Analogs of 6-methyl-9.beta.-D-ribofuranosylpurine

Montgomery, John A.; Hewson, Kathleen

doi:10.1021/jm00307a010

Cited by 87 publications

(59 citation statements)

References 1 publication

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“…These results support the observation that MeP kills resting as well as proliferating cells (10). Cells lacking adenine phosphoribosyltransferase activity are resistant to the cytotoxic effects of MeP (25), which indicated that this enzyme is involved in the conversion of MeP into cytotoxic nucleotides. In contrast, prodrug activation by enzymes such as HSV-TK and cytosine deaminase cannot generate toxins that kill resting cells.…”

Section: Discussionmentioning

confidence: 99%

Cell to Cell Contact Is Not Required for Bystander Cell Killing by Escherichia coli Purine Nucleoside Phosphorylase

Hughes¹,

King²,

Allan³

et al. 1998

Journal of Biological Chemistry

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Expression of Escherichia coli purine nucleoside phosphorylase (PNP) activates prodrugs and kills entire populations of mammalian cells, even when as few as 1% of the cells express this gene. This phenomenon of bystander killing has been previously investigated for herpes simplex virus-thymidine kinase (HSV-TK) and has been shown to require cell to cell contact. Using silicon rings to separate E. coli PNP expressing cells from nonexpressing cells sharing the same medium, we demonstrate that bystander cell killing by E. coli PNP does not require cell-cell contact. Initially, cells expressing E. coli PNP convert the non-toxic prodrug, 6-methylpurine-2-deoxyriboside (MeP-dR) to the highly toxic membrane permeable toxin, 6-methylpurine (MeP). As the expressing cells die, E. coli PNP is released into the culture medium, retains activity, and continues precursor conversion extracellularly (as determined by reverse phase high performance liquid chromatography of both prodrug and toxin). Bystander killing can also be observed in the absence of extracellular E. coli PNP by removing the MeP-dR prior to death of the expressing cells. In this case, 100% of cultured cells die when as few as 3% of the cells of a population express E. coli PNP. Blocking nucleoside transport with nitrobenzylthioinosine reduces MeP-dR mediated cell killing but not MeP cell killing. These mechanisms differ fundamentally from those previously reported for the HSV-TK gene.

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Section: Discussionmentioning

confidence: 99%

Cell to Cell Contact Is Not Required for Bystander Cell Killing by Escherichia coli Purine Nucleoside Phosphorylase

Hughes¹,

King²,

Allan³

et al. 1998

Journal of Biological Chemistry

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“…Mice were evaluated for weight loss, tumor mass, and overall appearance twice weekly. MeP-dR was made in our laboratories according to the method described by Montgomery and Rosman (17). F-araAMP was obtained from Schering A.-G. (Berlin, Germany).…”

Section: Methodsmentioning

confidence: 99%

Excellent In vivo Bystander Activity of Fludarabine Phosphate against Human Glioma Xenografts that Express the Escherichia coli Purine Nucleoside Phosphorylase Gene

Hong

Waud

Levasseur³

et al. 2004

Cancer Research

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Escherichia coli purine nucleoside phosphorylase (PNP) expressed in tumors converts relatively nontoxic prodrugs into membrane-permeant cytotoxic compounds with high bystander activity. In the present study, we examined tumor regressions resulting from treatment with E. coli PNP and fludarabine phosphate (F-araAMP), a clinically approved compound used in the treatment of hematologic malignancies. We tested bystander killing with an adenoviral construct expressing E. coli PNP and then more formally examined thresholds for the bystander effect, using both MuLv and lentiviral vectoring. Because of the importance of understanding the mechanism of bystander action and the limits to this anticancer strategy, we also evaluated in vivo variables related to the expression of E. coli PNP (level of E. coli PNP activity in tumors, ectopic expression in liver, percentage of tumor cells transduced in situ, and accumulation of active metabolites in tumors). Our results indicate that F-araAMP confers excellent in vivo dose-dependent inhibition of bystander tumor cells, including strong responses in subcutaneous human glioma xenografts when 95 to 97.5% of the tumor mass is composed of bystander cells. These findings define levels of E. coli PNP expression necessary for antitumor activity with F-araAMP and demonstrate new potential for a clinically approved compound in solid tumor therapy.

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“…17,18 Experimental therapy of allogeneic solid tumors M Heinkelein et al Prodrugs Gancyclovir (Cymeven from Roche) served as prodrug for herpes simplex virus tk. The pnp prodrug 9-D-2-deoxyerythropentofuranosyl-6-methylpurine (MePdR) 23 was synthesized via coupling of triacetyl-D-ribofuranose with silylated N-methylpurine in the presence of trimethylsilyltrifluoromethanesulfate. Deacetylation was achieved with ammonia in ethanol and the resulting mixture of nucleosides was separated into the pure a-and b-anomer by combination of conventional silica gel column chromatography, crystallization and preparative HPLC.…”

Section: Cells and Virusesmentioning

confidence: 99%

Experimental therapy of allogeneic solid tumors induced in athymic mice with suicide gene-transducing replication-competent foamy virus vectors

et al. 2005

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A replication competent foamy virus derived retroviral vector expressing suicide genes has been constructed and characterized in vitro. Here we used vectors expressing the purine nucleoside phosphorylase (FOV-7/pnp), the nitroreductase (FOV-7/ntr), or the thymidine kinase (FOV-7/tk) suicide gene in an in vivo athymic (nude) mice/human glioblastoma tumor model. Gliomas were induced by subcutanous injection of U87 tumor cells. The virus vector was injected when the tumor became visible. Mice with vector virus-injected tumors were treated with the respective prodrug. The treatment resulted in significant inhibition of tumor growth. Surprisingly, in mice with vector virus-injected tumors without prodrug treatment a similar suppression of tumor growth was observed. In 65% (pnp vector), 75% (ntr vector) and 37% (tk vector) of these mice the tumors stopped growing or vanished and the animals remained tumor free for the 25 weeks of the experiment, whereas all mice of the control groups had to be killed because of the tumor growth. In control experiments, the suppression of tumor growth could also be observed when wild-type foamy virus was injected instead of the suicide gene-transducing vectors. Similar results were obtained using the nude mice/G59 human glioblastoma tumor model. In conclusion, the experiments demonstrate an oncolytic activity of foamy virus replication in a nudemice glioblastoma xenograft tumor model. The analysis of vector virus DNA by PCR revealed that the vector persisted in different organs of the animals irrespective of the use of a prodrug or the elimination of a tumor. Cancer Gene Therapy (2005) 12, 947-953.

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Analogs of 6-methyl-9.beta.-D-ribofuranosylpurine

Cited by 87 publications

References 1 publication

Cell to Cell Contact Is Not Required for Bystander Cell Killing by Escherichia coli Purine Nucleoside Phosphorylase

Cell to Cell Contact Is Not Required for Bystander Cell Killing by Escherichia coli Purine Nucleoside Phosphorylase

Excellent In vivo Bystander Activity of Fludarabine Phosphate against Human Glioma Xenografts that Express the Escherichia coli Purine Nucleoside Phosphorylase Gene

Experimental therapy of allogeneic solid tumors induced in athymic mice with suicide gene-transducing replication-competent foamy virus vectors

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