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

Schmid et al. (Cancer Treat. Rep., 60: 23-27, 1976) reported rapid emergence of resistance of L1210 leukemia cells in mice to two schedules of six antimetabolites and much slower development of resistance to a third schedule. Such rapid development of resistance to six drugs presents a striking puzzle, and one whose solution gives some insights into the basis for general emergence of drug resistance. Our approach was to examine the consequences of applying these drugs singly or in pairs and, from the results, to infer interactions in six-drug combinations. 6-Thioguanine (TG) and 6-mercaptopurine are the key drugs since, as shown by Schmid et al., resistance of leukemic cells appeared to six-drug combinations at the same time as did resistance to the purine analogs; sensitivity to the other drugs remained. We demonstrated that cells which emerged were resistant to both of the purine analogs, owing to a deficiency of the activating enzyme hypoxanthine-guanine phosphoribosyltransferase. TG resistance arose in the presence of TG because of an overgrowth of TG-resistance mutants that were present as one cell in 10(4) in the original L1210 population. L1210 cultures were prepared free of TG-resistant mutants. With these cells, TG administered shortly after inoculation was very effective in delaying their death. The cells that finally grew out were still TG sensitive. Simultaneous treatment with all the drugs greatly delayed appearance of TG resistance in vivo and in vitro. Methotrexate alone was responsible for this result, owing to its ability preferentially to kill TG-resistant cells. The other three drugs were not effective in delaying TG resistance. Methotrexate was effective only if it was added daily; one large injection was ineffective. Therefore, TG and methotrexate added daily for 6 days (simultaneous schedule) was the most effective drug regimen tested.
Cancer Res 1981 Nov
PMID:Basis of observed resistance of L1210 leukemia in mice: methotrexate, 6-thioguanine, 6-methylmercaptopurine riboside, 6-mercaptopurine, 5-fluorouracil, and 1-beta-D-arabinofuranosylcytosine administered in different combinations. 719 6

Cocultures were established of mouse epidermal cells (HEL/37) and mouse fibroblast cells (PG-19) deficient in the enzyme hypoxanthine-guanine phosphoribosyltransferase. Metabolic cooperation between the cocultured cells was detected as labeling of PG-19 cells on incubation of cocultures with [3H]-hypoxanthine. The transfer of label from HEL/37 cells to PG-19 cells was inhibited by the tumor prmoters 12-O-tetra-decanoylphorbol-13-acetate (10(-8) M) and phorbol-12,13-di-decanoate (10(-7) M) but not by nonpromoting derivatives of these phorbol esters. The inhibition was partially prevented by the antiinflammatory steroid fluocinolone acetonide, which is an antagonist of mouse skin tumor promotion, and by prolonged exposure of the cocultures to 12-O-tetradecanoylphorbol-13-acetate.
Cancer Res 1980 Aug
PMID:Inhibition of intercellular communication by tumor-promoting phorbol esters. 738 43

Maternal cigarette smoking during pregnancy has been associated with increased perinatal mortality and low birth weight. Several epidemiological studies have demonstrated an association between smoking during pregnancy and an elevated risk of hematopoietic cancer in the child, but other studies have failed to confirm this association. We have used an assay for somatic cell mutation to evaluate the in utero effects of exposure to maternal cigarette smoking. Cord blood samples were obtained from 10 newborns whose mothers smoked cigarettes during pregnancy and 10 newborns of non-smoking mothers. Blood samples were also obtained from 5 of the smoking and 5 of the non-smoking mothers. Smoking status was confirmed in all samples by testing the blood plasma for cotinine. The frequency of lymphocytes containing mutations at the hypoxanthine phosphoribosyltransferase (hprt) locus was determined with an autoradiographic assay using cells that had been cryopreserved. The mothers who were smokers had a mean frequency (+/- SE) of 3.08 (+/- 0.55) variant (mutant) cells per 10(6) evaluatable lymphocytes. The frequency (Vf) in non-smokers was 1.07 (+/- 0.17) x 10(-6). The Vf of newborns of smokers was 2.17 (+/- 0.24) x 10(-6), and newborns of non-smokers had a Vf of 0.77 (+/- 0.13) x 10(-6). In both mothers and newborns the difference in Vf between smokers and non-smokers was statistically significant (p < 0.05). Maternal and newborn Vfs were significantly correlated (r = 0.88; p < 0.004), and there was a positive association (r = 0.86; p < 0.001) between the reported number of cigarettes smoked per day and the Vfs. This study provides further evidence that maternal smoking may be hazardous to the future health of children exposed in utero to mutagenic agents in cigarette smoke.
 ...
PMID:Elevated frequencies of hprt mutant lymphocytes in cigarette-smoking mothers and their newborns. 750 72

