Cytotoxic properties of a 4-nitroimidazole (NSC 38087): A radiosensitizer of hypoxic cells in vitro

Stratford, I J; Williamson, Christine J.; Hardy, Carolyn

doi:10.1038/bjc.1981.155

Cited by 18 publications

(6 citation statements)

References 14 publications

(17 reference statements)

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“…These cells are also more resistant than exponentially growing cells to mAMSA. Cells held at 41°C for long enough to modify their response to heat damage (Stratford et al, 1981a) or the cytotoxic action of some drugs (Stratford et al, 1981b) continue cycling, and this in turn is reflected in these cells having similar sensitivities to ADM and mAMSA when compared to exponentially growing cells held constantly at 37°C. Taken together these results are consistent with the proposal that the growth status of cells in vitro will be an important determinant of sensitivity to ADM or mAMSA.…”

Section: Discussionmentioning

confidence: 99%

“…Other experiments involving reduced pH were done with exponentially growing cells which had been cultured in medium at pH [6][7][8] for 16 h before drug treatment. Thermotolerant cells were prepared by maintaining log-phase cells at 41°C (pH 7 4) for 16 h (Stratford et al, 1981b The culture conditions described above were not inimical to our V79 cells, and all these cell populations had plating efficiencies > 9000 before treatment with cytotoxic drugs.…”

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confidence: 99%

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A comparison of adriamycin and mAMSA in vitro: Cell lethality and SCE studies

West¹,

Stratford²,

Barrass³

et al. 1981

Br J Cancer

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Summary.-We have compared the actions of ADM and mAMSA in Chinese hamster V79 cells in vitro, using cell survival and sister-chromatid exchange as end-points.Equimolar concentrations of ADM and mAMSA show similar toxicities to exponentially growing cells, and both drugs are less effective in killing chronically hypoxic and plateau-phase cells. Cytotoxicity to thermotolerant cells (41°C for 16 h previously) shows little difference from that for exponential cells. Pre-treating cells with misonidazole under hypoxic conditions reduces the toxicity of both ADM and mAMSA. In addition, an ADM-resistant Chinese hamster cell line, 77A-177, was crossresistant to mAMSA. Finally, low equimolar sub-toxic doses of both drugs were found to cause similar increases in the levels of sister-chromatid exchanges in V79 cells. These results reveal no major difference in activity between ADM and mAMSA in vitro.

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Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

A comparison of adriamycin and mAMSA in vitro: Cell lethality and SCE studies

West¹,

Stratford²,

Barrass³

et al. 1981

Br J Cancer

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“…This was observed not only with MISO and nitrofurantoin, which exhibit greater toxicity towards hypoxic than to aerobic cells, but also with NSC 38087, which has been shown to be more toxic in aerobic conditions (Stratford et al, 1981). Flurbiprofen did not protect against MISOinduced toxicity when added to cultures at the same time as the sensitizer.…”

Section: Discussionmentioning

confidence: 89%

“…A second sensitizer, NSC 38087, was examined which has been shown to be more toxic to aerobic than hypoxic cells (Stratford et al, 1981). Fig.…”

Section: Resultsmentioning

confidence: 99%

Flurbiprofen, a non-steroid anti-inflammatory agent, protects cells against hypoxic cell radiosensitizers in vitro

Millar¹,

Jinks²,

Powles³

1981

Br J Cancer

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Summary.-Overnight exposure of Chinese hamster cells (V79-753B) to 5 x 10-5M flurbiprofen (2-(2-fluoro-4-biphenyl)propionic acid) in vitro reduced the cytotoxic effects of misonidazole, 1-methyl -4-nitro -5 -phenoxysulphonylimidazole (NSC 38087) and nitrofurantoin, both in air and in hypoxia at 37°C. Flurbiprofen did not alter the cells' uptake of 14C-misonidazole, nor did it affect the radiosensitivity of aerobic or anaerobic cells, or the degree of hypoxic-cell radiosensitization produced by the sensitizers. When flurbiprofen-treated cells were exposed to melphalan there was no protection against cytotoxicity. These data suggest that flurbiprofen may inhibit the catabolism of radiosensitizers to toxic products and indicate the need to examine whether it will protect against misonidazole-induced toxicity in vivo.

