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At least 19 recordsLinked to original sources
PubMed1983

A study of the effect of misonidazole in conjunction with radiotherapy for the treatment of grades 3 and 4 astrocytomas. A report from the MRC Working Party on misonidazole in gliomas.

Four hundred and thirty-six patients were treated between January 1979 and November 1981 in a double-blind randomised study of the effect of the hypoxic cell sensitiser misonidazole (Ro 07-0582, MISO) in conjunction with radiotherapy on grades 3 and 4 astrocytoma. Radiotherapy was given in 20 fractions over 4 weeks to a minimum tumour dose of 4500 cGy. Misonidazole or placebo capsules were taken four to five hours before each radiotherapy treatment to a total dose of 11-13 g m-2. Survival rates at 12 months, among the 384 eligible patients, were similar in the misonidazole treated patients (25%) and those receiving placebo (28%). The estimated hazard ratio was 1.05, indicating a slight disadvantage to misonidazole which was not statistically significant (logrank test: chi 2 = 0.18 on 1 d.f., p = 0.7). Peripheral neuropathy was noted in 11% of the misonidazole group and was mostly mild. Possible reasons for the failure to demonstrate any therapeutic gain from misonidazole are discussed.

Adolescent↗
PubMed1984

Metabolism induced binding of 14C-misonidazole to hypoxic cells: kinetic dependence on oxygen concentration and misonidazole concentration.

Under conditions of extreme hypoxia, metabolic products of the metabolism of misonidazole bind to cellular molecules at a rate which is linear with time and proportional to the square root of misonidazole concentration. Very small amounts of oxygen reduce the overall rate of binding and cause a change in the dependence on misonidazole concentration from square root (half order) to linear (first order). Because of the known electron affinity of misonidazole, a model is presented whereby the nitro-group is reduced to a radical in a first order reaction. This radical binds to cellular molecules in a slow first order reaction and either disproportionates or dimerizes in a fast second order reaction. Based on the overall effect of oxygen on the kinetics of the rate of binding, the radical is tentatively assumed to be the 3 electron reduction product.

Animals↗
PubMed1984

A study of the effect of misonidazole in conjunction with radiotherapy for the treatment of head and neck cancer. MRC working party on misonidazole in head and neck cancer.

The effect of the hypoxic cell sensitiser misonidazole as an adjuvant to radiotherapy of head and neck cancer was tested in a randomised double blind study. Patients with squamous carcinoma of the upper alimentary and respiratory tract, excluding those with early disease for which the prognosis was good, who were deemed suitable for radical radiotherapy and fit to receive the drug were entered into the study. Two radiotherapy regimes were employed, 10 fractions in 3 weeks to a modal tumour dose of 4000-4500 cGy, and 20 fractions in 4 weeks to a modal tumour dose of 5000-5750 cGy. Participating radiotherapists opted for one of the two schemes. Misonidazole or placebo capsules were administered 4 to 5 hours before each fraction of radiotherapy to a total of 11 to 13 g/m2. 168 patients were treated with 10 fractions and 99 with 20 fractions, between March 1979 and November 1981, when entry was stopped because of the high incidence of drug toxicity and lack of benefit. The estimated hazard ratio for local control was 0.89, indicating a slight advantage to misonidazole which was not statistically significant (p = 0.5). Peripheral neuropathy occurred in 56 patients who received misonidazole, and was more severe when treatment was given in 10 fractions.

Adult↗
PubMed1984

Misonidazole neurotoxicity in rats: Part II. Effect of pre- and intermittent treatment with pentobarbital on misonidazole neurotoxicity in the rat.

Rats pretreated for 5 days with 50 mg/kg of pentobarbital tolerated statistically significant higher doses of misonidazole before the onset of misonidazole-induced neurotoxicity than rats treated intermittently with the same dose of pentobarbital. Presumably in pretreated rats, pentobarbital induced an increase in the activities of hepatic microsomal enzymes that led to a more rapid metabolism of misonidazole than in rats treated only intermittently.

Animals↗
PubMed1983

Cytotoxic properties of hydroxylamino- and amino-misonidazole, possible metabolic products of misonidazole, in hypoxic HeLa S3 cells.

Misonidazole, a derivative of 2-nitroimidazole, has selective cytotoxic activity on hypoxic cells in addition to its radiosensitizing activity. This cytotoxicity is considered to be due to metabolic reduction of the drug. A possible metabolite seems to be hydroxylaminomisonidazole, an intermediate product derived via reduction of the nitro group. Authentic samples of hydroxylamino- and aminomisonidazole (a final reduction product) were synthesized and their cytotoxicity towards HeLa S3 cells was compared with that of misonidazole. After a 3-hr exposure to 1mM hydroxylaminomisonidazole under aerobic and hypoxic conditions, the surviving cell fractions were 0.18 and 0.0056, respectively. This represents a cytotoxicity five and 125 times greater, respectively, than that of misonidazole. Under the same conditions, aminomisonidazole showed no apparent cytotoxicity.

