the delivery of prodrug-activating enzymes in the tumor cells by employing different carriers, such as tumor-associated monoclonal antibodies linked to prodrug-activating enzyme (antibody-directed enzyme prodrug therapy, ADEPT) [ 7 ], or the solid matrixes (immobilized-directed enzyme prodrug therapy, IDEPT) [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy

et al. 2021

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Herein we report the first proof for the application of type II 2′-deoxyribosyltransferase from Lactobacillus delbrueckii (LdNDT) in suicide gene therapy for cancer treatment. To this end, we first confirm the hydrolytic ability of LdNDT over the nucleoside-based prodrugs 2′-deoxy-5-fluorouridine (dFUrd), 2′-deoxy-2-fluoroadenosine (dFAdo), and 2′-deoxy-6-methylpurine riboside (d6MetPRib). Such activity was significantly increased (up to 30-fold) in the presence of an acceptor nucleobase. To shed light on the strong nucleobase dependence for enzymatic activity, different molecular dynamics simulations were carried out. Finally, as a proof of concept, we tested the LdNDT/dFAdo system in human cervical cancer (HeLa) cells. Interestingly, LdNDT/dFAdo showed a pronounced reduction in cellular viability with inhibitory concentrations in the low micromolar range. These results open up future opportunities for the clinical implementation of nucleoside 2′-deoxyribosyltransferases (NDTs) in cancer treatment.

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Use of E. coli Purine Nucleoside Phosphorylase in the Treatment of Solid Tumors

Abstract: The unique attributes distinguish this approach from other GDEPT strategies and are precisely those required to mediate significant improvements in antitumor therapy.

Cited by 6 publications

References 115 publications

Tricyclic Nucleobase Analogs and Their Ribosides as Substrates and Inhibitors of Purine-Nucleoside Phosphorylases III. Aminopurine Derivatives

Tricyclic Nucleobase Analogs and Their Ribosides as Substrates and Inhibitors of Purine-Nucleoside Phosphorylases III. Aminopurine Derivatives

Purine-Metabolising Enzymes and Apoptosis in Cancer

Molecular Basis of NDT-Mediated Activation of Nucleoside-Based Prodrugs and Application in Suicide Gene Therapy

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