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

Inhibition of poly (ADP-ribose) synthesis by agents such as 3-aminobenzamide (3-AB) potentiates the cytotoxic, carcinogenic, and clastogenic effects of certain DNA-damaging agents. Experiments were carried out in Chinese hamster ovary cells to compare chromosome aberration production and cytotoxicity with the induction of somatic mutations at the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) and sodium-potassium ATPase loci after treatment with 3-AB in combination with certain monofunctional alkylating agents. On its own, 1 to 10 mM concentrations of 3-AB were not mutagenic, reduced plating efficiencies only slightly, and produced a small elevation in the frequency of chromatid aberrations. In combination with ethyl methanesulfonate (EMS), 3-AB increased cytotoxicity and the frequency of alkylation-induced chromatid aberrations. 3-AB also increased the frequency of EMS and N-methyl-N'-nitro-N-nitrosoguanidine-induced 6-thioguanine-resistant cells (a marker for the HGPRT- phenotype). It had no effect on the frequency of EMS-induced ouabain-resistant cells (a marker for ATPase mutations). All the effects were dose dependent. Larger absolute increases were found with 10 mM 3-AB as compared with 1 mM 3-AB and with 2 mM EMS as compared to 1 mM EMS. The 3-AB-mediated increases in 6-thioguanine-resistant cells, which are often deletion mutations, and the lack of any increase in the frequency of ouabain-resistant cells, which can only arise through point mutation induction, along with the increases in chromosome aberration frequency, suggests that 3-AB increases the frequency of deletion mutations by increasing the frequency and duration of DNA strand breaks.
Cancer Res 1985 Apr
PMID:Comutagenic effects of 3-aminobenzamide in Chinese hamster ovary cells. 397 24

A pancreatic acinar cell-mediated mutagenicity assay was developed as an in vitro model system to study the metabolism of N-nitrosobis(2-oxopropyl)amine (BOP) and N-nitroso(2-hydroxypropyl)(2-oxopropyl)amino (HPOP) into forms mutagenic for Chinese hamster V79 cells. Mutations at the hypoxanthine:guanine phosphoribosyltransferase locus and the Na/K ATPase locus were scored by resistance to 6-thioguanine and ouabain, respectively. The ability of both Syrian golden hamster and Fischer rat pancreatic acinar cells to convert BOP and HPOP to mutagens for V79 cells was investigated in order to examine the basis for species specificity. Acinar cells of both species were capable of activating BOP and HPOP to mutagens for V79 cells in a dose-dependent manner. In the 6-thioguanine resistance assay, rat acinar cells induced higher mutation frequencies than hamster acinar cells with both BOP and HPOP. In the ouabain resistance assay, both cell types induced equivalent levels of mutation with the respective nitrosamines. BOP was a considerably more potent mutagen than HPOP after activation by either cell type. This is consistent with the known in vivo specificity of BOP versus HPOP in the hamster pancreas and suggests that BOP may be activated to mutagenic metabolites by a pathway(s) independent from its enzymatic reduction to HPOP. The comparable abilities of rat and hamster acinar cells to convert BOP or HPOP to mutagenic forms imply that pancreatic metabolic activation alone cannot explain the difference in organotropism of BOP and HPOP in the two species.
Cancer Res 1985 Nov
PMID:Activation of N-nitrosobis(2-oxopropyl)amine and N-nitroso(2-hydroxypropyl)-(2-oxopropyl)amine to mutagens for V79 cells by isolated hamster and rat pancreatic acinar cells. 405 2

We have produced somatic cell hybrids between mouse plasocytoma cells deficient in hypoxanthine phosphoribosyltransferase (P3 x 63 Ag8) and spleen cells derived from mice immunized with purified human plasma fibronectin. We report herein the properties of monoclonal anti-fibronectin antibodies released by eight different clones.
Int J Cancer 1980 Mar 15
PMID:Somatic cell hybrids producing antibodies specific to human fibronectin. 615 31