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“…2'nitroimidazole derivatives were considered drug of choice in treatment of hepatic hypoxia (low oxygen) conditions in parasitic infections, cancer and recently nitroimidazole derivatives are emerging as hypoxia markers and radiosensitizers in tumor treatment [1,2]. Several reports on first initial stage of nitroimidazole induced liver cell cytotoxicity indicated the apoptosis, glutathione, DNA interaction, oxygen depletion, lactate inhibition, enhanced NADPH cytochrome reductase and superoxide dismutase enzymes [3][4][5][6][7][8][9][10][11][12][13][14][15]. Still nitroimidazole structurefunction relationship of hypoxia, radiosensitization and cytotoxicity remain less understood perhaps due to its low sensitivity to clinical investigations and available enzyme alterations at the very late necrotic stage [16][17][18][19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

The Hepatocellular Hypoxia Criteria:2’Nitroimidazole Effect on Hepatocyte Carbohydrate Metabolizing Enzymes

Sharma

2008

Nat Prec

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Aim: to understand the 2'-nitroimidazole induced hypoxia and liver cell interaction, we proposed a "Hapatocellular Hypoxia Criteria". Hypothesis: The nitroimidazole induced metabolic energy loss and oxygen depletion (hypoxia) in liver cell mitochondria causes the phagocytosis. Based on it, ten control subjects with 2'-nitroimidazole therapy were studied for their carbohydrate metabolizing enzymes in serum and hepatocellular enzymes in liver biopsy tissues. Materials and Methods: Proven ten control subjects were studied for hypoxia by enzyme assays. The 2'nitroimidazole treated paired ten subjects were studied for hypoxia using enzyme assays and hepatocellular cytomorphology by electron microscopy. Results and Discussion: Out of ten subjects on 2'-nitroimidazole, nine showed elevated carbohydrate metabolizing and lysosomal enzyme levels in serum. The enzymes glucokinase (in 80% samples), aldolase (in 80% samples), phosphofructokinase (in 80% samples), malate dehydrogenase (in 75% samples), isocitrate dehydrogenase (ICDH) (in 60% patients) were elevated while succinate dehydrogenase and lactate dehydrogenase (LDH) levels remained unaltered. Lysosomal enzymes-glucuronidase, alkaline phosphatase, acid phosphatase, β showed enhanced levels in the serum samples. In control ten liver biopsies, the hepatocytes and Kupffer cell preparations showed altered enzyme levels. Hepatocytes showed lowered glucokinase (in 80%), LDH (in 80%), and higher content of aldolase (in 80%), pyruvate kinase (in 100%), malate dehydrogenase (in 80%), ICDH (in 80%), citrate dehydrogenase (in 70%), phosphogluconate dehydrogenase (in 80%). Kupffer cells showed higher enzyme levels of-β glucuroronidase (in 80%), leucine aminopeptidase (in 70%), acid phosphatase (in 80%) and aryl sulphatase (in 88%). In these 10 biopsy samples from subjects on 2'-nitronidazole clinical trial, the electron microscopy cytomorphology observations showed swollen bizarre mitochondria, proliferative endoplasmic reticulum, and anisonucleosis after 2'-Nitroimidazole effect in liver cell damage. Conclusion: The proposed "Hepatocellular Hypoxia Criteria" served to define origin of liver hypoxia and showed altered hepatic enzyme activities with active phagocytosis and cytotoxicity in subjects after 2'-nitroimidazole treatment. The study suggests the enzyme

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Cytotoxic properties of a 4-nitroimidazole (NSC 38087): A radiosensitizer of hypoxic cells in vitro

Cited by 18 publications

References 14 publications

A comparison of adriamycin and mAMSA in vitro: Cell lethality and SCE studies

A comparison of adriamycin and mAMSA in vitro: Cell lethality and SCE studies

Flurbiprofen, a non-steroid anti-inflammatory agent, protects cells against hypoxic cell radiosensitizers in vitro

The Hepatocellular Hypoxia Criteria:2’Nitroimidazole Effect on Hepatocyte Carbohydrate Metabolizing Enzymes

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