Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P00492 (hypoxanthine-guanine phosphoribosyltransferase)
 2,385 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A pilot study was conducted in patients with advanced non-small cell lung cancer to examine whether the gene-specific damage in mononuclear cells (MNCs) incubated with cisplatin in vitro correlates with chemotherapeutic outcome in cisplatin-based chemotherapy. Twenty-one patients received cisplatin-based chemotherapy, consisting of cisplatin (80 mg/m2 i.v. on day 1), vindesine (3 mg/m2 i.v. on days 1 and 8), with or without mitomycin (8 mg/m2 i.v. on day 1). MNCs from peripheral blood were obtained from each patient before chemotherapy. The cells were incubated with cisplatin for 3 h in vitro and the 2.7-kb fragment of the hypoxanthine phosphoribosyltransferase gene was amplified by PCR for quantitation of DNA damage. There was a 4-fold interpatient variation in DNA damage in MNCs. Seven of 21 patients had a partial response to chemotherapy. When the dose of cisplatin required to reduce amplification of the hypoxanthine phosphoribosyltransferase sequence by 63% (D63 value) of MNCs was compared in each patient (defined by a Poisson distribution as the dose that produced an average of one lesion per single strand of the 2.7-kb fragment), the mean D63 value in patients showing a partial response (n = 7; 52 +/- 11 micrograms/ml) was significantly lower than that in patients showing no change (n = 10; 81 +/- 20 micrograms/ml; P = 0.0045) and in patients with disease progression (n = 4; 115 +/- 34 micrograms/ml; P = 0.0012). The mean D63 in patients with no change was also significantly lower than that in the patients with disease progression (P = 0.0386). Seven (70%) of 10 patients with a D63 value < 70 micrograms/ml were responders. No relationship was observed between the D63 values and hematological and nonhematological toxicities. It is suggested that DNA damage in MNCs incubated by cisplatin treatment in vitro in responders was greater than that in nonresponders. Gene-specific damage in MNCs from peripheral blood incubated with cisplatin in vitro assayed by PCR may predict the chemotherapeutic response in cisplatin-based chemotherapy for non-small cell lung cancer.
Cancer Res 1995 Jun 01
PMID:Correlation of therapeutic outcome in non-small cell lung cancer and DNA damage assayed by polymerase chain reaction in leukocytes damaged in vitro. 775 84

Cysteine conjugate beta-lyase, an enzyme that converts cysteine S-conjugates to free thiols, pyruvate and ammonia, is normally expressed primarily in the liver and kidney. In theory, this selective distribution affords the opportunity to target thiol-containing drugs to these organs and, perhaps, to tumors derived from them. To assess the potential for delivery of such drugs to kidney-derived tissue, we have used a typical beta-lyase substrate, S-(2-benzothiazolyl)-L-cysteine, to measure the beta-lyase activity in normal and tumor tissue of kidneys removed from patients with renal carcinoma. Although considerable heterogeneity in enzyme activity levels was observed in normal and tumor-derived samples, a high proportion of tumor samples had enzyme activity that was at least 50% of that observed in adjacent normal tissue. Frequently, hypoxanthine-guanine phosphoribosyltransferase activity was observed to be greater in the tumor than in normal tissue. These results may aid in the development of therapy for renal carcinomas.
Cancer Biochem Biophys 1995 Jan
PMID:Cysteine conjugate beta-lyase activity in human renal carcinomas. 776 99

The effects of the differentiation-inducing agents sodium butyrate (NaOBt), dimethylsulfoxide (DMSO) and mycophenolic acid (MA), on purine nucleotide metabolism, was studied in an ovarian carcinoma cell line (GZL-8). Exposure to these agents inhibited cell proliferation, but did not affect cell viability. Three hours following exposure, NaOBt and DMSO moderately decelerated purine synthesis de novo, but MA accelerated it three-fold, this being associated with a two-fold increase in the excretion of hypoxanthine and xanthine into the incubation medium. NaOBt and DMSO did not affect the cellular nucleotide content, but MA caused a 73% decrease in GTP content and about a 50% increase in the cellular content of UTP. The following alterations in cellular enzyme activity were observed 72 h following exposure: NaOBt decreased the activity of hypoxanthine-guanine phosphoribosyltransferase and increased the activity of IMP and of AMP 5'-nucleotidases, DMSO increased the activity of IMP 5'-nucleotidase, and MA increased the activity of the two nucleotidases. The results suggest that, in the carcinoma cell line studied, the differentiation process induced by NaOBt and DMSO may be associated with a general shift in the direction of purine metabolism from anabolism to catabolism, whereas that induced by MA is associated with a specific decrease in the production of GTP.
J Cancer Res Clin Oncol 1994
PMID:Effects of differentiation-inducing agents on purine nucleotide metabolism in an ovarian cancer cell line. 779 96