Antineoplastic Agents↗
PubMed1985

Comparison of binding of [3H]misonidazole and [14C]misonidazole in multicell spheroids.

Uptake of [2-ring-14C]misonidazole and [3H]misonidazole with tritium in the side chain has been compared in 1-mm EMT-6/UW spheroids using liquid scintillation counting and autoradiography. The uptake of both labeled sensitizers as a function of incubation time was virtually identical. Uptake by the spheroids exceeded levels in the medium by 11/2 to 2 hr and was well modeled as a first-order binding process, with rate constants of 0.00324 hr-1 for 3H and 0.00388 hr-1 for 14C. The similar uptake of the two versions of this sensitizer labeled in different positions suggests that the metabolic actions which allow the drug to bind in hypoxic cells do not principally involve metabolites which separate the number 2 carbon of the imidazole ring from the side chain. The pattern of silver grains in autoradiographs was similar for both labeled sensitizers, with most labeled drug bound in an intermediate zone of cells between the necrotic center and the actively proliferating rim of the spheroids. The superior resolution possible with the tritiated compound showed that both nucleus and cytoplasm in viable looking cells were labeled while pycnotic cells were not labeled.

Animals↗
PubMed1984

The Medical Research Council trial of misonidazole in carcinoma of the uterine cervix. A report from the MRC Working Party on misonidazole for cancer of the cervix.

153 patients from 13 centres were entered into a randomised controlled trial of the hypoxic cell sensitiser , misonidazole, in the radiotherapy of Stage III carcinoma of the uterine cervix. In an interim analysis at a time when follow-up periods extended from 9 to 45 months, no benefit in survival or local tumour control has been demonstrated. When disease-free survival of all cases was considered it was found that the younger patients did less well than the older patients and that the greater the immediate response to radiotherapy the longer was the duration of survival free of disease.

Adult↗
PubMed1984

Misonidazole neurotoxicity in rats: Part I. Evaluation of misonidazole neurotoxicity in rats by analysis of brain stem auditory and cortical evoked potentials.

The effects of misonidazole (MISO) on brain stem evoked potentials (BAEPs) and cortical evoked potentials (CEPs) were evaluated in 16 Sprague-Dawley rats treated with the agent. As found in previous studies, serial BAEP values were diagnostic of the onset of MISO toxicity before clinical signs and symptoms appeared. However, MISO had no effects on CEPs, which remained essentially unchanged through the course of the experiment. At histologic examination, significant changes were found in the area of the brain stem, but there was no histologic evidence of damage to cortical or subcortical structures caused by MISO administration. The results of this study suggest that the neurotoxic effects of MISO are species-specific, and that while the rat model may be useful for comparison of the relative toxic effects of nitroimidazole radiosensitizers, it is not a model suited for measurement of neurotoxicity caused by MISO in humans and nonhuman primates.

Animals↗
PubMed1991

Effect of environmental conditions (pH, oxygenation, and temperature) on misonidazole cytotoxicity and radiosensitization in vitro and in vivo in FSaIIC fibrosarcoma.

The effect of pH on misonidazole-induced cell killing at normal and elevated temperatures and on radiosensitization by misonidazole at 37 degrees C was assessed in FSaIIC fibrosarcoma cells in vitro. At doses of 5-500 microM for 1 hr, misonidazole was 1.5- to 2-fold more toxic toward hypoxic versus euoxic cells at 37 degrees C and pH 7.40. At 42 degrees C and 43 degrees C at pH 7.40, a less than 2-fold increase in cytotoxicity was observed in both normally oxic and hypoxic cells as compared with 37 degrees C. At pH 6.45 and 37 degrees C, misonidazole was less cytotoxic toward both euoxic and hypoxic cells than at pH 7.40. Unexpectedly, exposure to misonidazole at 42 degrees C or 43 degrees C and pH 6.45 caused no significant increase in cytotoxicity over that attributable to hyperthermia alone. Similarly, the dose modifying effect of misonidazole on single radiation fractions in vitro was also reduced at pH 6.45 versus pH 7.40 (2.60 versus 2.40, p less than 0.01). In vivo, treatment of the FSaIIC tumor with misonidazole (1 g/kg) and/or local hyperthermia (43 degrees C for 30 min to the tumor-bearing limb) in conjunction with radiation (10, 20, or 30 Gy) yielded a radiation dose modifying factor for misonidazole of 1.32, for hyperthermia of 1.38, and for the combination of 2.06 (probably additive). Analysis of the cytotoxicity achieved by these treatments in Hoechst 33342 dye-selected tumor subpopulations demonstrated that, whereas radiation was more toxic toward bright (presumably euoxic) cells, misonidazole, hyperthermia, and the combination were significantly more toxic toward dim (presumably hypoxic) cells. The addition of both hyperthermia and misonidazole to radiation more than overcame the relative resistance of the dim subpopulation to 10 Gy. These results indicate that misonidazole is a reasonable drug for use with hyperthermia and radiation to increase killing of hypoxic cells, but the decrease in cytotoxicity and radiosensitizing abilities of this agent observed under acidotic conditions could reduce the effectiveness of this treatment.