Adriamycin (ADR), a commonly used cancer chemotherapy antibiotic, exhibits a variety of genotoxicities. In this study, we have examined the mutagenicity of ADR at the hypoxanthine-guanine phosphoribosyltransferase gene (hprt) in Chinese hamster ovary (CHO) cells and the xanthine-guanine phosphoribosyltransferase locus (gpt) in a pSV2gpt-transformed CHO cell line, AS52. Although ADR induced a dose-dependent increase of mutant frequency at both loci, it was more mutagenic to the gpt gene than to the hprt locus. Multiplex PCR analysis revealed that 35% of the 103 independent ADR-induced HPRT-deficient mutants carried large deletions. Among these deletion mutants, 33% were total gene deletions, 22% affected multiple exons, and 42% involved a single exon, of which most (9/15) were exon 1. The majority (63%) of ADR-induced AS52 mutants had a total deletion of the gpt gene. These observations indicate that ADR induces large deletions as a major type of gene mutation in mammalian cells, suggesting the involvement of reactive oxygen species as one mutagenic pathway in the mutagenesis of ADR.
 ...
PMID:Adriamycin induces large deletions as a major type of mutation in CHO cells. 752 37

A model system was developed to allow investigation of the frequency at which clastogenic and/or mutagenic events occur in situ in a transplantable murine fibrosarcoma tumour (MC1A-C1) compared with in vitro culture. The marker selected for detecting these events was the X-linked hprt (hypoxanthine-guanine phosphoribosyltransferase) gene. We found that the hprt gene in MC1A-C1 was not suitable for this purpose, most likely because multiple active copies were present. To circumvent the problem, HPRT- [6-thioguanine (6-TG)-resistant] clones were isolated by inactivating all hprt genes with methylnitrosourea. Spontaneous revertants to hypoxanthine/aminopterin/thymidine resistance (HATR) were isolated and found to be approximately 1000 times more sensitive than the parental tumour to induction of 6-TGR mutants by cobalt-60 gamma-rays. This sensitivity is expected for a heterozygous marker, these revertants may therefore possess only one functional hprt locus but two or more active X chromosomes. A clone with a stable hprt gene was identified and a neo gene was introduced. The resulting cell line (MN-11) could be grown as a subcutaneous tumour in syngeneic C57BL/6 animals. The frequency of mutations arising in vivo in the marker hprt gene could be estimated by culturing explanted tumour cells in the presence of 6-TG, using G418 selection to distinguish tumour from host cells. The frequency of mutants in MN-11 cells grown as tumours was found to be 3.4-fold higher than in tissue culture for an equivalent period of time. These data provide the first direct evidence for the existence of mutagenic factors in a tumour environment that might contribute to tumour progression.
Br J Cancer 1995 Nov
PMID:Hprt mutants in a transplantable murine tumour arise more frequently in vivo than in vitro. 757 74

A major portion of new cases of cancer may be linked to environmental carcinogens. The Ames (Salmonella) test is currently the most widely used short-term test to predict carcinogenic properties of compounds. However, approximately 50% of all carcinogens have been sufficiently tested in long-term animal bioassays do not induce mutations in the Salmonella assay, and many of these carcinogens are also not detectable by other short-term assays. In the work described here we determined the effect of carcinogen exposure on intrachromosomal recombination in a human cell line. The recombination events caused the deletion of one copy of a duplication of exons 2 and 3 of the hprt gene. We found that these deletion events were induced by exposure to the Salmonella assay positive carcinogens UV, gamma-rays and methyl methanesulfonate, as well as the Salmonella assay negative carcinogens Aroclor 1221, benzene and thiourea. These data may further support the accumulating evidence that recombination and deletions may be important in carcinogenesis.
 ...
PMID:Carcinogens induce intrachromosomal recombination in human cells. 758 7

The mutagenic impact of various environmental and therapeutic agents can now be directly assayed in humans by the T-lymphocyte cloning assay. We have previously reported that following radioimmunoglobulin therapy, cancer patients exhibited increased mutant frequency of the hprt locus and an increased yield of large intergenic deletions compared to unexposed controls. Here we report the results of the analysis of 26 independent hprt mutations in nine cancer patients who underwent radioimmunoglobulin therapy. The majority of mutations (52%) had lost exon sequences from the mRNA. The remaining mutations were 20% small deletions and frameshifts and 28% base substitutions. The type of mutations observed were similar to those seen in unexposed controls. The site distribution of the mutations, however, indicates that some sequence contexts may be more sensitive to radiation mutagenesis than others.
 ...
PMID:Analysis of point mutations in the hprt gene of cancer patients treated with radioimmunoglobulin therapy. 758 46