A review of the epidemiological and mechanistic data on 1,3-butadiene indicates that this chemical is a human carcinogen for which the mouse is an appropriate model for assessing human cancer risk. Butadiene is carcinogenic at multiple organ sites in laboratory animals, including the induction of lymphomas in mice, while epidemiological studies have consistently found associations between occupational exposure to butadiene and increased mortality from lymphatic and hematopoietic cancers. Activated oncogenes and inactivated tumor suppressor genes in butadiene-induced tumors in mice are analogous to genetic alterations frequently observed in human cancers. Butadiene is metabolized to mutagenic and carcinogenic epoxides in all mammalian species studied, including humans. These metabolites form N7-alkylguanine adducts which have been detected in liver DNA of mice exposed to butadiene and in urine of exposed workers. Increases in hprt mutations were observed in lymphocytes from mice exposed to butadiene and in occupationally exposed humans. The mutational spectra for butadiene and its epoxide metabolites at the hprt locus in mouse lymphocytes are similar to the mutational spectrum of ethylene oxide; all of these chemicals exhibit a high percentage of frameshift mutations. Ethylene oxide, an alkylating agent that also forms an N7-alkylguanine adduct, was recently classified by the International Agency for Research on Cancer as a human carcinogen. Based on these data, we suggest that cancer induction by ethylene oxide and butadiene involve similar molecular mechanisms.
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PMID:Mechanistic data indicate that 1,3-butadiene is a human carcinogen. 785 43

The molecular basis for putative aberrant splicing of hypoxanthine (guanine) phosphoribosyltransferase (hprt) pre-mRNA in Chinese hamster V-79 cells was determined for 75 independent (+)-7R,8S-dihydroxy-9S,10R-epoxy-7,8,9,10-tetrahydrobenzo[a]-pyrene [(+)-BPDE]-induced and 6 spontaneous 8-azaguanine-resistant mutant clones that had exon deletions in their hprt cDNA. Genomic DNA fragments corresponding to the missing exons and their flanking intron regions were amplified by PCR and sequenced. The results indicated that each of these mutants generated a normal-sized PCR product and resulted from aberrant splicing. For (+)-BPDE-induced aberrant splicing mutants, 81% (61 of 75 clones) had base substitution mutations, 5% (4 of 75 clones) had a single base deletion, and 13% (10 of 75 clones) lacked a detectable mutation in the skipped exon, its flanking intron sequences, or in the upstream donor site of the preceding intron. All mutations at a splice donor site resulted in skipping of the entire upstream neighboring exon, whereas alterations at a splice acceptor site caused skipping of the downstream neighboring exon or activation of a cryptic acceptor site in the downstream exon. Fifty-nine % of the splicing mutants had a mutation occurring at the splice site consensus sequence in the intron, and 28% of the splicing mutants had mutations within exon sequences. Among 21 aberrant splicing mutant clones with a mutation inside an exon sequence, seven were in exon 2, two were in exon 3, and twelve were in exon 4. Evidence is presented that a stemloop structure sequesters the splice donor site of exon 2 in pre-mRNA and plays a role in exon 2 skipping. Mutant clones with mutations stabilizing the proposed stemloop structure inhibited the use of the normal exon 2 splice site which resulted in exon 2 skipping in the hprt mRNA. These mutant clones expressed a mixed population of mRNAs, and both normal-sized and truncated mRNA were formed. Similar to our earlier finding that treatment of V-79 cells with (+)-BPDE resulted in a dose-dependent mutation profile within the coding region of the hprt gene, we also observed the presence of dose-dependence in the profile of (+)-BPDE-induced base substitutions in aberrant splicing mutants. As the dose of (+)-BPDE was decreased, the proportion of base substitution mutations at AT base pairs that affected RNA splicing was increased.
Cancer Res 1995 Apr 01
PMID:Characterization of hprt splicing mutations induced by the ultimate carcinogenic metabolite of benzo[a]pyrene in Chinese hamster V-79 cells. 788 64

