Inhibition of DNA synthesis by nitroheterocycles I. Correlation with half-wave reduction potential

Olive, Peggy L.

doi:10.1038/bjc.1979.144

Cited by 54 publications

(15 citation statements)

References 9 publications

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“…2) which is described by the equation: -log C=0-011 E71+4-474 (r= 0.97) This correlation is very similar to those obtained between electron affinity and cytotoxicity in hypoxic cells (Adams et al, 1980;Olive, 1979bOlive, , 1980. This latter correlation, however, arises as a consequence of the amount of drug reduced, as may be seen from Fig.…”

Section: Resultssupporting

confidence: 80%

“…1) which is almost identical to that found for anaerobic bacteria (Reynolds, 1981). However, if a unit timescale is considered, a positive correlation is obtained, identical to that found in hypoxic cells as indicated by cell survival, inhibition of cell growth, mutagenicity, inhibition of DNA synthesis or production of DNA strand breaks (Adams et al, 1979b;Olive, 1979bOlive, , 1980. Since the mechanism of action of cytotoxicity is identical in each case (viz.…”

Section: Discussionsupporting

confidence: 72%

“…3). The metabolic reduction rates of nitroimidazoles in hypoxic cells are well established (Olive, 1979a(Olive, , 1980 and show an identical correlation with electron affinity to those relative rates obtained by electrolytic reduction at constant potential. Thus from published data (Olive, 1979a(Olive, , 1980 the positive correlation obtained for E7 1 and cytotoxicity in hypoxic mammalian cells can be corrected for relative drugreduction rates to produce a negative correlation.…”

Section: Discussionmentioning

confidence: 75%

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Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

Knox¹,

Knight²,

Edwards³

1981

Br J Cancer

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Summary.-An electrolytic reduction system has been developed to model the cytotoxic action of a range of nitroimidazole drugs against DNA in hypoxic cells or anaerobic microorganisms. The degree of damage induced by these drugs (measured as the release of [14C]-dT from DNA) and their relative rates of reduction have been correlated with their redox potentials. The results show that the correlation of druginduced damage and electron affinity is related to the amount of drug reduced, and supports the hypothesis that at the molecular level the cytotoxic mechanism of reduced nitroimidazoles is identical in hypoxic mammalian cells, bacteria and protozoa.HYPoxic CELLS are more resistant to ionizing radiation than well oxygenated ones, and their presence in human tumours may lead to the failure of radiotherapy. In addition to their ability as radiosensitizers, nitroimidazoles are selectively cytotoxic to hypoxic cells (Adams et al., 1978). The basis of structure-activity relationships in the development of electron-affinic nitroheterocyclic hypoxic cell radiosensitizers is a linear correlation of the type: -log C = bo + bi E + b2 log P + b3 (log P)2 where C is the drug concentration required to cause a specific and relevant biological effect, E is the electron affinity, usually expressed as the one-electron redox potential (E71), and P is the lipidwater partition coefficient of the drug. Adams et al. (1979a,b) have shown that lipophilicity has a negligible effect on radiosensitizing efficiency and cytotoxicity. Thus coefficients b2 and b3 may be omitted, yielding the simplified equation

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Section: Resultssupporting

confidence: 80%

Section: Discussionsupporting

confidence: 72%

Section: Discussionmentioning

confidence: 75%

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Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

Knox¹,

Knight²,

Edwards³

1981

Br J Cancer

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“…Since the nitroheterocycles inhibit the incorporation of [3H]-thymidine by L-929 cells (mouse fibroblast cells) cultured under aerobic conditions, Olive 30 selected three of them, including MTZ, for detailed studies of the mechanism of inhibition of DNA synthesis. The incubation with MTZ for 1 hour under aerobic conditions produced marked inhibition of DNA-precursor incorporation.…”

mentioning

confidence: 99%

Metronidazole Decreases Viability of DLD-1 Colorectal Cancer Cell Line

Sadowska

Krętowski

Szynaka

et al. 2013

Cancer Biotherapy and Radiopharmaceuticals

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The aim of our study was to evaluate the impact of metronidazole (MTZ) on DLD-1 colorectal cancer cell (CRC) line. Toxicity of MTZ was determined by MTT test. Cells were incubated with MTZ used in different concentrations for 24, 48, and 72 hours. The effect of MTZ on DNA synthesis was measured as [3H]-thymidine incorporation. The morphological changes in human DLD-1 cell line were defined by transmission electron microscope OPTON 900. The influence of MTZ on the apoptosis of DLD-1 cell lines was detected by flow cytometry and fluorescence microscopy, while cell concentration, volume, and diameter were displayed by Scepter Cell Counter from Millipore. Our results show that cell viability was diminished in all experimental groups in comparison with the control, and the differences were statistically significant. We did not find any significant differences in [3H]-thymidine incorporation in all experimental groups and times of observation. Cytofluorimetric assays demonstrated a statistically significant increase of apoptotic rate in MTZ concentrations 10 and 50 lg/mL after 24 hours; 0.1, 10, 50, and 250 lg/mL after 48 hours; and in all concentrations after 72 hours compared with control groups. In the ultrastructural studies, necrotic or apoptotic cells were occasionally seen. In conclusion, MTZ affects human CRC cell line viability. The reduction of cell viability was consistent with the apoptotic test.

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“…The enzymatic formation of the nitro anion free radical is thought to play a key role in both the biological activity and toxicity of nitroaromatic compounds (3,4). Since the ease of formation of the nitro anion radical is related to the oneelectron reduction potential (EW) ofthe parent compound attempts have been made to correlate biological activity with this parameter (15)(16)(17)(18)(19)(20).…”

Section: R-no1 -H--r-nhoh H R-nh2mentioning

confidence: 99%

Structure-activity relationships in the free-radical metabolism of xenobiotics.

Chignell¹

1985

Environ Health Perspect

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Many xenobiotics, including naturally occurring compounds, drugs, and environmental agents, are metabolized both in vivo and in vitro to free-radical intermediates. The one-electron reduction of nitroaromatic compounds, quinones, and a wide variety of other chemicals is catalyzed enzymatically by a number of reductases and dehydrogenases. Structure-activity studies have shown that the cytotoxicities of nitroaromatic compounds and quinones are related to their one-electron reduction potentials (EW). Other factors such as oil:water partition coefficients may also be important. Xenobiotics may also be oxidized to free radicals by peroxidases and oxidases. Hammett's rules apply to the one-electron oxidation of simple meta-or para-substituted phenols and amines by horseradish peroxidase, compound I.

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Inhibition of DNA synthesis by nitroheterocycles I. Correlation with half-wave reduction potential

Cited by 54 publications

References 9 publications

Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

Interaction of nitroimidazole drugs with DNA in vitro: Structure-activity relationships

Metronidazole Decreases Viability of DLD-1 Colorectal Cancer Cell Line

Structure-activity relationships in the free-radical metabolism of xenobiotics.

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