To study the pathways associated with genomic instability in cancer, we examined UV-induced and spontaneous mutagenesis in clonal cell lines expressing human papillomavirus (HPV) proteins, either high-risk (HPV16) E6 or E7 or low-risk (HPV11) E6, in comparison to the parental RKO cells, a colon carcinoma cell line expressing only normal p53. High-risk E6 and E7 bind and functionally inactivate tumor suppressor proteins p53 and Rb, respectively, and both disrupt the G1 arrest in response to DNA damage. Low-risk HPV E6 proteins bind p53 with much lower affinity than high-risk E6 and fail to mediate p53 degradation or to disrupt the G1 checkpoint. We found that cells expressing HPV16 E6 had reduced survival and increased mutagenesis at the hprt locus when treated with low doses of UV. However, this analysis was complicated by the unexpected observation of a very high background of spontaneous mutagenesis in the unirradiated cells expressing the HPV16 E6 gene. Fluctuation analysis revealed a 5-fold elevated mutation rate in the cells expressing HPV16 E6. HPV11 E6 conferred a 2-fold elevation in the mutation rate, but HPV16 E7 had no effect. The increased spontaneous mutagenesis, therefore, appeared to be mediated by p53 inactivation and to be independent of Rb (which acts downstream of p53 in the G1 arrest pathway following DNA damage). Taken together, these findings suggest that the effect of p53 inactivation on spontaneous mutagenesis is manifested at the level of DNA repair, recombination, or coupling of transcription with one of these processes instead of by an alteration in G1 arrest.
Cancer Res 1995 Oct 01
PMID:p53 inactivation by HPV16 E6 results in increased mutagenesis in human cells. 767 Dec 55

The role of DNA alkylation at the O6 position of guanine in the induction of gene mutations in vivo was studied in the hprt gene of rat T-lymphocytes from spleen exposed in vivo to the monofunctional ethylating agents ethylmethanesulfonate (EMS) and N-ethyl-N-nitrosourea (ENU), or the hydroxyethylating agent N-(2-hydroxyethyl)-N-nitrosourea (HOENU). All chemicals showed an exposure-dependent increase in hprt mutant frequency. HOENU and ENU, however, were much more mutagenic than EMS when compared at equimolar levels. DNA sequence analysis was performed on PCR products of hprt cDNA from 40 EMS-, 35 HOENU-, and 46 ENU-induced 6-thioguanine-resistant T-lymphocyte clones. Thirty EMS-induced mutants contained a single base pair substitution with GC to AT transitions being the predominant type of mutation (26 of 30) which are probably caused by mispairing of O6-ethylguanine with T during DNA replication. No strand specificity of mutated G's among GC to AT transitions was observed. Twenty-three HOENU- and 42 ENU-induced mutants contained a single base pair substitution. In contrast to EMS, GC to AT transitions were found at a low frequency, 4 of 23 for HOENU and 5 of 42 for ENU, indicating that O6-hydroxyethylguanine and O6-ethylguanine are less important in HOENU- and ENU-induced mutagenesis in vivo, respectively. Also here no strand bias for mutated G's was observed, although the number of this type of mutation was limited. The most frequently induced base pair alterations by HOENU and ENU were transversions at AT base pairs, 16 of 23 and 28 of 42, respectively, with AT to TA being the predominant type of mutation. In both ENU and HOENU mutational spectra, an extreme strand bias for mutated T's toward the nontranscribed strand was found. The results suggest that DNA damage induced in rat T-lymphocytes in vivo by HOENU and ENU is processed in similar ways.
Cancer Res 1995 May 01
PMID:Marked differences in the role of O6-alkylguanine in hprt mutagenesis in T-lymphocytes of rats exposed in vivo to ethylmethanesulfonate, N-(2-hydroxyethyl)-N-nitrosourea, or N-ethyl-N-nitrosourea. 772 55

We investigated gene-specific damage in adenocarcinoma cells, obtained from pleural effusions of 9 primary lung cancer patients, induced by incubation with cisplatin for 3 h in vitro. The 2.7 kb fragment of the hypoxanthine phosphoribosyltransferase (HPRT) gene was amplified by the polymerase chain reaction (PCR) to quantify the DNA damage. A 7-fold difference in the extent of gene-specific damage among the patients was observed. Mononuclear cells (MNC) were obtained from freshly isolated blood from the same patients before they received chemotherapy. These cells were also incubated with cisplatin in vitro, and PCR amplification of the HPRT gene was carried out. A 4-fold variation of DNA damage among the patients was observed. Moreover, there was a linear correlation between the extents of the DNA damage in the tumor cells and MNCs (R2 = 0.676, P = 0.0016). These results suggest that the PCR-stop assay could be used to detect interindividual variations in the extent of gene-specific damage in both tumor cells and MNC from the same patients induced by cisplatin treatment. In conclusion, MNC could be used to analyze cisplatin-induced gene-specific damage in cancer patients whose tumor cells are inaccessible.
Jpn J Cancer Res 1995 Feb
PMID:Correlation of gene-specific damage with cisplatin between human adenocarcinoma cells and peripheral blood mononuclear cells analyzed by polymerase chain reaction-stop assay. 773 Jan 49


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>