In vivo sensitization of ovarian tumors to chemotherapy by expression of E. coli purine nucleoside phosphorylase in a small fraction of cells

Gadi, Vijayakrishna K.; Alexander, Sherrie D.; Kudlow, Jeffrey E.; Allan, Paula W.; Parker, William B.; Sorscher, Eric J.

doi:10.1038/sj.gt.3301286

Cited by 62 publications

(55 citation statements)

References 16 publications

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“…[1][2][3][4][5][6][7][8][9][10] E. coli PNP differs from human PNP in its ability to cleave adenosine (and analogs of adenosine ) to adenine and ribose-1 -phosphate. Excellent antitumor activity has been demonstrated with 9-( 2-deoxy -b -D -ribofuranosyl ) -6 -methylpurine ( MeP -dR ) against tumors that express E. coli PNP.…”

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confidence: 99%

Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase

et al. 2002

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The selective expression of Escherichia coli purine nucleoside phosphorylase ( PNP ) in solid tumors has been successfully used to activate two purine nucleoside analogs [ 9 -( 2 -deoxy -b -D -ribofuranosyl ) -6 -methylpurine ( MeP -dR ) and 9 -b -D -arabinofuranosyl -2 -fluoroadenine ( F -araA ) ] resulting in lasting tumor regressions and cures. E. coli PNP also cleaves 2 -fluoro -2 0 -deoxyadenosine ( F -dAdo ) to 2 -F -adenine, which is the toxic purine analog liberated from F -araA that has high bystander activity and is active against nonproliferating tumor cells. As F -dAdo is 3000 times better than F -araA as a substrate for E. coli PNP, we have evaluated its antitumor activity against D54 gliomas that express E. coli PNP and have characterized its in vivo metabolism in order to better understand its mechanism of action with respect to the other two agents. Like MeP -dR and F -araA -5 0 -monophosphate ( FaraAMP, a prodrug of F -araA ), treatment of mice bearing D54 tumors that express E. coli PNP with F -dAdo resulted in excellent antitumor activity. Although F -dAdo was as active as MeP -dR and better than F -araAMP, it was not dramatically better than either compound because of its short plasma half -life and the limited activation of F -adenine to toxic metabolites. Regardless, these results indicated that F -dAdo was also an excellent prodrug for use with gene vectors that deliver E. coli PNP to tumor cells.

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confidence: 99%

Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase

et al. 2002

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“…41 Such molecules are able to diffuse across cell membranes, resulting in potent bystander effects. 39,[42][43][44] Therefore, E. coli PNP in association with fludarabine seems to have all the required qualities to be used in suicide gene therapy in cancer.…”

Section: Gene Therapy and Nucleoside Analogues C Hébrard Et Almentioning

confidence: 99%

“…48 Both prodrug-activating systems induce apoptosis in Transduction of PNP gene followed by treatment with nucleoside analogues has been studied in vivo on bladder tumors, pancreatic adenocarcinomas, gliomas, ovarian or prostate tumors and showed different levels of growth inhibition. 40,44,[49][50][51][52][53][54][55][56] To increase the effect obtained with this gene-therapy approach by using new genes and new drugs, a study based on crystallographic and computer modeling of E. coli PNP, was performed. The mutated protein (M64V) had a more than 100-fold increased enzymatic efficiency (kcat/Km) toward the nontoxic 9-(6-deoxy-a-L-talofuranosyl)-6-methylpurine as compared to the wt protein.…”

Section: Gene Therapy and Nucleoside Analogues C Hébrard Et Almentioning

confidence: 99%

Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues

2009

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The clinical use of cytotoxic deoxynucleoside analogues is often limited by resistance mechanisms due to enzymatic deficiency, or high toxicity in nontumor tissues. To improve the use of these drugs, gene therapy approaches have been proposed and studied, associating clinically used deoxynucleoside analogues such as araC and gemcitabine and suicide genes or myeloprotective genes. In this review, we provide an update of recent results in this area, with particular emphasis on human deoxycytidine kinase, the deoxyribonucleoside kinase from Drosophila melanogaster, purine nucleoside phosphorylase from Escherichia coli, and human cytidine deaminase. Data from literature clearly show the feasibility of these systems, and clinical trials are warranted to conclude on their use in the treatment of cancer patients.