Animals↗
PubMed1983

The labelling of EMT-6 tumours in BALB/C mice with 14C-misonidazole.

14C-misonidazole was injected IP into BALB/C mice bearing EMT-6 tumours. Tumour and normal tissue levels of radioactivity were determined by liquid scintillation procedures for times up to 72 h after drug administration. At times longer than 8 h, levels of 14C in tumour were 2-6 times higher than 14C levels measured in other normal tissues, with the exception of liver. The levels of 14C from misonidazole retained in liver tissue were comparable to those retained in the tumours. The clearance of 14C-misonidazole from the tumours and all normal tissues could be characterised by two distinct phases: a rapid phase (0.7 h half-life) followed by a much slower phase (approximately 50 h half-life). The distribution of retained 14C from labelled misonidazole within tumour-bearing mice was also measured by whole animal autoradiographic techniques. This procedure confirmed the biodistribution of 14C-misonidazole determined by liquid scintillation procedures. To enhance binding to hypoxic cells in vivo, 14C-misonidazole was administered in multiple doses over a three-hour period, simulating a prolonged exposure to the drug. The 14C from labelled misonidazole retained in tumour tissue was 4-15 times greater than that retained in normal tissues, liver tissue being again an exception. Myocardial ischaemia was induced by isoproterenol treatment and a two-fold increase of 14C from labelled misonidazole was found in the heart tissue of mice treated by the drug compared to controls. The increased binding of 14C-misonidazole to tumour cells after prolonged exposure to the drug and the increased binding of 14C-misonidazole to ischaemic heart tissue suggests that hypoxia is a factor in sensitiser adduct formation in vivo.

Animals↗
PubMed1988

A randomized trial of hydroxyurea versus misonidazole adjunct to radiation therapy in carcinoma of the cervix. A preliminary report of a Gynecologic Oncology Group study.

Between June 1981 and December 1985, 296 evaluable patients with carcinoma of the cervix (stages IIB, III, or IVA) were randomized to radiation therapy and either hydroxyurea (139 patients) or misonidazole (157 patients). All patients had undergone clinical, radiographic, and surgical staging. Patients with metastasis to periaortic nodes were ineligible for study. Patients received external radiation therapy to the pelvis and either one or two intracavitary applications. Hydroxyurea was given in a dose of 80 mg/kg each Monday and Thursday during external radiation therapy. Misonidazole was given in a dose of 1 gm/m2 in the same schedule, not to exceed 12 gm/m2. Of the evaluable patients, 60.8% had stage IIB disease and 33.8% had stage IIIB disease. Negative pelvic lymph nodes were found in 79.2% of the patients. Median age was 49 years (first and third quartiles 40 and 60, respectively). There were 51 patients who had severe and 15 patients who had life-threatening adverse effects (including two treatment-related deaths). As of February 1987 half the patients have either failed or been followed-up for at least 43 months. The group treated with hydroxyurea had a longer progression-free interval, bordering on statistical significance, than those treated with misonidazole (p = 0.08). The median progression-free interval for all patients randomized to hydroxyurea is 42.9 months and for misonidazole it is 40.4 months. The median progression-free interval for patients with stage III and IV disease who received hydroxyurea has not been reached and for the misonidazole group it was 10.1 months. There have been 120 recurrences, 51 (36.7%) in the hydroxyurea group and 69 (43.9%) in the misonidazole group; 51.7% of the recurrences have been limited to the pelvis or vagina. Failure limited to the pelvis occurred in 18.0% of patients receiving hydroxyurea and 23.6% of patients receiving misonidazole. There were 108 deaths, 47 (33.8%) in the hydroxyurea group and 61 (38.9%) in the misonidazole group; survival does not differ statistically between the two regimens at this point in follow-up (p = 0.25). Hydroxyurea has more short-term gastrointestinal and marrow toxicity, but is free of long-term neurotoxicity. Preliminary analyses indicate that there is no role for radiation therapy with misonidazole in cervical carcinoma.

