Abstract
Escherichia coli purine nucleoside phosphorylase (PNP) catalyzes the cleavage of 9-(2-deoxy-β-Dribofuranosyl)- 6-methylpurine (MeP-dR), while human PNP does not. MeP-dR is well tolerated while the cleavage product, 6-methylpurine (MeP), is highly cytotoxic. This clinical profile suggests an anticancer gene therapy strategy in which solid tumors are transfected with the gene for E. coli PNP. Tumor cells expressing E. coli PNP will liberate MeP and be killed. Furthermore, MeP released from the cell via the purine transport system will enter nearby cells, resulting in bystander killing of tumor cells. To reduce toxicity resulting from activation of MeP-dR by intestinal tract flora, we redesigned the E. coli PNP active site to cleave prodrugs that are not cleaved by wild type E. coli PNP. It is possible that the variation of substrate specificity among enzymes that cleave nucleosides will have broader application in the gene therapy approach to prodrug activation. Here we review progress in the development of E. coli PNP anticancer gene therapy. We also review the structural basis for activity of nucleoside phosphorylases and suggest future directions for the development of activating enzymes for suicide gene therapy.
Keywords: activating enzyme, prodrug, cancer, suicide gene therapy, protein redesign, 6-methylpurine, glycosidic bond, bystander killing
Current Topics in Medicinal Chemistry
Title: PNP Anticancer Gene Therapy
Volume: 5 Issue: 13
Author(s): Yang Zhang, William B. Parker, Eric J. Sorscher and Steven E. Ealick
Affiliation:
Keywords: activating enzyme, prodrug, cancer, suicide gene therapy, protein redesign, 6-methylpurine, glycosidic bond, bystander killing
Abstract: Escherichia coli purine nucleoside phosphorylase (PNP) catalyzes the cleavage of 9-(2-deoxy-β-Dribofuranosyl)- 6-methylpurine (MeP-dR), while human PNP does not. MeP-dR is well tolerated while the cleavage product, 6-methylpurine (MeP), is highly cytotoxic. This clinical profile suggests an anticancer gene therapy strategy in which solid tumors are transfected with the gene for E. coli PNP. Tumor cells expressing E. coli PNP will liberate MeP and be killed. Furthermore, MeP released from the cell via the purine transport system will enter nearby cells, resulting in bystander killing of tumor cells. To reduce toxicity resulting from activation of MeP-dR by intestinal tract flora, we redesigned the E. coli PNP active site to cleave prodrugs that are not cleaved by wild type E. coli PNP. It is possible that the variation of substrate specificity among enzymes that cleave nucleosides will have broader application in the gene therapy approach to prodrug activation. Here we review progress in the development of E. coli PNP anticancer gene therapy. We also review the structural basis for activity of nucleoside phosphorylases and suggest future directions for the development of activating enzymes for suicide gene therapy.
Export Options
About this article
Cite this article as:
Zhang Yang, Parker B. William, Sorscher J. Eric and Ealick E. Steven, PNP Anticancer Gene Therapy, Current Topics in Medicinal Chemistry 2005; 5 (13) . https://dx.doi.org/10.2174/156802605774463105
DOI https://dx.doi.org/10.2174/156802605774463105 |
Print ISSN 1568-0266 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4294 |
Call for Papers in Thematic Issues
Chemistry Based on Natural Products for Therapeutic Purposes
The development of new pharmaceuticals for a wide range of medical conditions has long relied on the identification of promising natural products (NPs). There are over sixty percent of cancer, infectious illness, and CNS disease medications that include an NP pharmacophore, according to the Food and Drug Administration. Since NP ...read more
Current Trends in Drug Discovery Based on Artificial Intelligence and Computer-Aided Drug Design
Drug development discovery has faced several challenges over the years. In fact, the evolution of classical approaches to modern methods using computational methods, or Computer-Aided Drug Design (CADD), has shown promising and essential results in any drug discovery campaign. Among these methods, molecular docking is one of the most notable ...read more
Drug Discovery in the Age of Artificial Intelligence
In the age of artificial intelligence (AI), we have witnessed a significant boom in AI techniques for drug discovery. AI techniques are increasingly integrated and accelerating the drug discovery process. These developments have not only attracted the attention of academia and industry but also raised important questions regarding the selection ...read more
From Biodiversity to Chemical Diversity: Focus of Flavonoids
Flavonoids are the largest group of polyphenols, plant secondary metabolites arising from the essential aromatic amino acid phenylalanine (or more rarely from tyrosine) via the phenylpropanoid pathway. The flavan nucleus is the basic 15-carbon skeleton of flavonoids (C6-C3-C6), which consists of two phenyl rings (A and B) and a heterocyclic ...read more
- Author Guidelines
- Graphical Abstracts
- Fabricating and Stating False Information
- Research Misconduct
- Post Publication Discussions and Corrections
- Publishing Ethics and Rectitude
- Increase Visibility of Your Article
- Archiving Policies
- Peer Review Workflow
- Order Your Article Before Print
- Promote Your Article
- Manuscript Transfer Facility
- Editorial Policies
- Allegations from Whistleblowers
- Announcements
Related Articles
-
Malignant Intracranial High Grade Glioma and Current Treatment Strategy
Current Cancer Drug Targets Immunomodulatory Activity of MicroRNAs: Potential Implications for Multiple Myeloma Treatment
Current Cancer Drug Targets Recent Approaches and Success of Liposome-Based Nano Drug Carriers for the Treatment of Brain Tumor
Current Drug Delivery Meet Our Editorial Board Member
Current Medicinal Chemistry Serum Biochemical Markers of Brain Injury
Mini-Reviews in Medicinal Chemistry Production of Retroviral Vectors: Review
Current Gene Therapy Carbohydrate-Metal Complexes and their Potential as Anticancer Agents
Current Medicinal Chemistry Effect of DNA Repair Deficiencies on the Cytotoxicity of Drugs Used in Cancer Therapy - A Review
Current Medicinal Chemistry Recurrent Scalp Lesions from Glioblastoma: Case Report and Literature Review
Current Cancer Therapy Reviews Targeting Tumor Proteasome with Traditional Chinese Medicine
Current Drug Discovery Technologies The Role of the Endocannabinoid System in Alzheimers Disease: Facts and Hypotheses
Current Pharmaceutical Design Dietary Prevention of Cancer: Anticancer and Antiangiogenic Properties of Green Tea Polyphenols
Medicinal Chemistry Reviews - Online (Discontinued) A Fluorescent Alkyllysophospholipid Analog Exhibits Selective Cytotoxicity Against the Hormone-Insensitive Prostate Cancer Cell Line PC3
Anti-Cancer Agents in Medicinal Chemistry Novel Strategies in Cancer Therapeutics: Targeting Enzymes Involved in Cell Cycle Regulation and Cellular Proliferation
Current Cancer Drug Targets Dysfunctions of the Diffusional Membrane Pathways Mediated Hemichannels in Inherited and Acquired Human Diseases
Current Vascular Pharmacology State of Research Tracks and Property Protection of Photodynamic Sensitizers and Delivery Methodologies
Recent Patents on Chemical Engineering Cell-penetrating Peptide-based Intelligent Liposomal Systems for Enhanced Drug Delivery
Current Pharmaceutical Biotechnology Cancer: A Problem of Developmental Biology; Scientific Evidence for Reprogramming and Differentiation Therapy
Current Drug Targets Oxidative Stress and Mitochondrial Dysfunction in Type 2 Diabetes
Current Pharmaceutical Design Nutlins and Ionizing Radiation in Cancer Therapy
Current Pharmaceutical Design