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)

As an experimental strategy for potentially dissociating and studying the cytotoxic and cytodifferentiative antileukemic effects of 6-thioguanine (6-TG), cultured human promyelocytic leukemia cells (HL-60) were serially selected for growth in increasing concentrations of 6-TG (0.5 to 50 micrograms/ml). Three acquired characteristics, cytotoxic resistance, cytodifferentiative resistance, and double minute chromosomes (DM), were monitored at successive 6-TG selection levels. Approximately 200-fold resistance to the cytotoxic effect of 6-TG was acquired at the first selection step, and it neither increased at higher 6-TG selection levels nor reverted to greater sensitivity in cells subcultured off of drug. This was due to the irreversible loss of hypoxanthine-guanine phosphoribosyltransferase (HPRT) activity. In contrast, a lesser, not completely quantifiable, degree of resistance developed to the cytodifferentiative effects of the purine nucleobases hypoxanthine and 6-TG which varied as a function of 6-TG selection pressure. Numerous DM, not observed in the parental wild-type HL-60 cells, appeared at 6-TG (0.5 micrograms/ml) selection which varied substantially in parallel with 6-TG selection pressure up to 6-TG (20 micrograms/ml). At higher selection levels (50 micrograms/ml or prolonged culture on 20 micrograms/ml), a marked decrease in DM occurred which was associated with the acquisition of new marker chromosomes. The most consistent marker was a chromosome 6 with additional material in the short arm (6p+); this was noted as a single copy in the basal 6-TG/20 subline but as two copies (trisomy 6; 2p+) in independently selected higher 6-TG-resistant subcultures. These cytogenetic findings suggest the presence of amplified genes which increased in number and shifted from a predominance in extra-chromosomal DM to intrachromosomal sites as a function of 6-TG selection. Among the 6-TG-resistant sublines, there was no change or a decrease in the amplification level of the known amplified oncogene c-myc from that demonstrated in parental HL-60 cells. Although proof requires detailed analyses with specific gene probes, the overall results imply that: (a) the cytotoxic component of the resistance is due to an invariant loss of HPRT which, therefore, is not likely to be related to amplified genes; (b) the cytodifferentiative component of the resistance is due to a positively selectable mechanism which could be directly or indirectly related to 6-TG-selected amplified genes; and (c) variations in the cytogenetic indicators of amplified genes and the resistance to 6-TG cannot be simply ascribed to quantitative variations in c-myc amplification.
Cancer Res 1984 Jun
PMID:Cytotoxic and cytodifferentiative components of 6-thioguanine resistance in HL-60 cells containing acquired double minute chromosomes. 658 89

A novel mechanism of resistance to the antileukemic agent 6-thioguanine (TGua) was demonstrated in a clone (TGuo-30-2) derived from HL-60 human acute promyelocytic leukemia cells. The clone was isolated by prescreening mutagenized HL-60 cells in hypoxanthine-amethopterin-thymidine medium, followed by selection with 6-thioguanosine. TGuo-30-2 cells were cross-resistant to TGua and beta-2'-deoxythioguanosine. TGuo-30-2 cells exhibited a marked decrease in the capacity to accumulate intracellular TGua nucleotides after treatment with TGua. The decrease in accumulation was not caused by a defect in transport, a lack or alteration of hypoxanthine-guanine phosphoribosyltransferase activity, or enhanced degradation of TGua nucleotides but appeared to be due to the maintenance of a lowered level of 5-phosphoribosyl 1-pyrophosphate (PRPP) in the resistant variant, which corresponded to 20% of the parental concentration. Despite the decrease in PRPP levels, incorporation of glycine into purine nucleotides was greater in TGuo-30-2 than in parental cells. Measurement of PRPP amidotransferase activity using cell homogenates revealed altered kinetics for the enzyme from TGuo-30-2 cells, which included significant loss of sensitivity to feedback inhibition by 6-thioguanosine 5'-phosphate and greater catalytic activity at low concentrations of PRPP.
Cancer Res 1984 Sep
PMID:Altered 5-phosphoribosyl 1-pyrophosphate amidotransferase activity in 6-thioguanine-resistant HL-60 human acute promyelocytic leukemia cells. 658 43

Delayed growth arrest was observed in HL-60 acute promyelocytic leukemia cells after exposure to 6-thioguanine (TG). This growth arrest occurred in both wild-type HL-60 cells exposed to 2 microM TG and an HL-60 clone lacking hypoxanthine-guanine phosphoribosyltransferase (HGPRT) activity at a 500-fold higher concentration of drug. Both cell lines continued replication during an initial 4-day period of exposure to TG; however, upon removal of the purine antimetabolite and reincubation in fresh medium in the absence of drug, no further increase in cell number was observed over the next 4 days. Extensive differentiation, as measured by the reduction of nitroblue tetrazolium, occurred in TG-treated, HL-60 HGPRT-negative cells, whereas no significant increase in the number of nitroblue tetrazolium-positive cells was observed in wild-type HL-60 cells exposed to the purinethiol. Thus, termination of proliferation in wild-type cells appeared to be an expression of cytotoxicity, while in the HGPRT-negative clone, cell replication was apparently terminated by conversion of cells to end-stage forms with a mature phenotype. In support of this conclusion, differences occurred in the stage of the cell cycle arrest, determined on Day 6 after exposure to TG. Approximately 85% of parental HL-60 cells treated with TG were present in the S and G2 + M phases of the cell cycle, with the greatest proportional change from untreated controls being in the G2-M phase (i.e., a 63% increase over untreated controls). In contrast, HL-60 HGPRT-negative cells treated with TG accumulated in G1, with 68% of the population located in this phase (i.e., an 80% increase compared to controls), as might be expected for a differentiated population. Dimethyl sulfoxide, which produced differentiation in both parental HL-60 and HL-60 HGPRT-negative cells, was used as a positive control. Both cell lines responded identically to dimethyl sulfoxide, with growth arrest being due at least in part to differentiation, which corresponded to an increase in G1 cells.
Cancer Res 1984 Sep
PMID:Cell cycle events associated with the termination of proliferation by cytotoxic and differentiation-inducing actions of 6-thioguanine on HL-60 cells. 658 46

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


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