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)

We examined the toxicity, mutagenicity, and mutational spectra of N-ethyl-N-nitrosourea (ENU) in three Epstein-Barr virus-transformed human lymphoblastoid cell lines, each with a different DNA repair phenotype. One cell line lacks O6-alkylguanine-DNA alkyltransferase (AGT) activity; another, derived from a patient with xeroderma pigmentosum, complementation group A, lacks nucleotide exicision repair (NER) capability, and the third is competent in both repair functions. ENU-induced toxicity and mutagenicity at the hypoxanthine-guanine phosphoribosyltransferase locus were increased to a similar degree relative to the repair-competent cells in both AGT-deficient and NER-deficient cells. We determined the mutational spectra for ENU by identifying DNA sequence changes at the hypoxanthine-guanine phosphoribosyltransferase locus in at least 26 clones resistant to 6-thioguanine from each cell line. Of the characterized mutations, 89% were single-base pair substitutions. Transitions and transversions were found at AT and GC base pairs in all three cell lines. The biggest difference within the spectra was in the rate of transitions at GC base pairs. Compared to the repair-competent cell line, this mutation was elevated about 8-fold in the AGT-deficient cells and about 3-fold in the NER-deficient cells. We conclude that both AGT and NER play an important role in protecting human cells from the toxic and mutagenic effects of ENU. Furthermore, the mutational spectra suggest that both of these repair systems participate in the repair of O6-ethylguanine adducts.
Cancer Res 1991 Oct 01
PMID:Toxicity, mutagenicity, and mutational spectra of N-ethyl-N-nitrosourea in human cell lines with different DNA repair phenotypes. 165 49

Forty-nine women with breast cancer were enrolled in a prospective, longitudinal study of the genetic damage caused by treatment. Assays of mutant frequency at the hprt locus in peripheral blood lymphocytes were performed at approximately 6-month intervals for 2 years. Treatment consisted of surgery alone or additional tamoxifen, radiotherapy, or chemotherapy in various combinations. At 6 months, there was an elevation of mean mutant frequency compared to initial values (P = 0.004) which persisted for as many as 2 years. A significant elevation at 6 months occurred only in the group of women who received combination chemotherapy (P = 0.005). Within this group, 5 of 15 patients had striking elevations of mutant frequency following chemotherapy (greater than 3 SD). Three of these 5 women had serum folate levels in the deficient range, while only one of 9 patients with lesser responses to chemotherapy were folate deficient. The change in mutant frequency after chemotherapy was inversely related to serum folate levels (P = 0.05) and to the number of years of smoking cigarettes (P = 0.01). We conclude that of the various modalities used to treat breast cancer, only chemotherapy was accompanied by a high risk of somatic mutation. A subset of patients manifested substantial increases in mutant frequency, often in association with low serum folate levels.
Cancer Res 1991 Dec 15
PMID:Factors influencing mutation at the hprt locus in T-lymphocytes: women treated for breast cancer. 174 33

Solar ultraviolet radiation has been associated with the induction of skin cancer. Recent studies have indicated that near-ultraviolet, especially UVB, is mutagenic. Exposure to trivalent inorganic arsenic compounds has also been associated with increased skin cancer prevalence. Trivalent arsenic compounds are not mutagenic per se, but are comutagenic with a number of cancer agents. Here, we test the hypothesis that arsenite enhances skin cancer via its comutagenic action with solar ultraviolet radiation. Irradiation of Chinese hamster V79 cells with UVA (360 nm), UVB (310 nm) and UVC (254 nm) caused a fluence-dependent increase in mutations at the hprt locus. On an energy basis, UVC was the most mutagenic and UVA the least. However, when expressed as a function of toxicity, UVB was more mutagenic than UVC. Nontoxic concentrations of arsenite increased the toxicity of UVA, UVB and UVC. Arsenite acted as a comutagen at the three wavelengths; however, higher concentrations of arsenite were required to produce a significant (P less than 0.05) comutagenic response with UVB. The increased mutagenicity of UVB and UVA by arsenite may play a role in arsenite-related skin cancers.
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PMID:Comutagenesis of sodium arsenite with ultraviolet radiation in Chinese hamster V79 cells. 177 54

