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)

Variants of the mouse hepatoma cell clone inducible for aryl hydrocarbon (benzo(a)pyrene) hydroxylase (AHH) (EC 1. 14. 14.1) activity and deficient in hypoxanthine guanine phosphoribosyl-transferase (EC 2.4.2.8), and human primary lung carcinoma cell clone noninducible for AHH activity and deficient in thymidine kinase (EC 2.7.1.21) were isolated. The variant lines characterized for AHH inducibility and drug resistant phenotype were utilized to study somatic cell hybrids for the expression of AHH induction by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD). In two hybrids AHH activity was not expressed. In view of these results we conclude that aryl hydrocarbon hydroxylase activity is suppressed in AHH noninducible human lung carcinoma x AHH inducible mouse hepatoma cell hybrids.
 ...
PMID:Suppression of aryl hydrocarbon hydroxylase activity in human primary lung carcinoma x mouse hepatoma somatic cell hybrids. 281 4

6-Thio-3-deazaguanine (TDG), a relatively new purine antimetabolite, exhibits significant antitumor activity against a variety of experimental animal tumor models including C3H mammary adenocarcinoma, Lewis lung carcinoma, adenocarcinoma 755, and leukemias L1210 and P388. However, the drug was ineffective against 3-deazaguanine-resistant L1210 (both in vitro and in vivo) and CEM cells (in vitro). The resistant cells appear to lack HGPRTase activity because the extracts from these cell lines failed to convert hypoxanthine to IMP. These data indicate that TDG needs to be activated by hypoxanthine guanine phosphoribosyltransferase prior to its growth inhibitory effects. Cytotoxicity of TDG was completely reversed by hypoxanthine and inosine. TDG inhibited the synthesis of DNA and RNA equally and effectively, whereas the inhibition of protein synthesis required a prolonged drug exposure and appears to be a consequence of the inhibition of DNA and RNA synthesis. Data from these studies suggest that TDG is an effective antitumor agent, and its spectrum of antitumor activity and mechanism of action appears to be different from that of 3-deazaguanine.
 ...
PMID:Antitumor activity and mechanism of action of 6-thio-3-deazaguanine. 381 77

The enzymic capacities of the de novo and the salvage pathways for purine nucleotide synthesis were compared in rat in normal, differentiating, and regenerating liver, and in three hepatomas of widely different growth rates. The activities of the key de novo and salvage enzymes were also determined in mouse lung and Lewis lung carcinoma, in human kidney and liver, and in renal cell carcinoma and hepatocellular carcinomas. A precise and reproducible assay was worked out for measuring the activities of adenine phosphoribosyltransferase (EC 2.4.2.7) and hypoxanthine-guanine phosphoribosyltransferase (HGPRT; EC 2.4.2.8) in crude liver and hepatoma systems. Kinetic studies on the salvage enzymes were carried out in the crude 100,000 X g supernatant fluid from normal liver and rapidly growing hepatoma 3924A. In both tissue extracts, Michaelis-Menten kinetics was observed for adenine phosphoribosyltransferase and HGPRT. The reciprocal plots for 5-phosphoribosyl-1-pyrophosphate (PRPP) of liver and hepatoma enzymes gave apparent KmS of 2 microM for adenine phosphoribosyltransferase and 4 microM for HGPRT, showing two orders of magnitude higher affinities for PRPP than that of the rate-limiting enzyme of de novo purine synthesis, amidophosphoribosyltransferase (EC 2.4.2.14) (Km = 400 to 900 microM). The apparent Km values for adenine of liver and hepatoma adenine phosphoribosyltransferase were 0.6 to 0.9 microM, respectively. For both liver and hepatoma HGPRT, the reciprocal plots for hypoxanthine and guanine yielded the same Km of 3 microM. The specific activities of purine phosphoribosyltransferases were markedly higher than that of amidophosphoribosyltransferase in rat thymus, spleen, testis, bone marrow, colon, liver, kidney cortex, lung, heart, brain, and skeletal muscle, but were lower in the small intestine. In hepatomas and regenerating and differentiating liver, the activities of the salvage enzymes were 2.1- to 32-fold higher than that of amidophosphoribosyltransferase. The purine phosphoribosyltransferase activities were also higher than that of amidophosphoribosyltransferase in Lewis lung carcinoma (8.2- to 32-fold), human renal cell carcinoma (3.5- to 22-fold), and hepatocellular carcinoma (3.4- to 30-fold). The high activities and the high affinity to PRPP of the purine phosphoribosyltransferases might explain the lack of linkage of the behavior of these enzymic activities with proliferation in normal, regenerating, differentiating, or neoplastic tissues. In contrast, the specific activity of the amidophosphoribosyltransferase, which is lower than that of the salvage enzymes, is linked with transformation as it is increased in all examined tumors.4
 ...
PMID:Enzymic capacities of purine de Novo and salvage pathways for nucleotide synthesis in normal and neoplastic tissues. 632 16

