Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.4.2.8 (hypoxanthine-guanine phosphoribosyltransferase)
 2,527 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Two mammalian cell mutation assays, the HPRT/V79 assay and the TK/mouse lymphoma assay, were compared for their ability to respond to the genotoxic chemicals ethyl methanesulfonate (EMS) and mitomycin C (MMC). Whereas EMS induced a high mutant frequency at both loci, MMC produced few mutants at the hprt locus, but induced a large number of mutants at the tk locus. Southern blotting analysis showed that this difference was due to the type of genetic damage induced by the two chemicals. Intragenic changes ranging from point mutations to loss of the entire gene were recovered as viable mutants at both the hprt and tk loci. Thus, EMS which causes mainly intragenic mutations induced similar mutant frequencies at both loci. The large multilocus deletions induced by MMC, in which the damage was assumed in many cases to extend into a gene essential for growth since most TK mutants were slow-growing, could not be recovered at the hprt locus. Whereas both loci will detect intergenic mutations, mutants carrying large-scale damage are recoverable only at the heterozygous tk locus. At the hemizygous hprt locus no homologous chromosome exists to provide the function of essential genes if these are lost along with hprt in multilocus deletions. Most human cancers develop as a highly complex process involving both gene and multilocus mutations in oncogenes and tumour suppressor genes. Thus the TK/mouse lymphoma assay is a more appropriate in vitro test for the detection of chemicals capable of causing the types of DNA lesions important in human cancer.
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PMID:Molecular analysis of chemically-induced mutations in mammalian cell assays. 2065 Jan 22

When chemotherapy and radiotherapy are effective, they function by inducing DNA damage in cancerous cells, which respond by undergoing apoptosis. Some adverse effects can result from collateral destruction of non-cancerous cells, via the same mechanism. Therapy-related cancers, a particularly serious adverse effect of anti-cancer treatments, develop due to oncogenic mutations created in non-cancerous cells by the DNA damaging therapies used to eliminate the original cancer. Physiologically achievable concentrations of direct apoptosis inducing anti-cancer drugs that target Bcl-2 and IAP proteins possess negligible mutagenic activity, however death receptor agonists like TRAIL/Apo2L can provoke mutations in surviving cells, probably via caspase-mediated activation of the nuclease CAD. In this study we compared the types of mutations sustained in the HPRT and TK1 loci of clonogenically competent cells following treatment with TRAIL or the alkylating agent ethyl methanesulfonate (EMS). As expected, the loss-of-function mutations in the HPRT or TK1 loci triggered by exposure to EMS were almost all transitions. In contrast, only a minority of the mutations identified in TRAIL-treated clones lacking HPRT or TK1 activity were substitutions. Almost three quarters of the TRAIL-induced mutations were partial or complete deletions of the HPRT or TK1 genes, consistent with sub-lethal TRAIL treatment provoking double strand breaks, which may be mis-repaired by non-homologous end joining (NHEJ). Mis-repair of double-strand breaks following exposure to chemotherapy drugs has been implicated in the pathogenesis of therapy-related cancers. These data suggest that TRAIL too may provoke oncogenic damage to the genomes of surviving cells.
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PMID:TRAIL causes deletions at the HPRT and TK1 loci of clonogenically competent cells. 2694 63


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