The mechanism of action of acivicin and tiazofurin was compared in hepatoma 3924A. The results were evaluated by assessing the impact of these drugs on primary targets, the activities of key enzymes, and on secondary and tertiary targets, the concentrations of pools of ribonucleotides and deoxyribonucleotides. The action of acivicin entails inhibition and inactivation of the key enzymes of glutamine utilization in the biosynthesis of purines and pyrimidines. As a result, the GTP and CTP pools were markedly depleted, whereas those of ATP and UTP were unaffected. Acivicin also markedly decreased the concentrations of all 4 deoxynucleoside triphosphates. The nucleotide pools returned to normal or near normal range within 2 to 3 days after a single acivicin injection. The pharmacologic targets of acivicin in anticancer chemotherapy include prominently the activities of glutamine-utilizing enzymes and the pools of GTP and CTP and all 4 dNTP's. These biochemical targets also serve as indicators of acivicin action in cancer cells. The action of tiazofurin in hepatoma cells entails the primary target, IMP dehydrogenase. The subsequent effects include marked enlargement of IMP and PRPP pools and depletion of the pools of GDP and GTP. The increased IMP concentration selectively inhibited the activities of hypoxanthine-guanine phosphoribosyltransferase, but did not affect that of adenine phosphoribosyltransferase. The markedly decreased GTP pool de-inhibited the activity of AMP deaminase which permitted the channeling of AMP to IMP. An important indicator of tiazofurin action is the prolonged depletion of dGTP pools and similar but less pronounced declines in the pools of dCTP and dATP. In contrast, dTTP pools were increased. The crucial biochemical targets and indicators of tiazofurin action in sensitive cancer cells include inhibition of IMP dehydrogenase, a decrease in the concentrations of GDP, GTP, dGTP, dCTP, dATP and marked rise in the pools of IMP, PRPP and dTTP. Measurements of the molecular targets and indicators of drug action should be helpful in identifying cancer cells and tissues sensitive or resistant to the action of acivicin or tiazofurin. Identification of the targets and indicators should also be helpful in the design of frequency of administration of the drugs in combatting animal and human neoplasia.
 ...
PMID:Control of enzymic programs and nucleotide pattern in cancer cells by acivicin and tiazofurin. 620 92

We have established and characterized a diploid cell strain of normal human endothelial cells, RuBa 7E. RuBa 7E cells have an average cloning efficiency of 20% during early passages and undergo approximately 50 doublings in vitro before senescing spontaneously. At confluence, RuBa 7E cells form a homogeneous monolayer of flat polygonal cells. RuBa 7E cells react positively with antibody to human endothelial-specific Factor VIII. The toxic and mutagenic effects of N-methyl-N'-nitro-N-nitrosoguanidine on RuBa 7E cells were studied and are similar to those reported for diploid human fibroblasts. Mutant cells lacking hypoxanthine-guanine phosphoribosyltransferase were selected by their resistance to 6-thioguanine. The spontaneous incidence of mutants was less than or equal to 6 X 10(-6), and the induced incidence was 4.4 X 10(-4) at a survival frequency of 0.05. All 17 mutants that were tested lacked detectable hypoxanthine-guanine phosphoribosyltransferase activity, and none grew in medium containing azaserine and hypoxanthine. Autoradiography showed that mutant cells incorporated radioactive adenine but did not incorporate radioactive hypoxanthine. Unlike human fibroblasts, in which the recovery of 6-thioguanine-resistant mutants is reduced by contact feeding when the inoculum size during selection is increased above 10(4) cells per P60 dish, 5 to 10 X 10(4) RuBa 7E cells can be plated per P60 dish without reducing mutant recovery. This apparent lack of plating density suppression of mutant recovery makes RuBa 7E cells a comparatively compact and economical system for quantifying mutagenesis in diploid human cells. In order to determine whether RuBa 7E cells would undergo a distinct morphological transformation toward cancer in vitro, we infected them with SV40. As early as 14 days postinfection, discrete foci of morphologically transformed, mitotically active cells were seen against a monolayer background of normal cells when cultures were maintained in medium with low serum. Seven of the 33 foci which were obtained were studied for SV40-specific viral T-antigen, and all were positive. The facility with which RuBa 7E cells can be mutagenized and the ease with which morphological transformants can be identified make these cells potentially useful for studies comparing the mutagenic and transforming effects of chemicals and other agents on diploid human cells.
Cancer Res 1981 Mar
PMID:In vitro chemical mutagenesis and viral transformation of a human endothelial cell strain. 625 80

Two new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate (SL-1250) and 4-carbamoylimidazolium 5-olate (SM-108), were investigated for their antitumor activities against 6-mercaptopurine (6-MP)-resistant sublines of P388 and L1210 leukemia. It was found that both resistant sublines exhibited collateral sensitivity instead of cross-resistance to these new antipurine drugs. Since more potent cytotoxic activities of these drugs against 6-MP-resistant cells were observed even in vivo cell culture systems, this collateral sensitivity was proved on a cellular basis. Biochemical studies revealed that 6-MP-resistant sublines of both P388 and L1210 leukemia are deficient in hypoxanthine-guanine phosphoribosyltransferase activity. In these cells, not only the activation of 6-MP to its nucleotide but also the synthesis of guanosine 5'-monophosphate via the salvage pathway seems to be severely restricted. However, SL-1250 and SM-108 can be activated to their nucleotide even in these 6-MP-resistant cells because the activation of these compounds is proceeded by adenine phosphoribosyltransferase. In conclusion, suppression of de novo purine synthesis with SL-1250 and SM-108 seems to be a very efficient means of killing these 6-MP-resistant cells, which lack a salvage pathway for guanosine 5'-monophosphate.
Cancer Res 1982 Mar
PMID:Collateral sensitivity of 6-mercaptopurine-resistant sublines of P388 and L1210 leukemia to the new purine antagonists, 5-carbamoyl-1H-imidazol-4-yl piperonylate and 4-carbamoylimidazolium 5-olate. 627 74