Bronchioloalveolar lung carcinoma (BAC) is a unique type of lung cancer with distinguishing pathologic, biologic, epidemiologic, and perhaps etiologic features that set it apart from all other forms of lung cancer, including general adenocarcinoma, into which it is traditionally grouped. Recent studies at our institution have demonstrated a near exponential increase in BAC cases with 25% showing evidence of multifocality. Although some theories suggest that this multifocality is caused by intrapulmonary aerosol/aspiration or lymphatic spread, this study provides evidence for multiclonality as the basis for some cases of multifocal BAC by exploiting a novel strategy for clonality determinations that involves polymerase chain reaction amplification of a 511-base pair region located within the first intron of the human hypoxanthine phosphoribosyltransferase gene, a site that contains inactive X chromosomal obligately methylated HpaII/MspI sites and single-base allelic polymorphisms in 5 to 10% of females. BAC cells, obtained by enzymatic dissociation of different fresh/paraffin-embedded tumoral foci from polymorphic individuals with multilobar or bilateral BAC, were sorted to homogeneity with a fluorescein-conjugated anticarcinoembryonic antigen and then subjected to genomic DNA extraction and HpaII digestion before polymerase chain reaction amplification and subsequent analysis of the product on denaturing gradient gel electrophoresis. The differing migrations of the single homoduplexes generated were indicative of BAC clonal nonidentity or multiclonality in three separate cases. The demonstration of multiclonality in some cases of BAC provides an alternate explanation for multifocality.
 ...
PMID:The multifocality of bronchioloalveolar lung carcinoma: evidence and implications of a multiclonal origin. 752 41

The enzyme hypoxanthine-guanine phosphoribosyltransferase (HGPRT) expressed by the parasite Trypanosoma brucei (Tb) can convert allopurinol, a purine analogue, to corresponding nucleotides with greater efficiency than its human homologue. We have developed a retroviral system that expresses the parasitic enzyme and tested its capacity to activate the prodrug allopurinol to a cytotoxic metabolite. Cytotoxicity assays demonstrated that five non-small cell lung carcinoma cell lines transduced with the construct were sensitized to the prodrug by 2.1- to 7.6-fold compared with control values. This selectivity was not observed in seven other cell lines also expressing the construct, such as breast carcinoma. Assays indicated that enhanced cytotoxicity to allopurinol correlated with induction of apoptosis in lung cancer cells. The selectivity of this suicide gene was not explained either by the TbHGPRT expression or by the allopurinol accumulation. Our study shows that this novel system may represent a therapeutic tool for gene prodrug targeting of lung cancer, considering the fact that allopurinol is well tolerated in humans.
 ...
PMID:A novel parasite-derived suicide gene for cancer gene therapy with specificity for lung cancer cells. 1153 70

Microbial volatile organic compounds (MVOC), metabolites of fungi detected in indoor moulds and in working places in compost facilities are considered as a potential health hazard. Their toxicological relevance, however, is largely unknown and data are rare. The aim of this study was to evaluate in vitro the genotoxic, clastogenic and mutagenic potential of same typical MVOC. For the study of DNA damage human lung carcinoma epithelial A549 cells, V79 Chinese hamster fibroblasts and human peripheral blood cells were exposed and subjected to the alkaline comet assay (single cell gel test). Taking the Chinese hamster V79 cell line as a target clastogenic effects were studied by the micronucleus test and mutagenic effects by the hypoxanthine-guanine-phosphoribosyl transferase gene mutation test (HPRT test). The cytogenic effects of MVOC were assessed by a clonogenic assay using the A549 cell line. The alkylating agent methyl methanesulfonate (MMS) was taken as a positive control. The results indicate that MVOC induced DNA damage is only seen in conditions in which also cytotoxic effects are observed. Clastogenic and mutagenic effects could not be detected.
 ...
PMID:Evaluation of the genotoxic potential of some microbial volatile organic compounds (MVOC) with the comet assay, the micronucleus assay and the HPRT gene mutation assay. 1171 99

The hypoxia-inducible factor 1 (HIF-1) pathway is induced in many tumors and associated with poorer outcome. The hypoxia-responsive transcription factor HIF-1alpha dimerizes with the aryl hydrocarbon receptor nuclear translocator (ARNT), which is also an important binding partner for the aryl hydrocarbon receptor (AhR). AhR is an important mediator in the metabolic activation and detoxification of carcinogens, such as the environmental pollutant benzo[a]pyrene (BaP). We hypothesized that HIF-1alpha activation attenuates BaP-induced AhR-mediated gene expression, which may lead to increased genetic instability and malignant progression. Human lung carcinoma cells (A549) were simultaneously stimulated with CoCl(2), which leads to HIF-1alpha stabilization and varying concentrations of BaP. Both quantitative PCR and immunoblot analysis indicated that induction of the hypoxia response pathway significantly reduced the levels of AhR downstream targets CYP1A1 and CYP1B1 and AhR protein binding to ARNT. We further demonstrate that the BaP-induced hypoxanthine-guanine phosphoribosyltransferase mutation frequency and gamma-H2AX foci were markedly amplified when the HIF-1 pathway was induced. BaP-DNA adducts were only marginally increased, and transient strand breaks were diminished by HIF-1 induction, indicating changes in DNA repair. These data indicate that concurrent exposure of tumor cells to hypoxia and exogenous genotoxins can enhance genetic instability.
 ...
PMID:Diminished carcinogen detoxification is a novel mechanism for hypoxia-inducible factor 1-mediated genetic instability. 2022 66