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)

We have analyzed the relationship between the biological activities and chemical structure of five naphthofurans. The compounds studied included 2-nitro-7-methoxynaphtho[2,1-b]-furan (R 7000) (Compound A), 2-nitro-8-methoxynaphtho[2,1-b]-furan (Compound B), 2-nitronaphtho[2,1-b]furan (Compound C), 2-nitro-7-bromonaphtho[2,1-b]furan (Compound D), and 7-methoxynaphtho[2,1-b]furan (Compound E), the nonnitrated analogue of Compound A. The genotoxic activities of the compounds were studied in V79 cells using the micronucleus, sister chromatid exchange, and hypoxanthine-guanine phosphoribosyltransferase locus mutation tests. This allowed us to classify their mutagenic properties in the following order: A congruent to B much greater than C greater than D greater than E. However, in the in vivo short-term skin tests, the order in activities of the first three compounds is reversed, and the five compounds can be classified in decreasing rank of potency: C greater than B greater than A greater than or equal to E congruent to D. The two compounds tested for in vitro transformation, Compounds A and B, demonstrated a positive effect in both the C3H10T1/2 and the Syrian hamster embryo cell systems. The biological activities of Compounds A, B, C, and D appeared to be strongly linked to the presence of a NO2 group in position 2. These activities were enhanced or decreased by a methoxy group in position 7 or 8. Almost all activities were suppressed if the methoxy group in position 7 was replaced by a bromine (Compound D). The positive results obtained in the cell transformation assays and in the short-term skin tests indicate that Compounds A, B, and C are probably carcinogenic. Therefore, further in vivo studies should be accomplished before using the 2-nitronaphthofuran derivatives in human and animal treatments.
Cancer Res 1984 May
PMID:Relationship between the chemical structure and the mutagenic and carcinogenic potentials of five naphthofurans. 671 95

The mutagenic responses of 13 antineoplastic drugs, namely, chlorambucil, busulfan, lomustine, dacarbazine, Adriamycin, daunomycin, bleomycin, VM-26, VP16-213, ellipticine, actinomycin D, mitomycin C, and cis-diamminedichloroplatinum(II) have been determined in two different assay systems in Chinese hamster ovary cells which measure mutation induction at multiple genetic loci and the frequencies of sister chromatid exchanges. The five genetic loci whose responses have been measured include those conferring resistance to 6-thioguanine (Thgr or TGr), ouabain, emetine, methylglyoxal bis(guanylhydrazone), and 5,6-dichlororibofuranosylbenzimidazole; of these, only the Thgr marker affects a function (hypoxanthine-guanine phosphoribosyltransferase, hgprt locus) which is not essential for cellular growth. All of these drugs showed a dose-dependent increase in mutation frequency at the hgprt locus, but their responses at other genetic loci differed greatly and showed marked specificity for different chemical classes of the drugs. The observed locus-specific differences in response to these drugs suggest that they may differ in terms of their accessibility or affinity to different chromosomal regions. All of these drugs also led to a significant increase in the frequency of sister chromatid exchanges, and a very good correlation was observed between the activity of these drugs in the sister chromatid exchange assay and the mutagenic response of the hgprt locus. Of the drugs which were examined, VM-26, VP16-213, chlorambucil, mitomycin C, and cis-diamminedichloroplatinum(II) showed a particularly strong response in both of these assay systems. In terms of the minimum concentration which gave a mutagenic response, the drugs differed from each other by a factor of about 100,000, with actinomycin D, VM-26, and daunomycin being mutagenic in the range of 3 x 10(-8) to 1 x 10(-7) M, whereas dacarbazine produced a weak mutagenic response only at about 2 x 10(-3) M.
Cancer Res 1983 Feb
PMID:Mutagenic responses of thirteen anticancer drugs on mutation induction at multiple genetic loci and on sister chromatid exchanges in Chinese hamster ovary cells. 684 81

Cell culture studies have been performed to compare the mutagenic potential and the induction of sister chromatid exchanges for hematoporphyrin derivative photoradiation, ionizing radiation, and UV radiation. The mutation frequency in Chinese hamster ovary cells at the hypoxanthine-guanine phosphoribosyltransferase locus was measured using resistance to 6-thioguanine. Phenotypic expression time prior to mutation selection was also examined. Treatment with either X-rays or UV was effective in producing mutants resistant to 6-thioguanine, but treatment with hematoporphyrin derivative photoradiation (at comparable toxicity levels) did not induce any mutagenic activity above background levels. The hematoporphyrin derivative incubation and photosensitization conditions used in this study did induce sister chromatid exchanges at frequencies comparable to those induced by X-rays but at lower frequencies than for UV treatments.
Cancer Res 1983 Jun
PMID:Comparison of mutagenicity and induction of sister chromatid exchange in Chinese hamster cells exposed to hematoporphyrin derivative photoradiation, ionizing radiation, or ultraviolet radiation. 685 May 80

