Abstract
Normal human cells replicate their DNA with exceptional accuracy. It has been estimated that approximately one error occurs during DNA replication for each 109 to 1010 nucleotides polymerized. In contrast, malignant cells exhibit multiple chromosomal abnormalities and contain tens of thousands of alterations in the nucleotide sequence of nuclear DNA. To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, we have hypothesized that during tumor development, cancer cells exhibit a mutator phenotype. As a defining feature of cancer, the mutator phenotype remains an as-yet unexplored therapeutic target: by reducing the rate at which mutations accumulate it may be possible to significantly delay tumor development; conversely, the large number of mutations in cancer may make cancer cells more sensitive to cell killing by increasing the mutation rate. Here we summarize the evidence for the mutator phenotype hypothesis in cancer and explore how the increased frequency of random mutations during the evolution of human tumors provides new approaches for the design of cancer chemotherapy.
Keywords: Mutator phenotype, lethal mutagenesis, error catastrophe, cancer genome, DNA replication, Malignant cells, Mutations, Chemotherapy, Metastasis, Chromosomal alterations, Nucleotides, Adenocarcinomas, Tumor, DNA sequences, Frameshif mutations, Heterogeneity, Tumorigenesis, Acute myeloid leukemia, Evolution, Genetic diversity, Amplilfication, Primers, Random mutation capture (RMC) assay, Inflammation, Human immunjodeficiency virus, HIV therapy, KP-1212, Koronis Pharmaceuticals, KP-1461, Temozolomide, Radition, Mutagenic therapy
Current Drug Targets
Title: The Mutator Phenotype in Cancer: Molecular Mechanisms and Targeting Strategies
Volume: 11 Issue: 10
Author(s): Marc J. Prindle, Edward J. Fox and Lawrence A. Loeb
Affiliation:
Keywords: Mutator phenotype, lethal mutagenesis, error catastrophe, cancer genome, DNA replication, Malignant cells, Mutations, Chemotherapy, Metastasis, Chromosomal alterations, Nucleotides, Adenocarcinomas, Tumor, DNA sequences, Frameshif mutations, Heterogeneity, Tumorigenesis, Acute myeloid leukemia, Evolution, Genetic diversity, Amplilfication, Primers, Random mutation capture (RMC) assay, Inflammation, Human immunjodeficiency virus, HIV therapy, KP-1212, Koronis Pharmaceuticals, KP-1461, Temozolomide, Radition, Mutagenic therapy
Abstract: Normal human cells replicate their DNA with exceptional accuracy. It has been estimated that approximately one error occurs during DNA replication for each 109 to 1010 nucleotides polymerized. In contrast, malignant cells exhibit multiple chromosomal abnormalities and contain tens of thousands of alterations in the nucleotide sequence of nuclear DNA. To account for the disparity between the rarity of mutations in normal cells and the large numbers of mutations present in cancer, we have hypothesized that during tumor development, cancer cells exhibit a mutator phenotype. As a defining feature of cancer, the mutator phenotype remains an as-yet unexplored therapeutic target: by reducing the rate at which mutations accumulate it may be possible to significantly delay tumor development; conversely, the large number of mutations in cancer may make cancer cells more sensitive to cell killing by increasing the mutation rate. Here we summarize the evidence for the mutator phenotype hypothesis in cancer and explore how the increased frequency of random mutations during the evolution of human tumors provides new approaches for the design of cancer chemotherapy.
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Cite this article as:
J. Prindle Marc, J. Fox Edward and A. Loeb Lawrence, The Mutator Phenotype in Cancer: Molecular Mechanisms and Targeting Strategies, Current Drug Targets 2010; 11 (10) . https://dx.doi.org/10.2174/1389450111007011296
DOI https://dx.doi.org/10.2174/1389450111007011296 |
Print ISSN 1389-4501 |
Publisher Name Bentham Science Publisher |
Online ISSN 1873-5592 |
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