Abstract
The treatment of cancer with common anti-proliferative agents generally suffers from an insufficient differentiation between normal and malignant cells which results in extensive side effects. To enhance the efficacy and reduce the normal tissue toxicity of anticancer drugs, numerous selective tumor therapies have emerged including the highly promising approaches ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy) and PMT (Prodrug Monotherapy). These allow a selective release of cytotoxic agents from non-toxic prodrugs at the tumor site either by targeted antibody-enzyme conjugates, enzyme encoding genes or by exploiting physiological and metabolic aberrations in cancerous tissue. Herein, recent developments in the design and biological evaluation of prodrugs for use in ADEPT, GDEPT and PMT are reviewed. As a highlight, a series of novel glycosidic prodrugs based on the natural antibiotics CC-1065 and the duocarmycins will be discussed which show a therapeutic window of up to one million. Notably, the corresponding drugs have tremendously high cytotoxicities with IC50 values of down to 110 fM.
Keywords: Prodrugs, cancer, ADEPT, GDEPT, PMT, CC-1065, duocarmycins, glycosides, hypoxia, hepatotoxicity
Current Pharmaceutical Design
Title: Prodrugs for Targeted Tumor Therapies: Recent Developments in ADEPT, GDEPT and PMT
Volume: 17 Issue: 32
Author(s): Lutz F. Tietze and Kianga Schmuck
Affiliation:
Keywords: Prodrugs, cancer, ADEPT, GDEPT, PMT, CC-1065, duocarmycins, glycosides, hypoxia, hepatotoxicity
Abstract: The treatment of cancer with common anti-proliferative agents generally suffers from an insufficient differentiation between normal and malignant cells which results in extensive side effects. To enhance the efficacy and reduce the normal tissue toxicity of anticancer drugs, numerous selective tumor therapies have emerged including the highly promising approaches ADEPT (Antibody-Directed Enzyme Prodrug Therapy), GDEPT (Gene-Directed Enzyme Prodrug Therapy) and PMT (Prodrug Monotherapy). These allow a selective release of cytotoxic agents from non-toxic prodrugs at the tumor site either by targeted antibody-enzyme conjugates, enzyme encoding genes or by exploiting physiological and metabolic aberrations in cancerous tissue. Herein, recent developments in the design and biological evaluation of prodrugs for use in ADEPT, GDEPT and PMT are reviewed. As a highlight, a series of novel glycosidic prodrugs based on the natural antibiotics CC-1065 and the duocarmycins will be discussed which show a therapeutic window of up to one million. Notably, the corresponding drugs have tremendously high cytotoxicities with IC50 values of down to 110 fM.
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Cite this article as:
F. Tietze Lutz and Schmuck Kianga, Prodrugs for Targeted Tumor Therapies: Recent Developments in ADEPT, GDEPT and PMT, Current Pharmaceutical Design 2011; 17 (32) . https://dx.doi.org/10.2174/138161211798194459
DOI https://dx.doi.org/10.2174/138161211798194459 |
Print ISSN 1381-6128 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-4286 |
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