The thiopurines 6-thioguanine (6TG) and 6-mercaptopurine (6MP) are cytotoxic to proliferating cells by a mechanism involving incorporation into DNA via the purine salvage pathway, and resistance to these agents can be conferred by lack of the salvage pathway enzyme hypoxanthine-guanine phosphoribosyltransferase. However, human and murine hypoxanthine-guanine phosphoribosyltransferase-deficient leukemia cell lines have been shown to respond to 6TG by growth arrest and differentiation by a mechanism apparently not involving incorporation of 6TG into DNA. If so, leukemia cells resistant to 6MP should still respond to 6TG by growth arrest via an undescribed epigenetic mechanism. To test this, polyclonal 6MP-resistant variants were produced from three human leukemia cell lines, HL-60, U937, and CCRF-CEM. Treatment of both sensitive and resistant cells with 6TG induced growth arrest. The effect of 6TG in the 6MP-sensitive HL-60 and U937 cells was associated with significant loss of viability and DNA fragmentation. In contrast, the 6TG-treated 6MP-resistant cells exhibited a slower decline in viability and no DNA fragmentation. To identify the mechanism by which 6TG may induce growth arrest, tRNA was isolated from 6MP-resistant cells cultured for 48 h with 6TG. 6TG was found to be incorporated into tRNAs normally containing queuine in the anticodon wobble position. These studies may provide a basis for the development of new therapeutic regimens for the treatment of leukemia.
Cancer Res 1994 Oct 15
PMID:6-Thioguanine-induced growth arrest in 6-mercaptopurine-resistant human leukemia cells. 792 70

In order to investigate the metabolic activation pathway of food-derived heterocyclic amines, 2-amino-3-methylimidazo[4,5-f]quinoline (IQ) and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx), cultured cell lines which stably expressed human cytochrome P4501A2 (CYP1A2) and N-acetyltransferases (NATs) were developed by the method of complementary DNA (cDNA) transfection. First, a cell line expressing CYP1A2, designated A2R-5, was established from the cell line CR-68, which was previously established by introducing NADPH-cytochrome P-450 reductase cDNA into Chinese hamster CHL cells. The expression of CYP1A2 in the transfected cells was confirmed by determining sensitivity to aflatoxin B1. As the next step, the A2R-5 as well as CR-68 cells were further transfected with human monomorphic NAT (NAT1) or polymorphic NAT (NAT2) cDNAs. The expression of NAT in the transfected cells was confirmed using p-aminobenzoic acid and sulfamethazine as substrates, while no activity was seen in parental CR-68 and A2R-5 cells. The cell line, ANP-25, which expressed both CYP1A2 and NAT2, was approximately 370- and 100-fold more sensitive to IQ and MeIQx, respectively, than parental CR-68 cells in cytotoxicity assays. There were no clear differences in sensitivity to both compounds among CR-68, A2R-5, and the cell lines which expressed NAT1 alone, NAT2 alone, and CYP1A2 plus NAT1. Mutagenicity of IQ and MeIQx at the hypoxanthine-guanine phosphoribosyltransferase locus was also detectable only in ANP-25 cells but not in A2R-5 or the cell line expressing CYP1A2 plus NAT1. From these results, it is proposed that both CYP1A2 and NAT2 (but not NAT1) are required for mutagenic activation of these compounds, implying that acetylator polymorphism may be an important risk factor in the carcinogenicity of these compounds.
Cancer Res 1994 Jul 01
PMID:Stable expression of human CYP1A2 and N-acetyltransferases in Chinese hamster CHL cells: mutagenic activation of 2-amino-3-methylimidazo[4,5-f]quinoline and 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline. 801 61

In cancer cells, particularly in leukaemic cells, guanylate biosynthesis is up-regulated as shown by the increased activities of IMP dehydrogenase, the rate-limiting enzyme of de novo GTP biosynthesis, and of the salvage enzyme, hypoxanthine-guanine phosphoribosyltransferase (HGPRT). In enzyme pattern-targeted chemotherapy, tiazofurin inhibits IMP dehydrogenase activity in cancer cells and allopurinol-induced high serum hypoxanthine levels inhibit HGPRT activity. A triad of responses was observed in the blast cells of patients treated with tiazofurin infusions: chemotherapy, induced differentiation, and down-regulation of c-Ki-ras and c-myc oncogenes. Tiazofurin was synergistic in cytotoxicity and in causing differentiation with ribavirin, retinoic acid, and gemcitabine [corrected]. Induced differentiation plays an important role in the overall impact of antipurine agents.
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PMID:Role of differentiation induction in action of purine antimetabolites. 803 45

