Abstract

) This component within the overall NCDDG application is intended to improve the fundamental understanding and the use of E. coli purine nucleoside phosphorylase for cancer treatment. We have previously characterized E. coli PNP as a very efficient method for eliciting bystander killing of human tumor cells. The approach differs fundamentally from the HSV-tk and other prodrug activation strategies since it a) provides a toxin that kills tumors with a low growth fraction, b) generates a toxin that diffuses between and among tumor cells with potent bystander activity (even when less than 1 in 100 cells express the gene) and c) does not require cell-to-cell contact or gap junctions in order to mediate these effects. Laboratory Program 1 will characterize boundaries of bystander killing by E. coli PNP and provide important new information regarding toxicity of the strategy. The experiments will also develop novel vectors for delivery of E. coli PNP to pre-establish tumors in mouse models. Finally, these studies are intended to examine recent information developed in this NCDDG about the active site of E. coli PNP, and ways the crystal structure of the enzyme can facilitate development of better prodrug/enzyme combinations.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19CA067763-07
Application #
6450653
Study Section
Project Start
2001-05-03
Project End
2002-04-30
Budget Start
Budget End
Support Year
7
Fiscal Year
2001
Total Cost
Indirect Cost

  Institution

Name
Southern Research Institute
Department
Type
DUNS #
006900526
City
Birmingham
State
AL
Country
United States
Zip Code
35205

  Publications

Hassan, Abdalla E A; Abou-Elkhair, Reham A I; Parker, William B et al. (2016) 6-Methylpurine derived sugar modified nucleosides: Synthesis and evaluation of their substrate activity with purine nucleoside phosphorylases. Bioorg Chem 65:9-16
Hassan, Abdalla E A; Abou-Elkhair, Reham A I; Riordan, James M et al. (2012) Synthesis and evaluation of the substrate activity of C-6 substituted purine ribosides with E. coli purine nucleoside phosphorylase: palladium mediated cross-coupling of organozinc halides with 6-chloropurine nucleosides. Eur J Med Chem 47:167-74
Tai, C-K; Wang, W; Lai, Y-H et al. (2010) Enhanced efficiency of prodrug activation therapy by tumor-selective replicating retrovirus vectors armed with the Escherichia coli purine nucleoside phosphorylase gene. Cancer Gene Ther 17:614-23
Kang, You-Na; Zhang, Yang; Allan, Paula W et al. (2010) Structure of grouper iridovirus purine nucleoside phosphorylase. Acta Crystallogr D Biol Crystallogr 66:155-62
Hassan, Abdalla E A; Parker, William B; Allan, Paula W et al. (2009) Regioselective metalation of 6-methylpurines: synthesis of fluoromethyl purines and related nucleosides for suicide gene therapy of cancer. Nucleosides Nucleotides Nucleic Acids 28:642-56
Sorscher, E J; Harris, J; Alexander, M et al. (2006) Activators of viral gene expression in polarized epithelial monolayers identified by rapid-throughput drug screening. Gene Ther 13:781-8
Dontsova, Maria V; Gabdoulkhakov, Azat G; Molchan, Olga K et al. (2005) Preliminary investigation of the three-dimensional structure of Salmonella typhimurium uridine phosphorylase in the crystalline state. Acta Crystallogr Sect F Struct Biol Cryst Commun 61:337-40
Silamkoti, A V; Allan, P W; Hassan, A E A et al. (2005) Synthesis and biological activity of 2-fluoro adenine and 6-methyl purine nucleoside analogs as prodrugs for suicide gene therapy of cancer. Nucleosides Nucleotides Nucleic Acids 24:881-5
Toms, Angela V; Wang, Weiru; Li, Yingbo et al. (2005) Novel multisubstrate inhibitors of mammalian purine nucleoside phosphorylase. Acta Crystallogr D Biol Crystallogr 61:1449-58
Zang, Yang; Wang, Wen-Hu; Wu, Shaw-Wen et al. (2005) Identification of a subversive substrate of Trichomonas vaginalis purine nucleoside phosphorylase and the crystal structure of the enzyme-substrate complex. J Biol Chem 280:22318-25

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