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 determined clonality of thyroid tumors from female patients who had restriction fragment length polymorphisms (RFLP) in the X chromosome genes hypoxanthine phosphoribosyltransferase (HPRT) or phosphoglycerate kinase (PGK). We screened normal thyroid tissue from 59 female patients; of the informative cases 14 were heterozygous for a Bgl I site on PGK and 4 were heterozygous for a Bam HI site on HPRT. In monoclonal tumors, one of the polymorphic alleles was selectively digested after additional digestion with Hpa II, a methylation sensitive enzyme, whereas in polyclonal tissue both were decreased to a similar extent. Normal thyroid tissue from all patients showed a polyclonal pattern. Of the 18 tumors studied, 12 were solitary thyroid nodules, and 6 were obtained from multinodular goiters (MNG). The following were monoclonal: 6/6 follicular adenomas, 2/2 follicular carcinomas, and 1/1 anaplastic carcinoma. Two of the three papillary carcinomas showed intermediate patterns, possibly due to contaminating effects of stromal tissue present in most of these neoplasms. Of the six nodules from MNG, four were polyclonal. The two largest gave a distinct monoclonal pattern. Most solitary thyroid tumors are monoclonal, supporting a somatic cell mutation model of thyroid neoplasm formation. Nodules from MNG are largely hyperplastic, although monoclonal neoplasms do occasionally arise within these glands. The specific somatic mutations leading to clonal expansion and determination of tumor phenotype are presently unknown.
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PMID:Clonal composition of benign and malignant human thyroid tumors. 197 72

Using 32P-postlabelling, evidence of DNA adduct formation was sought in six mammalian cell lines, namely Chinese hamster ovary (CHO), human cervical carcinoma (HeLa S3), mouse lymphoma L5178Y tk +/- and L5178Y wild-type, human lymphoblastoid TK6 and Chinese hamster V79, following treatment with benzidine (BZD) in the presence of S-9. Adduct formation was also determined in calf thymus DNA reacted in vitro with N-hydroxy-N'-acetyl-BZD, and in liver DNA from mice given a single intraperitoneal injection of BZD. DNA adducts were detected in the calf thymus DNA sample and in mouse liver DNA, but not in DNA from any of the six cell lines. The absence of adduct formation is consistent with the lack of mutagenicity of BZD in CHO, and V79 and in L5178Y cells at the hprt locus, and in TK6 cells at the tk and hprt loci. These results also suggest that the observed mutagenicity of BZD at the tk locus in L5178Y cells may be due to a mechanism(s) not involving covalent binding to DNA.
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PMID:Determination of benzidine--DNA adduct formation in CHO, HeLa, L5178Y, TK6 and V79 cells. 218 24

1. Guanine-7-oxide is a novel purine antibiotic produced by a Streptomyces species, ATCC 39364. 2. Guanine-7-oxide is cytotoxic to murine and human leukemia cells in vitro at sub-micromolar concentrations. Murine and human carcinoma cells are much less sensitive. 3. Guanine-7-oxide has significant in vivo antitumor activity, particularly against the intraperitoneal and subcutaneous L1210 leukemia systems. 4. Guanine-7-oxide, at highly cytotoxic concentrations, has little effect on biosynthesis of RNA and DNA. 5. There is preliminary evidence for an early effect of guanine-7-oxide on cellular protein synthesis. 6. Guanine, guanosine and hypoxanthine protect cells from the cytotoxicity of guanine-7-oxide. 7. Activation of guanine-7-oxide requires the presence of the enzyme hypoxanthine-guanine phosphoribosyltransferase in the target cells. 8. Cytotoxic concentrations of guanine-7-oxide do not cause depletion of cellular guanine nucleotides during a two hr incubation period. 9. Guanine-7-oxide is converted within mouse and human cells to a metabolite with chromatographic mobility corresponding to a ribonucleoside 5'-triphosphate.
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PMID:Biochemical pharmacology and experimental chemotherapy studies with guanine-7-oxide, a novel purine antibiotic. 367 7