The autoradiographic 6-thioguanine-resistant mutant lymphocyte assay and a chromosome aberration assay were used to determine the time-course of appearance and persistence of elevated frequencies of hprt variants and dicentric chromosomes in patients receiving x-irradiation therapy. Twelve cancer patients, treated with 180-200 cGy/day, 5 days/wk, for 3-7 wk, were studied before treatment, at various weekly intervals during treatment, and after treatment. The hprt mutation assays were done with frozen/thawed lymphocytes isolated from aliquots of the same blood samples used for the chromosome aberration assays. The hprt variant frequencies (Vfs) of only 4 of the 7 patients assayed at 2 wk of treatment were elevated over pre-treatment Vfs, but during the 3rd and 4th weeks of treatment there were significant (P less than 0.01) 5- to 15-fold increases in all Vfs. By 6-32 wk after treatment Vfs had fallen to levels only slightly higher than the mean pre-treatment Vf. The frequencies of cells with dicentric chromosomes were significantly increased (P less than 0.01) after 1 wk of radiotherapy, continued to increase during therapy, and remained elevated after treatment. Five multiple sclerosis patients were also studied before and at 2 and 4 wk intervals after treatment with monthly i.v. doses of 750 mg/m2 of cyclophosphamide (CP). There were no significant elevations in chromosome aberrations at these post-treatment sample times. Previous assays for hprt mutants, done with aloquots of the same blood samples (Ammenheuser et al.: Mutat Res 204:509-520, 1988), had shown 8- to 20-fold increases in Vfs 2 wk after the 1st CP treatment. Our results demonstrate the complementary nature of these two human monitoring assays and emphasize the importance of careful selection of optimal sampling times.
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PMID:Comparison of hprt variant frequencies and chromosome aberration frequencies in lymphocytes from radiotherapy and chemotherapy patients: a prospective study. 187 4

Studies from several laboratories worldwide have developed a large database for in vivo hypoxanthine-guanine phosphoribosyltransferase gene mutations in human T-lymphocytes. Sufficient differences have been found thus far between the spectrum for spontaneous mutations in adults and that observed in the fetus to suggest fundamental differences in in vivo mutagenic mechanisms at these two life stages. In adults, only approximately 15% of hypoxanthine-guanine phosphoribosyltransferase mutations have structural alterations on Southern blots, while in the fetus 75% of mutations show alterations of which one-half are deletions of exons 2 and 3. We have now sequenced the breakpoint sites for these specific deletions in 18 mutant lymphocyte clones isolated from 13 normal newborns. Three classes of deletions were found. Each class had the same intron 1 breakpoint but a different intron 3 breakpoint. These mutations have all the signatures of a V(D)J recombinase-mediated event (a 5' consensus heptamer, 3' consensus heptamer and nonamer, nibbling, non-germline-encoded nucleotides, P-nucleotides). At the 3' breakpoint of the most common class (comprising 83% of the mutants) a perfect heptamer can be created by postulating a hairpin loop which could attain a Z-DNA configuration. This feature may indicate recombinase preference for certain DNA structures. These results implicate the V(D)J recombinase in illegitimate events causing mutation in this housekeeping gene during T-cell development. Inactivation of genes involved in the control of growth and differentiation (e.g., tumor suppressor genes) by this mechanism may have important implications for cancer development.
Cancer Res 1991 Nov 01
PMID:V(D)J recombinase-like activity mediates hprt gene deletion in human fetal T-lymphocytes. 193 63

The hprt T-lymphocyte cloning assay, which detects mutations occurring in vivo in humans, has been used to examine mutants induced in patients receiving radioimmunoglobulin therapy (RIT) for cancer. Samples from 13 patients before treatment (controls) and 15 samples from 12 patients after treatment were studied for both mutant frequencies and molecular changes in the hprt mutant T-cell clones. Patients were studied up to 48 months after treatment. Post-RIT patients showed increased mutant frequencies as compared to pre-treatment values. T-cell receptor (TCR) gene analysis of mutant T-cell clones demonstrated that 84% arose independently, both pre- and post-treatment, which is the same proportion as seen in normal individuals. However, several individuals did show large sets of mutants with the same TCR gene rearrangement patterns. Molecular analysis of mutants demonstrated a greater proportion of mutations with hprt gene changes on Southern blots after RIT treatment than before (40% versus 20%). RIT increases the proportion of mutations with total rather than partial gene deletions or other gross structural changes compared to normal individuals or pre-treatment patients. These studies are defining the spectrum for radiation-induced hprt gene mutations in vivo in human T-lymphocytes.
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PMID:In vivo ionizing irradiations produce deletions in the hprt gene of human T-lymphocytes. 194 53

