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)

We utilize T-cell HPRT mutations to monitor exposure to environmental mutagens in siblings of children who have developed cancer at a persistently high rate in Toms River, New Jersey, U.S.A. A preliminary epidemiological study has found a statistically-significant association between drinking public water (by pregnant mother or infant) and subsequent risk for childhood cancer. Three potential sources of mutagenic exposures in Toms River may have increased the rate of carcinogenic initiation significantly in children: 1. Benzidine-based, other azo dye and anthraquinone dye wastes released by Ciba-Geigy, 2. Styrene-acrylonitrile (SAN) trimer and other plastic wastes of Union Carbide, and 3. Radium-224, present in unusually high concentrations in the Cohansey aquifer. Specific patterns of HPRT mutations are utilized to distinguish these various potential sources of carcinogenic exposures in the drinking water of families with childhood cancer and to differentiate chemically or radiologically induced cancers from those which occur spontaneously.
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PMID:Distinguishing potential sources of genotoxic exposure via HPRT mutations. 1113 Sep 45

The survival rates of children treated for cancer have dramatically increased after the development of standardized multiple-modality treatment protocols. As a result, there is a rapidly growing population of pediatric cancer survivors in which the long-term genotoxic effects of chemotherapeutic intervention is unknown. To study the genotoxic effects of antineoplastic treatment in children, we performed a comparative analysis of the changes in the frequency of somatic mutations (Mfs) at the hypoxanthine-guanine phosphoribosyltransferase (HPRT)-reporter gene in children treated for acute lymphocytic leukemia (ALL). We measured HPRT Mfs from 130 peripheral blood samples from 45 children with ALL (13, low risk; 22, standard risk; and 10, high risk) from the time of diagnosis, as well as during and after the completion of therapy. We observed a significant increase in mean HPRT Mfs during each phase of therapy (diagnosis, 1.4 x 10(-6); consolidation, 52.1 x 10(-6); maintenance, 93.2 x 10(-6); and off-therapy, 271.7 x 10(-6)) that were independent of the risk group treatment protocol used. This 200-fold increase in mean somatic Mf remained elevated years after the completion of therapy. We did not observe a significant difference in the genotoxicity of each risk group treatment modality despite differences in the compositional and clinical toxicity associated with these treatment protocols. These findings suggest that combination chemotherapy used to treat children with ALL is quite genotoxic, resulting in an increased somatic mutational load that may result in an elevated risk for the development of multi-factorial diseases, in particular second malignancies.
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PMID:Genotoxicity of therapeutic intervention in children with acute lymphocytic leukemia. 1523 55

The development of risk-directed treatment protocols over the last 25 years has resulted in an increase in the survival rates of children treated for cancer. As a consequence, there is a growing population of pediatric cancer survivors in which the long-term genotoxic effects of chemotherapy is unknown. We previously reported that children treated for acute lymphocytic leukemia have significantly elevated somatic mutant frequencies at the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene in their peripheral T cells. To understand the molecular etiology of the increase in mutant frequencies following chemotherapy, we investigated the HPRT mutation spectra and the extent of clonal proliferation in 562 HPRT T cell mutant isolates of 87 blood samples from 47 subjects at diagnosis, during chemotherapy, and postchemotherapy. We observed a significant increase in the proportion of CpG transitions following treatment (13.6-23.3%) compared with healthy controls (4.0%) and a significant decrease in V(D)J-mediated deletions following treatment (0-6.8%) compared with healthy controls (17.0%). There was also a significant change in the class type percentage of V(D)J-mediated HPRT deletions following treatment. In addition, there was a >5-fold increase in T cell receptor gene usage-defined mean clonal proliferation from diagnosis compared with the completion of chemotherapeutic intervention. These data indicate that unique genetic alterations and extensive clonal proliferation are occurring in children following treatment for acute lymphocytic leukemia that may influence long-term risks for multifactorial diseases, including secondary cancers.
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PMID:Analysis of genetic alterations and clonal proliferation in children treated for acute lymphocytic leukemia. 1695 Nov 56

The impact of maternal exposure to carcinogens during pregnancy on childhood cancer risk may be especially relevant for genetically susceptible infants. A molecular epidemiological approach, which has the potential to characterize processes between exposure and subsequent health effects in newborns by using biomarkers, is expected to provide valuable information for actually identifying such vulnerable neonates. Therefore, biomarkers of exposure (e.g. levels of cotinine and metals in cord blood), biomarkers of the biologically relevant dose (e.g. DNA and protein adducts) and biomarkers of early effects (e.g. the occurrence of somatic mutations in cord blood) have been studied in relation to birth outcomes. In this MiniReview, the most important data concerning these biomarker studies in relation to potential adverse health effects in neonates will be summarized and will be compared to the outcome of a small study population (59 mother-child pairs) in which all these biomarkers were assessed simultaneously. Overall, it can be concluded that plasma cotinine levels, macromolecule-carcinogen adduct levels and hypoxanthine phosphoribosyltransferase mutant frequencies are increased in cord blood of neonates of mothers who were exposed during pregnancy and their levels correlated with proxies of health effects, such as reduced birth weight. Moreover, DNA damage was found to be the highest in those neonates that carried risk alleles in genes that code for biotransformation enzymes. These results were confirmed in our study, which indicates that it is possible to identify a susceptible subgroup of newborns. In summary, there is a reason for profound concern of genotoxic effects in newborns of exposed mothers.
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PMID:Characterization of the exposure-disease continuum in neonates of mothers exposed to carcinogens during pregnancy. 1822 63