Most drugs available for cancer chemotherapy exert their effects through cytodestruction. Although significant advances have been attained with these cytotoxic agents in several malignant diseases, response is often accompanied by significant morbidity and many common malignant tumours respond poorly to existing cytotoxic therapy. Development of chemotherapeutic agents with non-cytodestructive actions appears desirable. Considerable evidence exists which indicates that (a) the malignant state is not irreversible and represents a disease of altered maturation, and (b) some experimental tumour systems can be induced by chemical agents to differentiate to mature end-stage cells with no proliferative potential. Thus, it is conceivable that therapeutic agents can be developed which convert cancer cells to benign forms. To study the phenomenon of blocked maturation, squamous carcinoma SqCC/Y1 cells were employed in culture. Using this system it was possible to demonstrate that physiological levels of retinoic acid and epidermal growth factor were capable of preventing the differentiation of these malignant keratinocytes into a mature tissue-like structure. The terminal differentiation caused by certain antineoplastic agents was investigated in HL-60 promyelocytic leukaemia cells to provide information on the mechanism by which chemotherapeutic agents induce cells to by-pass a maturation block. The anthracyclines aclacinomycin A and marcellomycin were potent inhibitors of N-glycosidically linked glycoprotein biosynthesis and transferrin receptor activity, and active inducers of maturation; temporal studies suggested that the biochemical effects were associated with the differentiation process. 6-Thioguanine produced cytotoxicity in parental cells by forming analog nucleotide. In hypoxanthine-guanine phosphoribosyltransferase negative HL-60 cells the 6-thiopurine initiated maturation; this action was due to the free base (and possibly the deoxyribonucleoside), a finding which separated termination of proliferation due to cytotoxicity from that caused by maturation.
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PMID:The 1985 Walter Hubert lecture. Malignant cell differentiation as a potential therapeutic approach. 389 54

To study the activation and cytotoxic mechanism of bredinin (4-carbamoyl-1-beta-D-ribofuranosylimidazolium-5-olate), a novel nucleoside antibiotic with potent cytotoxic and immunosuppressive effects, we isolated in a single-step manner five mutants resistant to 10 microM bredinin from cultured mouse mammary carcinoma FM3A cells mutagenized with N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). Such resistant (Brdr) mutants were 15- to 19-fold less sensitive to the antibiotic than wild-type cells and maintained stably their resistant phenotypes in the absence of bredinin for more than 3 months. They were cross-resistant to tubercidin, an adenosine analog. Like wild-type cells, Brdr mutants were capable of incorporating radioactivity from ring-labeled adenosine into the acid-insoluble macromolecular fraction. However, hypoxanthine-guanine phosphoribosyltransferase-deficient (HGPRT-) mutants derived from the Brdr cells did not incorporate the radioactivity at all or at a markedly reduced rate, indicating that blockade of the pathway via adenosine deaminase present in the Brdr cells resulted in loss of their ability to utilize adenosine. Enzyme assays using cell-free extracts revealed that all the Brdr mutants had less than 3% of the adenosine kinase (AK) activity found in wild-type cells. These results demonstrate that the bredinin resistance is attributed to a defective AK activity and, therefore, that bredinin is metabolized by AK, which may phosphorylate it to a toxic nucleotide, bredinin 5'-monophosphate (Brd-MP), in sensitive cells. Among exogenously added purine bases, guanine was able to reverse the cytotoxic effect of bredinin on both wild-type cells and F5 cells carrying the vector pSV2-Escherichia coli xanthine-guanine phosphoribosyltransferase (XGPRT) gene, while xanthine was able to do so only in F5 cells because the base was metabolized to XMP by the cells. These results support the mechanism of bredinin cytotoxicity, that Brd-MP formed in sensitive cells exposed to the antibiotic blocks the conversion of IMP to XMP by inhibiting IMP dehydrogenase.
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PMID:Genetic and biochemical studies on the activation and cytotoxic mechanism of bredinin, a potent inhibitor of purine biosynthesis in mammalian cells. 614 13

Primary nasopharyngeal carcinoma (NPC) cells were fused to hypoxanthine-guanine phosphoribosyltransferase (HGPRT)-defective cells derived from adenoid tissues using Sendai virus. Some of the fused cells developed into epithelial-like hybrid cells in a selective HAT medium. The hybrid cells (NPC-KT) were Epstein-Barr virus (EBV)-associated nuclear antigen (EBNA)-positive cells. There have been no reports on the establishment of EBNA-positive epithelial cell lines derived from NPC. Thus, the epithelial-like hybrid cells might serve as an in vitro model for studying the biologic activity of NPC-associated EBV.
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PMID:Establishment of Epstein-Barr virus (EBV)-associated nuclear antigen (EBNA)-positive nasopharyngeal carcinoma hybrid cell line (NPC-KT). 631 11