The cytotoxicity and DNA lesions induced by methotrexate (MTX) were compared in wild-type, hypoxanthine-guanine phosphoribosyltransferase-deficient (HGPRT-) and thymidine-kinase-deficient (TK-) HL-60 cells. TK- and HGPRT- cells were approximately 10 and 3 times more sensitive to MTX than wild-type cells, respectively. Following incubation with 2 microM MTX for 16 hr, TK- cells showed a significantly higher number of DNA strand breaks. Concomitantly, DNA fragmentation at the nucleosomal linker region was detected more prominently in TK- cells. Although MTX tended to decrease TTP pools similarly in all 3 cells types, the initial TTP level in TK- cells was only about one-fifth of that found in the wild type. These results indicate that the thymidine salvage pathway has a pivotal role in mediating MTX-induced toxicity and DNA lesions.
Int J Cancer 1991 Apr 22
PMID:Increased methotrexate-induced DNA strand breaks and cytotoxicity following mutational loss of thymidine kinase. 201 62

The isolation of deoxyguanosine-resistant 10T1/2 mouse cell lines following stepwise selection in the presence of increasing concentrations of drug led to the identification of a highly metastatic line, as measured by the ability to form secondary tumors in syngenic mice after intravenous injection. This metastatic deoxyguanosine-resistant mutant was determined to be deficient in hypoxanthine-guanine phosphoribosyltransferase activity, accounting for the resistance to deoxyguanosine. Lectin-binding studies determined that the metastatic potential of high- and low-metastatic revertant clones of this deoxyguanosine-resistant mutant was negatively correlated to soybean agglutinin binding, but not to concanavalin A or wheat germ agglutinin binding. Examination of labelled cell-surface glycoproteins led to the identification of two glycoproteins, gp80 and gp48, which were present on the low-metastatic wild-type cell line but absent from the highly metastatic drug-resistant cells. Our studies suggest that these cell-surface glycoprotein alterations play a role in determining the malignant properties of the cells, and indicate that metastatic variants with the properties described in this report would be useful biological tools for investigations into the roles played by specific cell-surface structures in mechanisms of tumor progression.
J Cancer Res Clin Oncol 1991
PMID:Characterization of deoxyguanosine-resistant hypoxanthine-guanine phosphoribosyltransferase(-)metastatic variants altered in soybean-agglutinin-binding properties and cell-surface glycoproteins. 206 50

Strong evidence points to mutation induction as one mechanism by which changes are introduced into normal cells to convert them into cancer cells. To understand the mechanisms by which mutations are induced in human cells by carcinogens, we are determining the kinds and spectra of mutations induced in the coding region of the hypoxanthine(guanine)phosphoribosyltransferase (hprt) gene. This region, composed of 654 bp, represents nine exons from a 44 kbp gene. To be able to analyze a large number of independent mutants rapidly and economically, we have optimized the conditions for copying mRNA directly from lysates of a small number of cells (e.g., 100) from a 6-thioguanine-resistant clone using reverse transcriptase and oligo(dT)12-18 primers. Then two 20-mer primers, specific for the cDNA of the hprt gene, are used to amplify the first and second strand cDNA 5 x 10(7)-fold during 30 cycles of polymerase chain reaction (PCR). The product (2 to 10 ng) is then purified by ultrafiltration, diluted 1:10, and subjected to an additional 30 cycles of PCR, using two 20-mer primers located just interior to the first set. The amplification product, 5 to 10 ug, is sequenced directly using three other end-labeled primers and Sequenase. To date, we have analyzed 26 mutants induced by (+-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha,epoxy-7,8,9,10-tetrahydrobenzo [a]pyrene and found that 24/26 involved base substitutions. 97% of these involved G.C, predominantly G.C----T.A, distributed over seven exons, with many of the substitutions located in exon 3.
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PMID:Amplification of mRNA of the hprt gene from lysates of mutant human cells and direct DNA sequencing to determine the spectrum of mutations induced by (+/-)-7 beta,8 alpha-dihydroxy-9 alpha,10 alpha, epoxy-7,8,9,10-tetrahydrobenzo[a]pyrene. 211 60

The enzymatic pattern of five enzymes involved in the purine salvage pathway, namely purine nucleoside phosphorylase (EC 2.4.2.1), adenosine deaminase (EC 3.5.4.4), 5'-nucleotidase (EC 3.1.3.5), alkaline phosphatase (EC 3.1.3.1), and hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) has been evaluated both in human intestinal and breast carcinomas and compared to that of normal tissues. A higher level of hypoxanthine-guanine phosphoribosyltransferase was associated with tumor tissues. This metabolic alteration should lead to an elevated synthesis of nucleotides in cancer cells, might confer selective growth advantages to neoplastic tissues, and account, at least in part, for the difficulties encountered in the chemotherapy of human tumors, by using compounds affecting only the purine de novo biosynthesis.
Cancer Biochem Biophys 1990 Jul
PMID:Purine salvage enzyme activities in normal and neoplastic human tissues. 212 39


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