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)

The mutagenicity and cytotoxicity of 19 ICR compounds, including 6 reported previously, have been determined in the Chinese hamster ovary/hypoxanthine-guanine phosphoribosyltransferase system. As with other physical and chemical agents, ICR 170 and 191 exhibit a phenotypic expression time of 7 to 9 days, independent of concentrations tested. Thirteen of these compounds are mutagenic. At equimolar concentrations, the compounds with the tertiary amine-type side chain (ICR 217, 340, 355, 368, 170, and 292) are more mutagenic than the compounds with the secondary amine-type side chain (ICR 449, 371, 191, and 372). All secondary amine types show a "plateau" in their concentration-dependent mutagenesis curves at 3 to 4 microM. Shortening of the side chain by one carbon (ICR 171) results in a reduced mutagenicity. Substitution of a sulfur atom for a nitrogen in the side chain (ICR 342) increases both mutagenicity and cytotoxicity. The presence of two 2-chloroethyl groups on the side chain (ICR 220) also results in greatly increased cytotoxicity and mutagenicity. When the 2-chloroethyl group of ICR 340, 372, 292, 191, or 170 is replaced by a 2-hydroxyethyl group (ICR 340-OH, 372-OH, 292-OH, 191-OH, or 170-OH), a mutagenically inactive compound results which remains toxic. Replacement of the amine linkage with an ether linkage (ICR 283) also yields a mutagenically inactive compound.
Cancer Res 1979 Dec
PMID:Mutagenicity and cytotoxicity of nineteen heterocyclic mustards (ICR compounds) in cultured mammalian cells. 9 29

Purine metabolism and reutilization pathways were studied as they applied to normal and leukemic leukocytes. The enzyme activities were expressed in terms of the quantity of protein extracted and per 10(10) cells. Whereas the protein extracted and the enzyme activities from normal lymphocytes were relatively constant, considerable variation was noted in cases of chronic lymphocytic leukemia (CLL). This variability in the properties of the leukemic cells suggests that the difference may be useful in the subclassification of the leukemias. The studies of the complete enzyme system were done with 300 million cells. The extraction of 350,000 normal lymphocytes/mul gave a soluble protein concentration of 1.46+/-0.16 mg protein per ml, and the yield from the same number of CLL lymphocytes varied between 0.72 and 8.32 mg protein per ml. The 5'-nucleotidase activity gave an inverse correlation with the amount of extractable protein. In individual cases of CLL, the protein concentrations and the 5'-nucleotidase activities were found on either side of the normal values. In most cases, the adenosine deaminase of CLL lymphocytic cell extracts was lower than normal, and the adenosine kinase was higher; in the CLL cells, these two enzymes gave a positive correlation with one another. Little or no difference was observed in the activities of the purine nucleoside phosphorylases in extracts of normal or leukemic lymphocytes and granulocytes. The hypoxanthine-guanine and adenine phosphoribosyltransferase activities increased in the leukemic granulocytes but almost always showed a decrease in the CLL lymphocytes when compared with the normal cells. Most of the leukemic cells had greater than normal activities of the enzymes synthesizing phosphoribosyl pyrophosphate when tested with the purines. The total nucleotide produced from adenine and guanine with adenine- and hypoxanthine-guanine phosphoribosyltransferase was about equal in normal and leukemic lymphocytes, but the proportion of the adenosine 5'-triphosphate in the product was much greater with the leukemic cells. This suggested that the ribosyltransferase activities were the same in both types of cells, but the nucleoside kinases and the nucleoside diphosphate kinases were more active in the leukemic cells. Inosine monophosphate dehydrogenase was less active than normal in the CLL cell extracts and was not directly related to the amount of inosine monophosphate generated from hypoxanthine.
Cancer Res 1977 Feb
PMID:Purine metabolic cycle in normal and leukemic leukocytes. 18 45

Concentration dependence of mutation in equigenerational exposures to methyl, ethyl, propyl, and butyl methanesulfonates has been determined in diploid human lymphoblasts and Salmonella typhimurium. Forward mutation was measured at the hypoxanthine guanine phosphoribosyltransferase locus in human lymphoblasts and at the putative guanine phosphoribosyltransferase locus in S. typhimurium. Reverse mutation at the his G46 locus was also measured in S. typhimurium. This analysis and previous reports support the conclusion that S. typhimurium and mammalian cells are essentially equisensitive to the mutagenic effects of ethyl methanesulfonate when concentration and exposure time are taken into account. Comparison of forward and reverse mutation assays in S. typhimurium reveals no important differences in sensitivities for the four compounds studied.
Cancer Res 1978 Jun
PMID:Alkyl methane sulfonate mutation of diploid human lymphoblasts and Salmonella typhimurium. 20 53