4-Carbamoylimidazolium 5-olate (CIO), the aglycone of the nucleoside antibiotic, bredinin (4-carbamoyl-1-beta-D-ribofuranosylimidazolium 5-olate), exhibited potent cytotoxic effects of subclonal line F28-7 of C3H mouse mammary carcinoma FM3A cells in culture. We isolated 11 cell lines resistant to CIO from wild-type F28-7 cells mutagenized with N-methyl-N'-nitro-N-nitrosoguanidine. These resistant (cio') lines were 160- to 400-fold less sensitive to CIO than were the wild-type cells and inherited the resistant phenotypes during subculture for more than 3 months in the drug-free medium. They were cross-resistant to an adenine analog, 2,6-diaminopurine, while 2,6-diaminopurine-resistant (dap') lines, isolated independently, were cross-resistant to CIO. Neither of the cio' lines tested were able to form colonies in agar medium containing azaserine and adenine, nor were they able to incorporate tritiated adenine into the macromolecular fraction, indicating that they could not utilize exogenous adenine for growth. Enzyme assays using cell-free extracts revealed that all the cio' lines had undetectable levels of adenine phosphoribosyltransferase (EC 2.4.2.7) activity, but they, except one, had normal levels of hypoxanthine-guanine phosphoribosyltransferase (EC 2.4.2.8) and adenosine kinase (EC 2.7.1.20) activities. These results demonstrate that the CIO resistance in these lines is attributed to deficient adenine phosphoribosyltransferase activity and therefore that CIO is activated by adenine phosphoribosyltransferase to form a cytotoxic nucleotide within the drug-sensitive cells.
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PMID:Adenine phosphoribosyltransferase deficiency in cultured mouse mammary tumor FM3A cells resistant to 4-carbamoylimidazolium 5-olate. 710 14

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.
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PMID:Effects of differentiation-inducing agents on purine nucleotide metabolism in an ovarian cancer cell line. 779 96

The spectrum of deletion sizes in mutants of two human bladder carcinoma cell lines has been examined. The cell lines were MGH-U1 and a radiation-sensitive subline (U1-S40b) that has been developed in this laboratory. Three groups, each of 20-30 mutants at the hprt locus were investigated: arising spontaneously, or induced after exposure to 10 Gy gamma-radiation either at high dose-rate (2 Gy/min) or low dose-rate (0.01 Gy/min). Data on the mutation frequency of the two cell lines at low dose-rate were obtained to supplement previously published data at high dose-rate. The mutation frequency was lower in U1-S40b than in MGH-U1 both for high and low dose-rate irradiation. The presence of intact copies of each of the nine hprt exons was examined using multiplex PCR, supplemented by single-exon PCR. The incidence of small hprt mutations (i.e. leading to no change in the size of the PCR products) was the same for spontaneous mutations in the two cell lines; for radiation-induced mutants it was higher in U1-S40b. The incidence of total deletions (i.e. no positive exon amplification) was lower in U1-S40b both for high and low dose-rate irradiation. The results are consistent with the hypothesis that large deletions tend to lead to the loss of adjacent essential genes and thereby to the death of potential mutants.
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PMID:Hprt- mutation spectrum in a closely related pair of human bladder tumour cell lines after gamma-irradiation at different dose-rates. 912 Mar 53

Fifteen variants with >/=30-fold resistance to N-methyl-N-nitrosourea were isolated from the Burkitt's lymphoma Raji cell line. Eight had received a single treatment with a highly cytotoxic dose. The remainder, including the previously described RajiF12 cell line, arose following multiple exposures to initially moderate but escalating doses. Surprisingly, methylation resistance arose in three clones by reactivation of a previously silent O6-methylguanine-DNA methyltransferase gene. Five clones, including RajiF12, displayed the microsatellite instability and increased spontaneous mutation rates at the hypoxanthine-guanine phosphoribosyltransferase locus, consistent with deficiencies in mismatch repair. Defects in either the hMutSalpha or hMutLalpha mismatch repair complexes were identified in extracts of these resistant clones by in vitro complementation using extracts from colorectal carcinoma cell lines. Defects in hMutLalpha were confirmed by Western blot analysis. Remarkably, five methylation-resistant clones in which mismatch repair defects were demonstrated by biochemical assays did not exhibit significant microsatellite instability.
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PMID:Mismatch repair defects and O6-methylguanine-DNA methyltransferase expression in acquired resistance to methylating agents in human cells. 935 25


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