Quantitative cytochemical assessment of the neurotoxicity of misonidazole in the mouse

Clarke, Claire; Dawson, K.B.

doi:10.1038/bjc.1982.95

Cited by 6 publications

(4 citation statements)

References 10 publications

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“…As they predict, brain exposure (assessed on the basis of AUC) is correlated with distribution coefficient (Tables I & III) (Table III), we know that these 2 drugs are equally toxic for peripheral neuropathy in man (Dische et al, 1981;Coleman et al, 1982). Unfortunately, no laboratory assay in rodents has correctly ranked MISO, Ro 05-9963 and metronidazole, the neurotoxic dose limits of which have all been established in man (Hirst et al, 1979;Clarke et al, 1980;Conroy et al, 1980;Brown et al, 1981). The selection of compounds for extensive animal toxicology before clinical trial therefore remains arbitrary.…”

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confidence: 99%

In vivo assessment of basic 2-nitroimidazole radiosensitizers

Williams¹,

Denekamp²,

Minchinton³

et al. 1982

Br J Cancer

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Summary.-The radiosensitizing efficiencies of 4 structural analogues of misonidazole (MISO) have been compared with that of the parent compound. Three of these were charged basic compounds, previously shown in vitro to be 10 times more efficient. Enhancement ratios were measured from pairs of tumour growth-delay curves for the mouse fibrosarcoma SA Fab. Two routes of administration and ranges of drug dose and intervals between injection and irradiation were tested.Drug concentrations in blood, brain and tumour were measured using highperformance liquid chromatography. The peak concentration in tumours coincided with the peak in radiosensitization: 20 min after i.v. injection and 40 min after i.p. injection. The concentration in tumours was similar for either route.Comparison of radiosensitizing efficiency on the basis of equal administered dose showed no difference between the 5 compounds, but after equimolar doses the charged compounds achieved lower tumour concentrations. Comparison of sensitizing efficiency on the basis of tumour concentration showed that they were 3 times more potent than MISO, as predicted from their higher electron-affinity. The resultant improvement in radiosensitization at low, clinically relevant, concentrations is so slight that any therapeutic benefit would depend on reduced drug toxicity in man.

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confidence: 99%

In vivo assessment of basic 2-nitroimidazole radiosensitizers

Williams¹,

Denekamp²,

Minchinton³

et al. 1982

Br J Cancer

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“…This compound appeared to be 2-3 times less toxic in mice than MISO (e.g. Clarke et al, 1980) but in man it gives qualitatively and quantitatively similar peripheral neuropathy, and is limited to the same total dose of -12 g/m2 (Dische et al, 1981). This inability to predict toxicity in mice may result from the gross differences in pharmacokinetics, or because the clinical symptoms are reflecting sensory defects whereas the rodent tests are mainly for motor function.…”

Section: Discussionmentioning

confidence: 99%

Comparative studies of hypoxic-cell radiosensitization using artificially hypoxic skin in vivo

Denekamp¹,

Michael²,

Minchinton³

et al. 1982

Br J Cancer

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Summary.-The survival of epidermal cells in vivo has been used to assess potential radiosensitizers. Mouse skin was made acutely hypoxic for the irradiations, to give radioprotection by a factor of 2-7-3-0. Several concentrations of each drug were used to determine whether any of them were more effective sensitizers than misonidazole. The SER at each concentration was determined from radlobiological dose-response curves. The blood concentration and toxicity of the compounds were also determined. The sensitizing efficiency, assessed in several ways, indicated that only Ro 03-8799 gave significantly greater sensitization than misonidazole, and then only when assessed by comparing the compounds on the basis of equimolar blood concentrations. If the comparison of efficiency was made in terms of LDso the ranking order changed.

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“…This may well relate to central neuropathy, but does not seem to predict for clinical peripheral neuropathy, for the following reason: although the AUC value for Ro 05-9963 is one fifth that for MISO in the mouse (Table III), we know that these 2 drugs are equally toxic for peripheral neuropathy in man (Dische et al, 1981;Coleman et al, 1982). Unfortunately, no laboratory assay in rodents has correctly ranked MISO, Ro 05-9963 and metronidazole, the neurotoxic dose limits of which have all been established in man (Hirst et al, 1979;Clarke et al, 1980;Conroy et al, 1980;Brown et al, 1981). The selection of compounds for extensive animal toxicology before clinical trial therefore remains arbitrary.…”

Section: Discussionmentioning

confidence: 99%

Commentary: Discussion of "Health Effects of Air Pollution"

Palmes¹

1989

Environmental Health Perspectives

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The radiosensitizing efficiencies of 4 structural analogues of misonidazole (MISO) have been compared with that of the parent compound. Three of these were charged basic compounds, previously shown in vitro to be 10 times more efficient. Enhancement ratios were measured from pairs of tumour growth-delay curves for the mouse fibrosarcoma SA Fab. Two routes of administration and ranges of drug dose and intervals between injection and irradiation were tested. Drug concentrations in blood, brain and tumour were measured using highperformance liquid chromatography. The peak concentration in tumours coincided with the peak in radiosensitization: 20 min after i.v. injection and 40 min after i.p. injection. The concentration in tumours was similar for either route. Comparison of radiosensitizing efficiency on the basis of equal administered dose showed no difference between the 5 compounds, but after equimolar doses the charged compounds achieved lower tumour concentrations. Comparison of sensitizing efficiency on the basis of tumour concentration showed that they were 3 times more potent than MISO, as predicted from their higher electron-affinity. The resultant improvement in radiosensitization at low, clinically relevant, concentrations is so slight that any therapeutic benefit would depend on reduced drug toxicity in man.

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Quantitative cytochemical assessment of the neurotoxicity of misonidazole in the mouse

Cited by 6 publications

References 10 publications

In vivo assessment of basic 2-nitroimidazole radiosensitizers

In vivo assessment of basic 2-nitroimidazole radiosensitizers

Comparative studies of hypoxic-cell radiosensitization using artificially hypoxic skin in vivo

Commentary: Discussion of "Health Effects of Air Pollution"

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