Imaging and quantitation of the hypoxic cell fraction of viable tumor in an animal model of intracerebral high grade glioma using [18F]fluoromisonidazole (FMISO).

We have demonstrated that FMISO uptake is significantly higher in tumor tissue in the C6 intracerebral glioma rat model compared to normal brain, and that there is persisting hypoxia in gliomas independent of tumor size. FMISO uptake was observed homogeneously throughout viable glioma tissue in tumor sizes ranging from 2mm to almost 1cm. Quantitation of uptake of FMISO showed a tumor/brain ratio of 1.9 and a tumor/blood ratio of 2.6 at 2 hours post injection.

Renal elimination of the hypoxic cell radiosensitizer misonidazole in Wistar rats: influence of some drugs on its excretion.

The hypoxic cell radiosensitizing drug, misonidazole (Miso) (Ro 07-0582) and its demethylated metabolite were administered to Wistar rats at different dose levels to examine their renal elimination. The data were consistent with a model in which Miso is eliminated mainly after biotransformation into desmethylmisonidazole (Demiso) which is eliminated according to its renal clearance. The study of Miso renal elimination process shows a tubular reabsorption. So we analyzed the interaction of various drugs on urinary 24 hours elimination of this radiosensitizer. Following results were observed: Furosemide and acetazolamide do not change the rate of renal elimination of the drug; Soludactone increases the elimination level of unmetabolized Miso (p less than 0.01); Under probenecid treatment, the elimination of Miso and its O-demethylated derivative are increased; On the other hand, after a pretreatment with phenobarbital, the urinary level of desmethylmisonidazole is strongly increased (p less than 0.001).

Detection of a reactive metabolite of misonidazole in human urine.

Chemical studies have indicated that, following reduction of misonidazole to the hydroxylamine derivative, reaction with guanosine leads to the formation of a 2-carbon addition product of guanosine. In this study, the formation of the guanosine product is used to detect the presence of a reactive metabolite of misonidazole in the urine of patients treated with misonidazole. Urine samples were incubated with [14C]guanosine and the guanosine product was separated by HPLC analysis. The quantities of product vary as much as 10-fold from patient to patient and it is suggested that the assay might be useful as a predictor of patients susceptible to the development of peripheral neuropathy or other effects of misonidazole.

Reduction of nitroheterocyclic compounds by mammalian tissues in vivo.

To determine whether nitro group reduction occurs in mammalian tissues, metronidazole (0.021, 0.064 and 10 mg/kg), misonidazole (0.015 mg/kg) and nitrofurazone (0.13 mg/kg), respectively, were administered to germfree rats. A reduced metabolite [1-(2-aminoimidazol-1-yl)-3-methoxypropan-2-ol] and two of its hydrolysis products, urea and (2-hydroxy-3-methoxypropyl)-guanidine, were found in the urines of germfree rats that received misonidazole. When nitrofurazone was administered, a reduced metabolite, 4-cyano-2-oxobutyraldehyde semicarbazone, was detected in the urines. However, acetamide and N-(2-hydroxyethyl)oxamic acid, fragmentation products from the reduction of metronidazole, were not found in significant concentrations in the urine when germfree rats received metronidazole. Apparently metronidazole is reduced so much more slowly than misonidazole and nitrofurazone in the tissues of germfree rats that its reductive metabolites are not detectable. This observation may be explained by the one-electron reduction potentials (E1 7) of these drugs, that of metronidazole (E1 7 = -486 mV) being lower than those of either misonidazole (E1 7 = -389 mV) or nitrofurazone (E1 7 = -257 mV). Under these circumstances, metronidazole reduction is not detected, either because its radical anion forms more slowly than that of the other nitroheterocyclic compounds or because its radical anion interacts more rapidly with oxygen to restore the parent compound.

Final report on the United States Phase I Clinical Trial of the hypoxic cell radiosensitizer, misonidazole (Ro-07-0582; NSC #261037).

The hypoxic cell sensitizer misonidazole began phase I evaluation in the United States in July 1977. One hundred two patients received 104 individual courses of drug. Drug was administered from once to five times per week over time spans from one to six weeks. The individual doses ranged 1-5 g/m2, and 411 mean 4-6 hour serum levels were determined. The mean 4-6 hour serum level ranged from 30 micrograms/ml at 1 g/m2 to 183 micrograms/ml at 5 g/m2. The major toxicity noted was neurologic; 49% of evaluable courses showed peripheral neuropathy, and 9% of evaluable courses showed central nervous system effects and/or ototoxicity. In addition, 48 of 102 patients exhibited some degree of nausea and vomiting. The concomitant administration of dexamethasone and phenytoin sodium appeared to lower the incidence of neuropathy. Observations of efficacy were made comparatively in five patients who had multiple lesions treated with and without misonidazole. All five showed increased response in the lesions treated with misonidazole. It is concluded that misonidazole is a reasonably safe and potentially effective hypoxic cell sensitizer whose dose-limiting toxicity is neurologic.