The effect of human O6-methylguanine-DNA methyltransferase (MGMT) on the cytotoxicity, the mutagenicity, and the specific kinds of base substitutions induced by N-methyl-N'-nitro-N-nitrosoguanidine (MNNG) were examined in non-MGMT transfected Chinese hamster ovary cells (CHOM cells) and in those cells which had been transfected with human MGMT complementary DNA (AGT cells). AGT cells containing a high level of human MGMT activity were markedly more resistant to the cytotoxic and mutagenic effects of MNNG than CHOM cells which had no detectable MGMT activity. The dosages of MNNG which reduced to 50% of colony forming ability were estimated to be 0.8 microM for CHOM and 10 microM for AGT cells. The induction frequency of 6-thioguanine-resistant cells was significantly declined in AGT cells. At 4 microM MNNG, this frequency was declined from 273 mutants/10(6) viable CHOM cells to 13 mutants/10(6) viable AGT cells. The entire coding region of the hypoxanthine (guanine) phosphoribosyltransferase (hprt) gene in 37 AGT and 22 CHOM mutants was characterized by direct sequencing of the mRNA-polymerase chain reaction-amplified complementary DNA. Base changes at the intron-exon boundaries of the hprt DNA in the splicing mutants were further examined. Those results indicated that G to A transitions were significantly reduced in MNNG-treated AGT cells (chi 2 test, P < 0.001), suggesting that O6-methylguanine was repaired error free by human MGMT. In contrast, no difference arose in the frequencies of T to C transitions induced by MNNG in these two populations. All of the G to A transitions induced in AGT cells were located on the nontranscribed strand, assuming that the causative lesion was O6-methylguanine (P < 0.05). Such a strand specificity was not observed in CHOM mutants. Most of the G to A transitions observed in CHOM mutants were located at the middle guanine of 5'-GGPu sequences. Transitions observed at these sites, particularly 5'-GGG, were significantly reduced in AGT mutants (P < 0.05). Our results have suggested that human MGMT specifically repairs O6-methylguanine with a preference to remove those located on the transcribed strand and middle guanine of 5'-GGG.
Cancer Res 1994 Jul 15
PMID:Strand- and sequence-specific attenuation of N-methyl-N'-nitro-N-nitrosoguanidine-induced G.C to A.T transitions by expression of human 6-methylguanine-DNA methyltransferase in Chinese hamster ovary cells. 803 7

The detection of an increase in the frequency of mutants in the hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene of circulating T-cells has been proposed as a method to evaluate the biological effects of human exposure to environmental mutagens. We exposed adult human T-cells in vitro to 1-nitrosopyrene (1-NOP), a partially reduced metabolite of 1-nitropyrene, a ubiquitous environmental carcinogen. In populations of T-cells from two unrelated donors, a dose of 1-NOP that reduced survival to 40% of the untreated cells increased the HPRT mutant frequency 6 to 7 times over the background frequency of 5 x 10(-6). The coding region of 35 independent mutants was amplified by polymerase chain reaction and sequenced. Single base substitutions were found in 63% of the mutants (22 of 35). These were distributed randomly throughout the gene. Most of the substitutions (82%) involved G-C base pairs, mainly G.C-->A.T transitions and G.C-->T.A transversions. Fifteen mutants were lacking one or more exons; 9 of the 15 were lacking exons 2 and 3. Examination showed that at least four of the latter had resulted from V(D)J recombinase acting illegitimately to recombine sites located in introns 1 and 3 of the HPRT gene. T-cells from a second unrelated donor were exposed to 1-NOP and 38 additional independent mutants were analyzed. The results indicated that such mutations occurred at a frequency of 2.4 x 10(-6) compared to a background frequency of less than 0.3 x 10(-6). This recombinase, which plays an important role in leukemogenesis, is normally present in developing, but not mature, B- and T-cells such as those used here as target cells for 1-NOP. The present study is the first report showing that exposure to an environmental carcinogen can cause mutations induced by the action of this enzyme.
Cancer Res 1994 Aug 01
PMID:Kinds and locations of mutations induced in the hypoxanthine-guanine phosphoribosyltransferase gene of human T-lymphocytes by 1-nitrosopyrene, including those caused by V(D)J recombinase. 803 53


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