Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Adult rat liver contained variant forms of thioredoxin reductase with isoelectric points at pH 4.9 and at approximately pH 4.7 compared to pH 5.1 for the enzyme from Novikoff ascites hepatoma. Fetal and regenerating liver contained only the form with the isoelectric point at pH 4.9. All three enzymes precipitated with and were inhibited by a rabbit antibody to purified enzyme from Novikoff tumor.
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PMID:Comparison of thioredoxin reductases from Novikoff ascites hepatoma cells and normal liver of rats. 20 14

A pyrimidine nucleoside monophosphate kinase has been purified 2100-fold from rat liver. With ATP and dATP as phosphate donors the kinase uses CMP, dCMP, and UMP as phosphate acceptors. Ara-CMP is also phosphorylated by the kinase. In contrast to dCMP and UMP, CMP can be phosphorylated by dCTP. CTP and ara-CTP cannot substitute for dCTP. The stringent specificity of the phosphate donor site for ATP and dATP is lost when CMP serves as acceptor. All nucleoside triphosphates act as donors to a significant extent. No evidence has been found to suggest more than one enzyme. All activities, to different degrees, are strictly dependent upon preincubation at 37 degrees with a sulfhydryl reducing agent. Various reagents (85 mM) are ranked in order of increasing effectiveness of reactivation as follows: dithiothretiol greater than glutathione larger than or equal to 2-mercaptoethanol greater than L-cysteine greater than DL-alpha-lipoic acid. A NADP+-dependent thioredoxin (17 muM)-thioredoxin reductase system from Novikoff ascites rat tumor was found to be the most powerful reducing agent tested. CTP, dCTP, UTP, and dTTP (1 mM) do not affect the kinase activity regardless of the phosphate acceptor.
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PMID:A pyrimidine nucleoside monophosphate kinase from rat liver. 112 84

Fotemustine is a highly reactive chloroethyl-nitrosourea anti-tumor drug that is currently undergoing phase III clinical trials in stage IV metastatic malignant melanoma. The drug is a potent alkylating agent and rapidly chloroethylates the active sites of the important thioproteins thioredoxin reductase (TR), glutathione reductase (GR) and ribonucleotide reductase (RR). These enzymes control ribonucleotide reduction and, consequently, DNA synthesis in the S phase of the cell cycle. Side effects are minor due to the rapid metabolism of the drug. [14C]Fotemustine exhibited a half-life of 90 min in the vascular system after the administration of 100 mg/m2. Fotemustine was shown to yield the volatile degradation product acetylene (a) in distilled water (4.1%/h), (b) in melanoma cell culture medium (MCDB) supplemented with 10% fetal calf serum (33%/h) and (c) in fotemustine-sensitive human melanoma cells in culture medium (70.5%/h). Due to its rapid metabolism and its low toxicity, high concentrations of fotemustine (55 x 10(-3) M) were injected directly into cutaneous and subcutaneous melanoma metastases (n = 36) of seven patients, resulting in minor necrosis followed by total remission of the metastases. Untreated metastases adjacent to the treated tumors were not affected by fotemustine, confirming that rapid local metabolism of this drug occurs only in the vicinity of injected tumors without producing any systemic effects.
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PMID:Local treatment of cutaneous and subcutaneous metastatic malignant melanoma with fotemustine. 176 Aug 62

Plasma membrane-associated thioredoxin reductase activities have been determined on primary melanoma tissues and their surrounding skin in 29 patients. Compared to patient's normal skin, enzyme activities in melanoma were higher in some patients (n = 24) and lower in others (n = 5). Those melanomas with high TR activities yielded low activities in the adjacent epidermis, reaching normal activity 3 to 5 cm away from each primary site (n = 4). Tumors with low activities showed higher than normal activities on the immediate surrounding skin (i.e., 1 cm away from the tumor) compared to the normal skin (n = 3). Earlier it was shown that in both keratinocytes and melanoma cells, calcium regulates thioredoxin reductase activity by an allosteric mechanism. The differences in TR activities within the high and low groups may be caused by a calcium flux between the primary tumor and the surrounding epidermis, and vice versa. A comparison of TR activities to tumor invasiveness (Breslow level) in 28 primary melanomas showed a significant correlation using regression analysis (p = 0.031). A 4-fold difference in TR activity corresponds to a one-unit change in Breslow determination. These preliminary results suggest that TR activity may be another useful and sensitive assay for melanoma spread.
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PMID:Thioredoxin reductase activity at the surface of human primary cutaneous melanomas and their surrounding skin. 201 54