We describe an episode of obstructive uropathy produced by xanthine precipitation in the tubules of the kidney of a patient with histiocytic lymphoma during intensive chemotherapy, despite allopurinol therapy. Urinary oxypurine-uric acid ratio suggested a subclinical deficiency of hypoxanthine-guanine phosphoribosyltransferase. Results of an assay of this enzyme confirmed the abnormality. Both parents and three brothers of the patient had normal enzyme activity. The continued importance of adequate hydration for patients who receive allopurinol during initial periods of cancer therapy is emphasized.
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PMID:Xanthine nephropathy during chemotherapy in deficiency of hypoxanthine-guanine phosphoribosyltransferase. 34 39

The mutagenicity of six heterocylic nitrogen mustards (ICR compounds) has been determined in a cultured mammalian cell system by use of resistance to the purine analog 6-thioguanine to select for mutation induction at the hypoxanthine-guanine phosphoribosyltransferase locus in Chinese hamster ovary cells. The six compounds tested are ICR 191, 170, 292, 372, 191-OH, and 170-OH. The first four contain a single 2-chloroethyl group (nitrogen half-mustard) on the side chain and are mutagenic, with the tertiary amine types (170 and 292) 3 to 5 times more mutagenic than the secondary amine types (191 and 372). The remaining two compounds (191-OH and 170-OH) are not mutagenic, indicating that the 2-chloroethyl group is needed for mutation induction.
Cancer Res 1978 Mar
PMID:Mutagenicity of heterocyclic nitrogen mustards (ICR compounds) in cultured mammalian cells. 62 55

In male BALB/c mice, a combination of individually non-lethal doses of 6-mercaptopurine and endotoxin was significantly lethal. In contrast, mice treated with phenobarbital were resistant to this lethal effect. The high levels of thioinosinic acid in mice that were treated with endotoxin contrasted significantly with the levels in phenobarbital-treated mice. On the other hand, the concentration of hypoxanthine was increased by the administration of phenobarbital and decreased by the administration of endotoxin. The sleeping time and levels of pentobarbital hydroxylase found in endotoxin-treated mice were consistent with the lethality and levels of thioinosinic acid. After mice were treated with endotoxin, their sleeping time was prolonged, which agrees with the course of the stimulatory effects of 6-mercaptopurine anabolism. However, there were no significant differences in hypoxanthine-guanine phosphoribosyltransferase. Furthermore, contrary to expectation, there were significant increases in xanthine oxidase after treatment with endotoxin. Thus, the metabolism of 6-mercaptopurine might be modified by hepatic microsomal enzyme activity.
Cancer Res 1977 Oct
PMID:Effects of phenobarbital and endotoxin on the lethality and metabolism of 6-mercaptopurine in male BALB/c mice. 90 14

Nitrobenzylthioinosine (NBMPR), an inhibitor of nucleoside transport, was tested in combination with 1-beta-D-arabinofuranosylcytosine (ara-C) for therapeutic activity against mouse leukemia L1210. NBMPR alone had no activity, whereas therapy with NBMPR and ara-C in combination was significantly better than with ara-C alone. The therapeutic potentiation resulting from the combination of NBMPR and ara-C appeared to be host mediated since NBMPR alone was not toxic to cultured L1210 cells. NBMPR treatment of normal mice increased the plasma half-time of ara-C and decreased rates of urinary excretion of ara-C and 2'-deoxycytidine; however, these effects were not large enough to explain the therapeutic potentiation. Because the drug combination appeared to be no more effective than ara-C alone in therapy of mouse leukemia L1210/TG (a thiopurine-resistant L1210 subline lacking hyposanthine-guanine phosphoribosyltransferase), the host-mediated therapeutic potentiation was attributed in in vivo breakdown of NBMPR to 6-mercaptopurine.
Cancer Res 1975 May
PMID:Combination therapy of mouse leukemia L1210 by 1-beta-D-arabinofuranosylcytosine and 6-[(4-nitrobenzyl)thio]-9-beta-D-ribofuranosylpurine. 112 Mar 8