Adenocarcinoma↗
PubMed1989

Reductive metabolism and DNA binding of misonidazole.

Misonidazole (1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol) is an experimental anticancer drug. Reductive metabolism is thought to be important for the cytotoxicity of misonidazole. In this study, the DNA binding of misonidazole was examined after chemical and enzymatic reduction. Under anaerobic conditions, both rat liver microsomes and cytosol catalyzed the reductive metabolism and DNA binding of misonidazole. The misonidazole utilized in these studies was radiolabeled on the side chain. The adduct(s) formed was too unstable for structural analysis. Little or no metabolism of misonidazole was detected in aerobic incubations. Likewise, very little DNA binding occurred in the presence of oxygen. Xanthine oxidase, a model nitroreductase, also was capable of catalyzing the DNA binding of misonidazole. However, unlike the xanthine oxidase catalyzed DNA binding of carcinogenic nitropolycyclic aromatic hydrocarbons, the DNA binding of misonidazole was not increased at slightly acidic pH. The putative reactive intermediate, the N-hydroxylamine, was synthesized by zinc reduction of misonidazole. The DNA binding of the N-hydroxylamine derivative increased with increasing pH. The observed pH dependence of the reactions with DNA is similar to other heterocyclic N-hydroxylamines, but is in contrast to the reactivity of a number of aromatic N-hydroxylamines.

Animals↗
PubMed1982

The effect of misonidazole on the cytotoxicity and DNA cross-linking activity of an activated sulfidocyclophosphamide in hypoxic mouse leukemia cells.

The effect of misonidazole on the cytotoxicity of 4-S-(propionic acid)-sulfidocyclophosphamide (C-2) was assessed by measuring the colony-forming ability of mouse L1210 leukemia cells. C-2 under physiological conditions spontaneously hydrolyzes to 4-hydroxycyclophosphamide. Misonidazole alone at a concentration of 2.5 mM was only slightly toxic to hypoxic L1210 cells and allowed a greater than 90% survival following a 2-hr exposure. Combined treatment of C-2 and 2.5 mM misonidazole resulted in a cell kill that was greater than the additive toxicities of C-2 and misonidazole. The synergistic toxicity of the C-2 and misonidazole (2.5 mM) combination increased with increasing C-2 concentration, and at 0.01 survival the dose-modification ratio of C-2 alone versus the combination was approximately 1.5. Similarly, when the concentration of C-2 was held constant (10 microM) and the concentration of misonidazole varied from 2.5 to 25 mM, a cell kill greater than the additive toxicities of misonidazole and C-2 alone was observed. The kinetic patterns of formation and removal of DNA interstrand cross-links following a 2-hr treatment of 10 microM C-2 or 10 microM C-2 plus 2.5 mM misonidazole were similar. However, with the exception of the 0-hr time point, cells treated with the C-2 plus misonidazole combination showed consistently greater cross-linking of DNA than did cells treated with C-2 alone. The interstrand cross-link ratio closely correlated with the cytotoxic dose-modification ratio of the combination compared with C-2 alone.

Anaerobiosis↗
PubMedDate not supplied

Effect of misonidazole therapy on human granulopoietic stem cells.

Misonidazole is a 2-nitroimidazole compound currently being assessed as a radiosensitizing agent. The effects of misonidazole on human bone marrow hematopoiesis were assayed by culture of committed granulocyte-macrophage progenitor cells (CFU-C). Three groups of patients with nonhematologic malignancies were selected for study. The first group of patients received a single, large dose of misonidazole; the second group received smaller, multiple doses of misonidazole; and the third group who did not receive any misonidazole served as irradiation controls. In 14 of 16 patients who received single or multiple doses of misonidazole, there was a significant decrease in the number of CFU-C present in the bone marrow after misonidazole therapy. In five patients who received irradiation only, there was no difference in the number of pre- and post-treatment bone marrow CFU-C. In misonidazole treated patients, extensive washing of post-treatment bone marrow samples failed to return CFU-C growth to control values. Suppression of CFU-C growth persisted for 3 weeks and returned to control values by 8 weeks. This reduction in the proliferative capacity of human bone marrow progenitor cells suggests that misonidazole may add to the myelotoxicity already associated with radiotherapy, systemic chemotherapy, or as combination of the two.

Hematopoietic Stem Cells↗