Fotemustine is a novel chloroethylnitrosourea derivative currently used in Phase III clinical trials for disseminated metastatic melanoma. This drug has been shown to inhibit enzymes in the ribonucleotide reduction pathway (i.e., thioredoxin reductase, glutathione reductase and ribonucleotide reductase). 14C chloroethyl-labelled Fotemustine covalently labels the thiolate active sites of thioredoxin reductase and glutathione reductase yielding 14C chloroethyl-thioether enzyme-inhibitor complexes. Enzyme activities can be restored by a reduced thioredoxin or reduced glutathione mediated beta-elimination of the chloroethyl group. 14C Fotemustine has been used to determine its reactivity and metabolism in drug sensitive and resistant melanoma metastases and in cultures of sensitive and resistant clones of human melanoma cells. Melanoma metastases from four different patients who were treated with Fotemustine could be labelled with radioactive drug only under reducing conditions with NADPH as electron donor and DTNB as substrate. FPLC analysis of these extracts revealed two radioactive proteins (I) glutathione reductase and (II) an unidentified protein with 95 and 50 kDa subunits. A similar labelling pattern was also found in extracts of Fotemustine sensitive melanoma cells (Cal 1). Fotemustine resistant tumors were melanotic and contained more glutathione reductase than thioredoxin reductase, whereas sensitive tumors were clinically amelanotic with more thioredoxin reductase than glutathione reductase. Fotemustine resistant melanoma cells (Cal 7) showed a slower uptake of 14C-label with 34% less isotope intracellularly in 1 h compared to sensitive melanoma cells (Cal 1). These results strongly indicate (I) the induction of alternate electron donors thioredoxin reductase or glutathione reductase for ribonucleotide reduction determines tumor and melanoma cell responses to the drug and (II) Fotemustine transport and the intracellular redox status seems to regulate resistance in melanoma cells and tissues.
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PMID:Sensitivity and resistance in human metastatic melanoma to the new chloroethylnitrosourea anti-tumor drug Fotemustine. 206 1

The cDNA sequences of thioredoxin obtained by PCR cloning from human colon cancer cells, human lymphoblastoid cells, and human liver have been found to be identical with the cDNA sequence reported for the autocrine growth factor, human adult T-cell leukemia derived factor (ADF). Recombinant human thioredoxin was 95% reduced by dithiothreitol and was a substrate for reduction by human thioredoxin reductase. Human non-small cell primary lung tumors from subjects who were not cigarette smokers at the time of surgery showed significantly increased levels of thioredoxin mRNA compared to thioredoxin mRNA in paired normal human lung tissue. Subjects who were smokers did not show a significant increase in lung tumor thioredoxin mRNA. The results of the study show that human thioredoxin and ADF are identical species and suggest that there may be increased production of thioredoxin (ADF) by some human cancers.
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PMID:The predicted amino acid sequence of human thioredoxin is identical to that of the autocrine growth factor human adult T-cell derived factor (ADF): thioredoxin mRNA is elevated in some human tumors. 804 54

Selenium compounds like selenite and selenate have strong inhibitory effects, particularly on mammalian tumor cell growth by unknown mechanisms. We found that the addition of sodium selenite and sodium selenate inhibited the growth of human 3B6 and BL41 lymphocytes. Selenite was more potent because 10 microM selenite produced a growth inhibitory effect similar to that of 250 microM selenate. The mechanism of action of selenite and selenate appears to be different. 3B6 and BL41 cells treated with selenite accumulated in the S-phase; however, selenate caused an accumulation of cells in G2. Selenite-mediated growth inhibition was irreversible, although the effects of selenate could be reversed. Selenite, in contrast to selenate, is efficiently reduced by the thioredoxin system (thioredoxin, thioredoxin reductase, and NADPH). At concentrations required to observe a similar effect on cell growth, the activity of thioredoxin reductase, recently shown to be a selenoprotein, increased in selenite-treated cells and decreased in selenate-treated cells. Ribonucleotide reductase activity was inhibited in an in vitro assay by selenite and selenodiglutathione but not by selenate. These results show that selenite and selenate use different mechanisms to inhibit cell growth.
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PMID:Selenite and selenate inhibit human lymphocyte growth via different mechanisms. 881 34