Constitutional loss or inactivation of one copy of a tumor-suppressor gene, as exemplified by hereditary retinoblastoma, increases the propensity for malignancies by reducing the number of events necessary for the complete loss of the negative regulatory function. We developed a selectable mutation assay employing a human lymphoblastoid cell line (LCL) derived from a heterozygous carrier of 2,8-dihydroxyadenine urolithiasis, adenine phosphoribosyltransferase (APRT) deficiency, for dissecting the second step in loss-of-function mutations and for determining the potential of physical and chemical agents for producing such mutations. The mode of mutational events arising in the wild-type allele of the functionally heterozygous APRT gene resembled that reported for tumor-suppressor genes in malignancies in that mitotic non-disjunctions or recombinations as well as deletions prevailed. Ultraviolet light (UV) was much less efficient in inducing these types of mutations than ionizing radiation. A group of autosomal recessive cancer-prone diseases, including xeroderma pigmentosum (XP), has been characterized as being more susceptible to genomic insults, owing to some defects in DNA processing, such as replication, repair, or recombination. This increased genomic instability may accelerate the gain-of-function mutation at a proto-oncogene and/or the loss-of-function mutation at a tumor-suppressor gene. XP complementation group A (XP-A) LCLs were extremely sensitive to UV-mutagenesis at the hypoxanthine phosphoribosyltransferase (HPRT) locus even at equicytotoxic doses. Some unique mechanism may operate in UV-mutagenesis in XP-A. We have succeeded for the first time in rendering XP-A cells tumorigenic in athymic mice by applying multiple exposures to UV and subsequent treatment with TPA.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Molecular bases for hereditary cancer-prone diseases. 129 55

To understand molecular mechanisms of the mutation fixation process induced by a mutagen and carcinogen, a multi-system approach is suggested to reduce the probability that the results are biased by the assay used. In this light we described our different approaches to answer basic questions on the mutagenesis induced by the chemical carcinogen 4-Nitroquinoline-1-oxide. We determined mutations at the molecular level in three experimental systems: a) in prokaryotes (ss M13mp19 lacZ'/E. coli F'lacZ delta M15); b) in eukaryotes (i) ss and ds pZ189 supF/CV1-P/E.coli lacZam and (ii) HPRT in CHO cells with different repair capacity. We think this type of approach can be used to study the genetic effects of new cancer drugs for which the molecular mechanisms of action at the molecular level are still not well understood. We think to apply the know-how to study mutational spectra in tumor derived tumor suppressor genes.
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PMID:Multi-system approach to study mutagenesis induced by chemical carcinogens. 129 65

The mutagenic potentials of the human bladder carcinogen 4-amino-biphenyl (ABP) and three of its proximate carcinogenic metabolites, N-hydroxy-4-aminobiphenyl (N-OH-ABP), N-hydroxy-4-acetylaminobiphenyl (N-OH-AABP) and N-acetoxy-4-acetylaminobiphenyl (N-OAc-AABP) were tested on a prime human target cell type for carcinogenesis, human uroepithelial cells (HUC). SV-HUC (PC), a near diploid, clonally derived, nontumorigenic SV40-immortalized human uroepithelial cell line that is transformable to tumorigenicity after exposure to ABP and its metabolites, was used for quantitative mutation assays. The end point used was the induction of mutations in the hypoxanthine-guanine phosphoribosyltransferase (HGPRT) locus, selected using 6-thioguanine resistance (TGr). A single, 24-h exposure of SV-HUC to ABP, N-OH-ABP, N-OH-AABP, or N-OAc-AABP caused a statistically significant, dose-dependent increase in mutation frequency resulting in a 2-30-fold increase in the number of TGr mutants in carcinogen-exposed groups compared to untreated controls. These chemicals were similarly mutagenic towards MC-T11, an SV-HUC-derived low grade tumor cell line that was also shown to be responsive to transformation (in a separate study) by ABP, N-OH-ABP, or N-OH-AABP as judged by the generation of higher grade tumors. In contrast, the mutagenic potencies of ABP and N-OH-ABP were lower when tested on a subclone of SV-HUC (BC) that is refractory to transformation by these chemicals. Thus, these data support a model of transformation in which ABP as well as its metabolites contribute to tumorigenic transformation and neoplastic progression of HUC by inducing mutations in susceptible target cell genes.
Cancer Res 1992 Mar 15
PMID:Induction of thioguanine-resistant mutations in human uroepithelial cells by 4-aminobiphenyl and its N-hydroxy derivatives. 131 36


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