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“…[19][20][21] The ePNP/ MePdR system differs from other GDEPT systems, because the toxic metabolites of this system will readily cross the cell membrane and not require direct cell-to-cell contact or the presence of a gap junction. 22 In previous papers, the ePNP/MePdR system has been reported to be an efficient suicide gene/prodrug system with significant antitumor activities on ovarian cancers, 17 gliomas, 23 prostate cancers, 24 melanomas, 25 pancreatic cancers, 26,27 hepatomas 28,29 and bladder tumors. 30 However, an exploitation of this method using attenuated Salmonella as a carrier to deliver the ePNP gene has never been attempted.…”

Section: Introductionmentioning

confidence: 99%

“…[9][10][11][12][13] Therefore, expression of ePNP is able to kill a number of cancer cells in vitro when a small fraction of cells (for example, 0.1-3%) express this suicide gene, in combination with MePdR administration. 8,[14][15][16][17][18] As expression of suicide genes will not be achieved in all the tumor cells, a bystander effect is necessary to produce toxic metabolites to kill not only the positive cells but also the bystander cells. [19][20][21] The ePNP/ MePdR system differs from other GDEPT systems, because the toxic metabolites of this system will readily cross the cell membrane and not require direct cell-to-cell contact or the presence of a gap junction.…”

Section: Introductionmentioning

confidence: 99%

Synergistic antitumor efficacy of suicide/ePNP gene and 6-methylpurine 2′-deoxyriboside via Salmonella against murine tumors

Lan

et al. 2008

Cancer Gene Ther

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Some anaerobes and facultative anaerobes have been used in tumor-specific gene therapy by reason of their selective growth in tumors. In this work, we aimed to evaluate the anticancer efficacy of attenuated Salmonella typhimurium as a carrier to deliver the Escherichia coli purine nucleoside phosphorylase (ePNP) gene for GDEPT (gene-directed enzyme-prodrug therapy). A live attenuated purine-auxotrophic strain of S. typhimurium (SC36) was used to carry the pEGFP-C1-ePNP vector that contains a green fluorescent protein (GFP) and an ePNP gene under the control of the human cytomegalovirus (CMV) promoter. The function of the ePNP expression vector was confirmed in vitro using the enzymic conversion of 6-methylpurine 2 0 -deoxyriboside (MePdR) into 6-methylpurine. We also observed a high bystander effect induced by the ePNP/MePdR system with a very low proportion (1%) of ePNP-positive cells. The killing effect and increased apoptosis induced by SC/ePNP (SC36 carrying the ePNP expression vector) infection were detected by cytotoxicity assay and PI staining flow cytometry analysis, in combination with MePdR administration. Furthermore, SC/ePNP was administered orally into mice bearing melanomas or pulmonary tumors, and its anti-tumor effect was evaluated. When the tumor was huge (500 mm 3 ) at the beginning of MePdR administration, SC/ePNP plus MepdR significantly inhibited tumor growth by about 59-80% and prolonged survival of mice. Complete tumor regression and long-term cure were achieved by MePdR administration, even when the tumor was large (100 mm 3 ) at the beginning of MePdR treatment. Our data support a hopeful view that tumor-targeting SC36 could improve antitumor efficacy of the ePNP/MePdR system due to its preferential accumulation and anticancer activity in tumors.

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In vivo sensitization of ovarian tumors to chemotherapy by expression of E. coli purine nucleoside phosphorylase in a small fraction of cells

Cited by 62 publications

References 16 publications

Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase

Antitumor activity of 2-fluoro-2′-deoxyadenosine against tumors that express Escherichia coli purine nucleoside phosphorylase

Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues

Synergistic antitumor efficacy of suicide/ePNP gene and 6-methylpurine 2′-deoxyriboside via Salmonella against murine tumors

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