The genotoxicity of benzo(a)pyrene (BP) was investigated in combined cultures of rat hepatocytes and human diploid fibroblasts. Freshly isolated rat hepatocytes were shown to activate BP to a species which bound to and damaged hepatocyte and fibroblast DNA. A significant increase in the hypoxanthine-guanine phosphoribosyltransferase mutation frequency was induced when 10 to 100 microM BP was added to the cocultures. A comparative analysis of the binding of BP metabolites to hepatocyte and fibroblast DNA revealed that approximately 4 times more [3H]BP metabolites were bound to the fibroblast DNA than were bound to the hepatocyte DNA (per microgram DNA). Activation of BP by the fibroblasts themselves was shown not to be the cause of the relatively greater binding of BP to fibroblast DNA than to the hepatocyte DNA. These results suggest that proximate and/or ultimately carcinogenic metabolites of BP are readily released from isolated hepatocytes and that the metabolites are sufficiently stable and long lived so as to bind to the DNA of an adjacent cell. The relative protection of the hepatocytic DNA from BP metabolites that generated in the cytoplasm of the hepatocyte may be significant in view of the observations that the liver is not under normal conditions a target of BP carcinogenicity in vivo.
Cancer Res 1982 Nov
PMID:Mutagenesis and DNA binding of benzo(a)pyrene in cocultures of rat hepatocytes and human fibroblasts. 629 39

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
Cancer Res 1984 Jun
PMID:Enzymic capacities of purine de Novo and salvage pathways for nucleotide synthesis in normal and neoplastic tissues. 632 16

The effect of diethylstilbestrol (DES) on sister chromatid exchange (SCE) induction was measured in four cell lines to determine whether metabolic activation of DES is a factor in its genotoxic potential. Two of these, cell lines derived from a human hepatoblastoma (HepG2-GW) and a rat hepatoma (H4-AG), have been shown previously in our laboratory to be capable of metabolizing several procarcinogens to their active forms. DES, in a dose range of 1 X 10(-8) M to 1 X 10(-5) M, increased SCE frequencies by 50 to 60% in both the rat and human hepatoma lines but had no effect on SCE induction in Chinese hamster lung fibroblasts (V79-GW) or human diploid skin fibroblasts (MGH 2C-GW), both of which are nonmetabolizing cell lines. Furthermore, pretreatment of the responsive cell lines (H4-AG and HepG2-GW) with indomethacin, an inhibitor of prostaglandin synthetase-mediated metabolism of DES, effectively prevented the induction of SCE by DES. DES failed to increase the frequency of hypoxanthine-guanine phosphoribosyltransferase locus mutants in H4-AG cells, over a dose range which induced SCE. These observations suggest that DES induces SCE but does not induce gene mutation. These data strongly support growing evidence that metabolic activation of DES may be an important factor in its genotoxic and carcinogenic mechanisms.
Cancer Res 1984 Sep
PMID:Induction of sister chromatid exchange by diethylstilbestrol in metabolically competent hepatoma cell lines but not in fibroblasts. 633 58

The mutagenicity and cytotoxicity of five antitumor compounds (ellipticines) were investigated in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay and in six strains of Salmonella. All five compounds (ellipticine, 9-methoxyellipticine, 9-hydroxyellipticine, 9-aminoellipticine, and 2-methyl-9-hydroxyellipticinium) were cytotoxic and mutagenic in the Chinese hamster ovary cell hypoxanthine-guanine phosphoribosyltransferase assay in the presence or absence of Aroclor 1254-induced rat liver S9, and all except the last compound were mutagenic in Salmonella. Based on the reversion pattern obtained in various frame-shift and DNA repair-proficient (uvrB+) or -deficient (uvrB) strains of Salmonella in the presence or absence of S9, the first three compounds appear to cause frame-shift mutations by both intercalation and covalent bonding with DNA; thus, these are classified as reactive intercalators. However, 9-aminoellipticine intercalates only weakly and may instead exert its mutagenic activity primarily (or exclusively) by forming a covalent adduct with DNA. Compared to the published antitumor data obtained in mice, the results in Salmonella and Chinese hamster ovary cells suggest that the ability of ellipticine, 9-methoxyellipticine, and 9-hydroxyellipticine to intercalate with DNA, induce frame-shift mutations, and cause cell killing is associated with and may be the basis for their antitumor activity. The observation that the ellipticines are mutagenic in mammalian cells suggests that these antitumor agents may be carcinogenic.
Cancer Res 1983 Aug
PMID:Mutagenicity and cytotoxicity of five antitumor ellipticines in mammalian cells and their structure-activity relationships in Salmonella. 634 86


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