Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.5.4.1 (cytosine deaminase)
 747 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic information should be accurately transmitted from cell to cell; conversely, the adaptation in evolution and disease is fueled by mutations. In the case of cancer development, multiple genetic changes happen in somatic diploid cells. Most classic studies of the molecular mechanisms of mutagenesis have been performed in haploids. We demonstrate that the parameters of the mutation process are different in diploid cell populations. The genomes of drug-resistant mutants induced in yeast diploids by base analog 6-hydroxylaminopurine (HAP) or AID/APOBEC cytosine deaminase PmCDA1 from lamprey carried a stunning load of thousands of unselected mutations. Haploid mutants contained almost an order of magnitude fewer mutations. To explain this, we propose that the distribution of induced mutation rates in the cell population is uneven. The mutants in diploids with coincidental mutations in the two copies of the reporter gene arise from a fraction of cells that are transiently hypersensitive to the mutagenic action of a given mutagen. The progeny of such cells were never recovered in haploids due to the lethality caused by the inactivation of single-copy essential genes in cells with too many induced mutations. In diploid cells, the progeny of hypersensitive cells survived, but their genomes were saturated by heterozygous mutations. The reason for the hypermutability of cells could be transient faults of the mutation prevention pathways, like sanitization of nucleotide pools for HAP or an elevated expression of the PmCDA1 gene or the temporary inability of the destruction of the deaminase. The hypothesis on spikes of mutability may explain the sudden acquisition of multiple mutational changes during evolution and carcinogenesis.
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PMID:Genome-wide mutation avalanches induced in diploid yeast cells by a base analog or an APOBEC deaminase. 2403 93

One of the important strategies for the treatment of cancer is gene therapy which has the potential to exclusively eradicate malignant cells, without any damage to the normal tissues. Gene-directed enzyme prodrug therapy (GDEPT) is a two-step gene therapy approach, where a suicide gene is directed to tumor cells. The gene encodes an enzyme that expressed intracellularly where it is able to convert a prodrug into cytotoxic metabolites. Various delivery systems have been developed to achieve the appropriate levels of tumor restricted expression of chemotherapeutic drugs. Nowadays, mesenchymal stem cells (MSCs) have been drawing great attention as cellular vehicles for gene delivery systems. Inherent characteristics of MSCs make them particularly attractive gene therapy tools in cell therapy. They have been used largely for their remarkable homing property toward tumor sites and availability from many different adult tissues and show anti-inflammatory actions in some cases. They do not stimulate proliferative responses of lymphocytes, suggests that MSCs have low immunogenicity and could avoid immune rejection. This review summarizes the current state of knowledge about genetically modified MSCs that enable to co-transduce a variety of therapeutic agents including suicide genes (i.e., cytosine deaminase, thymidine kinase) in order to exert potent anti-carcinogenesis against various tumors growth. Moreover, we highlighted the role of exosomes released from MSCs as new therapeutic platform for targeting various therapeutic agents.
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PMID:Mesenchymal stem cells: A new platform for targeting suicide genes in cancer. 2870 13