Back to Search Start Over

In vivo gene therapy of cancer with E. coli purine nucleoside phosphorylase.

Authors :
Parker WB
King SA
Allan PW
Bennett LL Jr
Secrist JA 3rd
Montgomery JA
Gilbert KS
Waud WR
Wells AH
Gillespie GY
Sorscher EJ
Source :
Human gene therapy [Hum Gene Ther] 1997 Sep 20; Vol. 8 (14), pp. 1637-44.
Publication Year :
1997

Abstract

We have developed a new strategy for the gene therapy of cancer based on the activation of purine nucleoside analogs by transduced E. coli purine nucleoside phosphorylase (PNP, E.C. 2.4.2.1). The approach is designed to generate antimetabolites intracellularly that would be too toxic for systemic administration. To determine whether this strategy could be used to kill tumor cells without host toxicity, nude mice bearing human malignant D54MG glioma tumors expressing E. coli PNP (D54-PNP) were treated with either 6-methylpurine-2'-deoxyriboside (MeP-dR) or arabinofuranosyl-2-fluoroadenine monophosphate (F-araAMP, fludarabine, a precursor of F-araA). Both prodrugs exhibited significant antitumor activity against established D54-PNP tumors at doses that produced no discernible systemic toxicity. Significantly, MeP-dR was curative against this slow growing solid tumor after only 3 doses. The antitumor effects showed a dose dependence on both the amount of prodrug given and the level of E. coli PNP expression within tumor xenografts. These results indicated that a strategy using E. coli PNP to create highly toxic, membrane permeant compounds that kill both replicating and nonreplicating cells is feasible in vivo, further supporting development of this cancer gene therapy approach.

Details

Language :
English
ISSN :
1043-0342
Volume :
8
Issue :
14
Database :
MEDLINE
Journal :
Human gene therapy
Publication Type :
Academic Journal
Accession number :
9322865
Full Text :
https://doi.org/10.1089/hum.1997.8.14-1637