Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1522282 (EMT)
 2,868 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Experiments were designed to test the hypothesis that mild heat treatment would selectively increase misonidazole (MISO) chemopotentiation of CCNU toxicity in hypoxic versus aerobic cells in vitro and in tumours in vivo via an augmentation of nitroreduction. EMT-6 cells were exposed to CCNU +/- 1.0 mM MISO under aerobic or hypoxic conditions for 4 h either at a constant 37 degrees C or at 41 degrees C for the first hour followed by 37 degrees C for the remaining 3 h. Chemopotentiation was not observed under aerobic conditions and heat treatment did not modify CCNU toxicity. Co-incubation with MISO and CCNU under hypoxic conditions resulted in enhanced toxicity (i.e. chemopotentiation) with either incubation protocol; however, the magnitude of the enhancement was significantly larger (P less than 0.025) when 41 degrees C incubation was included. Systemic heat treatment produced a similar enhancement of chemopotentiation in KHT tumours in C3H/HeN mice treated with MISO (0.5 mg g-1) and whole body hyperthermia (41 degrees C, 1 h) prior to administration of CCNU (15 mg kg-1). Heating had no effect on CCNU response but doubled the median growth delay produced by the CCNU-MISO combination. Heat treatment did not enhance myelosuppression of the combination. Both the in vitro and in vivo data indicate that mild hyperthermia can selectively enhance the magnitude of MISO chemopotentiation.
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PMID:Enhancement of misonidazole chemopotentiation by mild hyperthermia (41 degrees C) in vitro and selective enhancement in vivo. 349 11

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

In order to assess the effect of oxygen on chemopotentiation by misonidazole (MISO), EMT-6/Ro tumor cells were exposed in vitro to combinations of CCNU and 1.0 mM MISO in culture medium equilibrated at various oxygen concentrations. The effect of oxygen on MISO cytotoxicity was similarly determined and compared with the relationship obtained for chemosensitization. MISO cytotoxicity and chemopotentiation were both oxygen sensitive, being maximal under anoxic conditions. Furthermore, the pattern of oxygen sensitivity was virtually identical for the two activities. These results suggest that a similar metabolic pathway, i.e., the oxygen-sensitive reduction of MISO to the nitroradical anion by cellular nitroreductases, is involved in the mechanism of both activities. The data further indicate that chemopotentiation can be expressed in cells treated at intermediate oxygen tensions. The implications of these findings with respect to the magnitude of chemopotentiation in vivo and the enhancement of normal tissue damage in animals treated with MISO and chemotherapy agents is discussed.
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PMID:Effect of oxygen on misonidazole chemosensitization and cytotoxicity in vitro. 646 2

Nitro-compounds containing an acetylated acetohydroxamic acid side chain in the N-1 position of a 5-membered ring nitrogen heterocycle have been synthesized. These compounds, which can generate isocyanates via a Lossen rearrangement, were evaluated in order to test the hypothesis that they may be effective radiation and chemosensitizing agents by nature of their isocyanate-associated carbamoylating potential. Evaluation of one such compound, DJW-77 (1(O-Acetyl-Acetohydroxamic acid)-3-nitropyrazole) as a radiation sensitizer, chemosensitizer and hypoxic cell toxin is reported. In vitro DJW-77 demonstrates a potent selective cytotoxicity toward hypoxic EMT-6 tumor cells, is an effective potentiator of CCNU toxicity and is comparable to MISO with respect to its radiation-sensitizing potential. The activity of the drug is eliminated under aerobic conditions. To test the hypothesis that the activity of DJW-77 is related to isocyanate generation, the non-acetylated analog of DJW-77 (which does not directly undergo the Lossen rearrangement) and the parent 3-nitropyrazole ring structure were evaluated. Neither compound enhanced CCNU toxicity, and on an equimolar basis were inferior to DJW-77 as radiation sensitizers. While the non-acetylated analog was cytotoxic to hypoxic cells, relative to DJW-77 this activity was substantially reduced. These studies indicate that the addition of a side chain capable of generating an isocyanate can enhance the cytotoxicity and sensitizing activity of nitroheterocycles.
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PMID:Preliminary evaluation of isocyanate-generating nitroheterocycles as chemosensitizers, radiosensitizers and hypoxic cell cytotoxic agents. 654 10