We have examined contact-mediated intercellular communication by measuring the transfer of thioguanine sensitivity to a hypoxanthine phosphoribosyltransferase (EC 2.4.2.8)-negative clone (66cl-4) selected from one subline isolated previously from a spontaneously arising mammary tumor of a BALB/cfC3H mouse. We tested other sublines from the same tumor and unrelated cell types for their ability to serve as 6-thioguanine nucleotide donors to 66cl-4 cells. The degree of communication, measured by the number of donor cells required to reduce the number of thioguanine-resistant colonies, varied with the donor cell type. The 66cl-4 line communicated with the parent cell line from which the thioguanine-resistant cell was selected and with other sublines from the parent tumor, with some unrelated tumor cells, and with some nonneoplastic cells (3T3, hamster kidney and lung fibroblasts, and mouse mammary epithelial cells). There was a quantitative difference in the amount of communication which took place with the various cells tested, but no pattern of difference could be discerned. Line 66cl-4 did not preferentially communicate with cells of epithelial versus fibroblast morphology, nor with tumor versus nontumor cells. The 66cl-4 cells retained the ability of their parent line to form metastatic tumors when injected s.c. into BALB/c mice. A quantitative selectivity of communication is thus expressed in these malignant metastatic cells, but it is apparently unrelated to either the morphological or malignant phenotype of the donor. Contact-mediated communication between tumor subpopulations may differentially affect growth and drug sensitivity within a tumor.
Cancer Res 1983 Sep
PMID:Quantitative selectivity of contact-mediated intercellular communication in a metastatic mouse mammary tumor line. 687 51

To determine whether the antitumor activities of thioguanine-platinum(II) [TG-Pt(II)] and selenoguanine-platinum(II) [SeG-Pt(II)] are due to direct actions of these compounds or to the actions of their hydrolysis products, studies were made on a purine antagonist-resistant, murine lymphoma L5178Y/MP subline that lacked the anabolic enzyme hypoxanthine-guanine phosphoribosyltransferase necessary for tumor inhibition. The L5178Y/MP subline proved to be highly resistant to both TG-Pt(II) and thioguanine; the resistance ratios to the two compounds were almost identical. The subline showed high resistance to selenoguanine, but the cross-resistance to SeG-Pt(II) was negligible. Whether the compounds exhibit the delayed cytotoxicity characteristic of purine antagonists was also investigated. Delayed cytotoxicity was demonstrated for TG-Pt(II) as well as for thioguanine and other purine antagonists but not for SeG-Pt(II) or cis-dichlorodiammineplatinum(II). Experiments on cross-resistance and delayed cytotoxicity showed differences in the cytotoxicities of TG-Pt(II) and SeG-Pt(II): TG-Pt(II) exerted its activity through its hydrolysis product thioguanine, whereas SeG-Pt(II) compound was cytotoxic itself.
J Natl Cancer Inst 1982 Feb
PMID:Murine lymphoma L5178Y cells resistant to purine antagonists: differences in cross-resistance to thioguanine-platinum(II) and selenoguanine-platinum(II). 695 Jan 60

Cultured Chinese hamster ovary cells were incubated with dilutions of an oil shale retort process water and exposed to nautral sunlight. An enhancement of sevenfold to ninefold was seen in photoinduced cytotoxicity (by a colony-forming assay) and mutagenicity [at the hypoxanthine phosphoribosyltransferase (HPRT) locus] for cells pretreated with the process water compared to effects seen in cells exposed to sunlight only. Significant photoinduced cytotoxicity was also observed in cultured human skin fibroblasts when exposed to the process water before being exposed to near UV (NUV) radiation. The mutation frequencies (determined for the HPRT locus) induced by the process water and NUV radiation were as great as those frequencies seen for far UV light alone. Increases in genotoxicity were observed in excision repair-deficient xeroderma pigmentosum skin fibroblasts when compared to the responses seen in normal cells. Risks to health resulting from the phototransformation of these oil shale retort process waste waters are unassessed at this time.
J Natl Cancer Inst 1982 Jul
PMID:Genotoxic effects of sunlight-activated waste water in cultured mammalian cells. 695 12

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.
Cancer Res 1982 Oct
PMID:Adenine phosphoribosyltransferase deficiency in cultured mouse mammary tumor FM3A cells resistant to 4-carbamoylimidazolium 5-olate. 710 14

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


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