Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A series of acetohydroxamic acid derivatives of 3-nitropyrazole were synthesized and evaluated for their ability to potentiate (chemosensitization) the activity of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) against EMT-6 mouse mammary tumor cells in vitro. The compounds were designed to test the hypothesis that the chemosensitizing activity of the analogues would be proportional to the rate of isocyanate formation via a Lossen rearrangement, in part a function of the leaving group at the N terminus of each acetohydroxamate. Substitution of acetohydroxamic acid side chains at the N-1 position of the parent 3-nitropyrazole resulted in compounds which were preferentially toxic to cells treated under hypoxic conditions, and which were capable of enhancing the toxicity of CCNU in hypoxia. As was observed for cytotoxicity, the enhancement of CCNU toxicity by these sensitizing agents was significantly reduced under aerobic treatment conditions. A strong correlation was established between hypoxic toxicity and chemosensitizing potency. The activity of the analogue, however, was not proportional to their excepted rates of Lossen rearrangement. Nevertheless, several potent chemosensitizing compounds were identified; some of which were 10-50 X's more potent on a molar basis than Misonidazole, the reference chemosensitizing compound.
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PMID:Enhancement of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) toxicity by acetohydroxamic acid analogues of 3-nitropyrazole in vitro. 366 63

The binding rate of 14C-Misonidazole was determined for freshly isolated mouse hepatocytes, mouse hepatoma cells, EMT-6 tumor cells, and V79 Chinese hamster lung fibroblasts. At 10 microM drug concentration, the four different cell lines bound 14C-Misonidazole at rates of 12.4, 29.9, 51.6, and 13.5 pmoles/10(6) cells/hr, respectively. This relative order of binding was observed over a drug concentration range of 10-100 microM. These data indicate that in extreme hypoxia, mouse hepatocytes do not bind 14C-Misonidazole at a uniquely high rate in vitro, compared to other normal and tumor cell lines. This observation suggests that the increased binding to liver in vivo observed by other investigators is due to the liver existing at a reduced oxygen tension, compared to other normal tissues.
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PMID:In vitro binding of 14C-misonidazole to hepatocytes and hepatoma cells. 374 47

Experiments were designed to determine whether carbamoylation-related inhibition of glutathione reductase (GR) was involved in the previously reported correlation between nitrosourea carbamoylating activity (defined by the extent of binding to L-lysine) and the magnitude of Misonidazole (MISO) chemopotentiation. The extent to which 12 different nitrosoureas (NUs) inhibited GR activity in extracts of EMT-6/Ro cells was determined and compared to the magnitude of chemopotentiation realized when each was combined with MISO for the treatment of EMT-6/Ro cells in vitro. No correlation was observed between glutathione reductase inhibition and the potentiation of nitrosourea cytotoxicity by MISO in vitro, suggesting that inhibition of GR was not involved in the mechanism of MISO chemopotentiation. Furthermore, when the original correlation was re-examined with the inclusion of additional chemopotentiation data for four hydroxylated analogs of CCNU, including two which possess little or no lysine-carbamoylating activity but which were significantly enhanced by MISO, a correlation between carbamoylation and the magnitude of MISO chemopotentiation could not be established. From these studies we conclude that NU-carbamoylating activity is not the prime determinant of interaction between MISO and the NUs.
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PMID:Carbamoylation, inhibition of glutathione reductase and chemopotentiation of nitrosoureas by misonidazole. 375 62

Misonidazole (MISO), a selective radiosensitizer of hypoxic cells, forms adducts with cellular biomolecules with rates which are 30-50 X higher under hypoxic as compared to aerobic conditions of incubation. This technique of sensitizer adduct formation was proposed as a possible means of measuring the hypoxic fraction of solid tumors by noninvasive procedures. Iodoazomycin riboside (5'-IAZR) and 5'-[125I]AZR were synthesized and chemically characterized. Measurements of in vitro cytotoxicity and radiosensitizing ability with EMT-6 tumor cells in vitro indicated that 5'-IAZR is approximately 3 X more toxic and effective than is azomycin riboside (AZR) and approximately 10 X more toxic and effective than is MISO. 5'-[125I]AZR was shown to selectively bind to hypoxic EMT-6 cells at rates which were 2.5-3 X faster than those of MISO. The absolute rates of binding of 5'-IAZR to hypoxic cells at concentrations of 10-100 microM are the highest observed in this laboratory for any hypoxic cell radiosensitizer tested to date. These data suggest that 5'-IAZR, when labeled with an appropriate radioisotope (e.g., 131I), might be a useful marker for hypoxic cells in solid tumors amenable to noninvasive detection. Additional studies with animal tumor models appear to be warranted.
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PMID:Iodoazomycin riboside (1-(5'-iodo-5'-deoxyribofuranosyl)-2-nitroimidazole), a hypoxic cell marker. I. Synthesis and in vitro characterization. 395 69

[82Br]Misonidazole ( [82Br]MISO) was investigated as a potential agent for scintillation imaging and indexing of hypoxic areas in tumor masses. [82Br]MISO was prepared by irradiating samples of Br-MISO in a SLOWPOKE reactor for 2 h at a thermal neutron flux of 10(12) n cm-2 s-1. Radiochemical yields ranged from 11 to 16%. [82Br]MISO had a plasma clearance half-life of approximately 40 min in BALB/c mice bearing EMT-6 tumors. The major metabolic product was identified as [82Br]Desmisonidazole. [82Br]MISO showed relatively high tumor uptake and persistently high plasma levels.
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PMID:Synthesis and in vivo studies of the radiosensitizer 4-[82Br]bromomisonidazole. 666 23

[14C]Misonidazole (MISO) becomes bound to macromolecules of mammalian cells upon hypoxic incubation. Intracellular enzyme processes are implicated since the temperature dependence for this process showed an activation energy of 33.5 kcal/mol. The sensitizer bound to both hypoxic and aerobic cells was associated with the macromolecular fraction and the soluble fraction in the proportion, 23 and 77%, respectively. The initial rate of binding of [14C]MISO to the macromolecular (acid-insoluble) fraction of hypoxic EMT-6 mouse tumor and V-79 hamster cells increased proportionally with the square root of extracellular concentration of MISO up to at least 5mM. High concentrations of dimethyl sulfoxide (an effective OH radical scavenger), allopurinol (an effective inhibitor of xanthine oxidase), and diamide (a chemical which can deplete cellular levels of glutathione) had little or no effect on this metabolism-induced binding process. The addition of high concentrations of exogenous cysteamine to hypoxic cell cultures resulted in almost complete inhibition of binding. Extracellular bovine albumin at high concentration in hypoxic cell cultures had little effect on the production of adducts to cell macromolecules and only small amounts of [14C]MISO were found to bind to the extra-cellular bovine albumin. This result suggests that MISO preferentially binds to molecules within the cell in which it is metabolically activated. In experiments where cells labeled under hypoxic conditions with [14C]MISO were subsequently permitted to proliferate in aerobic monolayers, a half-life of the acid-insoluble addition products of approximately 55 hr was measured. A large number of [14C]MISO adducts (approximately 10(9)/cell) can be generated in hypoxic cells without any evidence of cytotoxicity, and they are slowly cleared from cells. These are favorable characteristics as regards the development of this technique as a marker for hypoxic cells in solid tumors.
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PMID:Characteristics of the metabolism-induced binding of misonidazole to hypoxic mammalian cells. 683 1