A strong growth inhibition is observed when the human p53 tumor suppressor gene product is expressed in the fission yeast Schizosaccharomyces pombe. This growth inhibition is specific for wild-type p53; mutant alleles of p53 derived from human tumors show a greatly decreased ability to inhibit growth. These data suggest that there may be a p53-responsive pathway in S. pombe. To identify elements in this pathway genetically, we isolated a mutant yeast strain in which the growth inhibitory activity of p53 is largely suppressed. In addition, the activity of p53 as a transcription factor is also decreased in this strain. The suppression of p53 activity is not due to a decrease in p53 expression or a failure of p53 to localize to the nucleus. This p53 suppressor mutation is in a novel S. pombe gene with homology to thioredoxin reductase genes, and has been named trr1. Strains with a mutation of, or deletion in, trr1 are sensitive to oxidizing agents, suggesting that the trr1 suppressor mutation causes partial loss of trr1 function. Since oxidizing agents are able to suppress p53 activity in vitro, this trr1 mutation may affect the activity of p53 in fission yeast by increasing the oxidation state of the tumor suppressor.
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PMID:A mutation in a thioredoxin reductase homolog suppresses p53-induced growth inhibition in the fission yeast Schizosaccharomyces pombe. 891 13

Thioredoxin (Trx) is a widely distributed redox protein that regulates several intracellular redox-dependent processes and stimulates the proliferation of both normal and tumor cells. We have found that when stored in the absence of reducing agents, human recombinant Trx undergoes spontaneous oxidation, losing its ability to stimulate cell growth, but is still a substrate for NADPH-dependent reduction by human thioredoxin reductase. There is a slower spontaneous conversion of Trx to a homodimer that is not a substrate for reduction by thioredoxin reductase and that does not stimulate cell proliferation. Both conversions can be induced by chemical oxidants and are reversible by treatment with the thiol reducing agent dithiothreitol. SDS-PAGE suggests that Trx undergoes oxidation to monomeric form(s) preceding dimer formation. We have recently shown by X-ray crystallography that Trx forms a dimer that is stabilized by an intermolecular Cys73-Cys73 disulfide bond. A Cys73-->Ser mutant Trx (C73S) was prepared to determine the role of Cys73 in oxidative stability and growth stimulation. C73S was as effective as Trx in stimulating cell growth and was a comparable substrate for thioredoxin reductase. C73S did not show spontaneous or oxidant-induced loss of activity and did not form a dimer. The results suggest that Trx can exist in monomeric forms, some of which are mediated by Cys73 that do not stimulate cell proliferation but can be reduced by thioredoxin reductase. Cys73 is also involved in formation of an enzymatically inactive homodimer, which occurs on long term storage or by chemical oxidation. Thus, although clearly involved in protein inactivation, Cys73 is not necessary for the growth stimulating activity of Trx.
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PMID:Oxidative inactivation of thioredoxin as a cellular growth factor and protection by a Cys73-->Ser mutation. 898 37

Thioredoxin and thioredoxin reductase are redox proteins that have been implicated in the control of cell proliferation and transformation. We report the levels and activity of these proteins and their mRNAs in human primary tumors and tumor cell lines. Half of human primary colorectal carcinomas (5/10) examined had increased thioredoxin mRNA, of 3- to over 100-fold, compared to adjacent normal colonic mucosa from the same subject. Thioredoxin reductase protein and activity were increased an average of 2-fold in human colorectal tumors compared to normal mucosa. A number of human hematologic and solid tumor cell lines were studied and showed a 10-fold range of thioredoxin mRNA and a 23-fold range of thioredoxin reductase mRNA. Increased proliferation and hypoxia are factors that might contribute to the increased expression in solid tumors. We found that serum stimulation of growth arrested MCF-7 breast cancer cells caused a 59% increase in thioredoxin mRNA and a 62% increase in thioredoxin reductase mRNA by 24 hours. Exposure of HT-20 colon cancer cells to hypoxia resulted in a 14-fold increase in thioredoxin mRNA by 16 hours, and a transient 4-fold increase in thioredoxin reductase mRNA at 1 hour that had returned to control levels by 8 hours. Cancer cells were found to release thioredoxin into the medium at rates between 1 to 2 pmole/10(6) cells/3 hours. The rate of secretion was not, however, related to cellular-levels of thioredoxin. The results of the study show that the expression of thioredoxin and thioredoxin reductase are increased several fold in some human solid tumors compared to normal tissue. Secretion of thioredoxin, which is known to have a direct growth stimulating activity, by human tumor cells might lead to the stimulation of cancer cell growth.
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PMID:Thioredoxin and thioredoxin reductase gene expression in human tumors and cell lines, and the effects of serum stimulation and hypoxia. 904 7


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