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European Journal of Cancer Jan 1981
Topics: Animals; Half-Life; Injections, Intravenous; Injections, Spinal; Kinetics; Macaca mulatta; Male; Misonidazole; Nitroimidazoles
PubMed: 6894901
DOI: 10.1016/0014-2964(81)90208-5 -
International Journal of Hyperthermia :... 1992Tumour control by local hyperthermia (43.5 degrees C, 30 min) and radiation (20 Gy) given in combination with misonidazole (MISO) or metronidazole (METRO) was studied... (Comparative Study)
Comparative Study
Tumour control by local hyperthermia (43.5 degrees C, 30 min) and radiation (20 Gy) given in combination with misonidazole (MISO) or metronidazole (METRO) was studied using FSa-II murine fibrosarcoma. When MISO or METRO (5 mmol/kg) was given 30 min before heat and subsequently treated with radiation, tumour regression was observed for both agents. Radiation dose-response curves for MISO and METRO with heating at 43.5 degrees C for 30 min were identical. Mouse foot reaction was used to evaluate local toxicity following combined heat, a nitroimidazole and radiation treatment. MISO enhanced the magnitude of foot reaction and prolonged the recovery time compared with heat plus radiation controls. There were no observable differences of foot reaction between animals treated with heat plus radiation and those animals treated with heat, radiation and METRO. Pharmacokinetics of the nitroimidazoles heated at 43.5 degrees C for 30 min in FSa-II tumours were investigated as a possible mechanism of thermal sensitization. Local hyperthermia did not alter the pharmacokinetics of METRO. Tumour concentration and tumour/plasma ratio of MISO were slightly decreased during heating. Since the hypoxic metabolism of the nitroimidazoles did not increase significantly during the heat treatment, the thermal enhancement of MISO or METRO radiosensitization cannot be explained by the increase in hypoxic cytotoxicity of the nitroimidazoles at elevated temperature alone. The two nitroimidazoles also were not accumulated in the tumour after heating. Therefore, alternation of pharmacokinetics is not the major mechanism for the thermal enhancement of nitroimidazole radiosensitization. The METRO radiosensitization effect became identical to that of MISO at elevated temperatures is of particular importance in clinical radiosensitization. The very low local and systemic toxicity together with the high efficacy of METRO at elevated temperatures will make it an attractive candidate as a future clinical radiosensitizer.
Topics: Animals; Combined Modality Therapy; Hyperthermia, Induced; Metronidazole; Mice; Mice, Inbred C3H; Misonidazole; Radiation Tolerance; Sarcoma, Experimental
PubMed: 1402141
DOI: 10.3109/02656739209038000 -
International Journal of Radiation... Jun 1979
Clinical Trial
Topics: Anorexia; Clinical Trials as Topic; Drug Eruptions; Female; Humans; Male; Misonidazole; Nausea; Neoplasms; Nitroimidazoles; Peripheral Nervous System Diseases; Seizures
PubMed: 227822
DOI: 10.1016/0360-3016(79)90070-1 -
Cancer Jun 1980Several modalities involving a Multiple Daily Fractionation (MDF) course in combination with hyperthermia and/or the hypoxic sensitizer misonidazole have been tested on...
Several modalities involving a Multiple Daily Fractionation (MDF) course in combination with hyperthermia and/or the hypoxic sensitizer misonidazole have been tested on a mouse tumor system and then applied, with the proper sequencing, to a group of patients with multiple (N2-N3) neck node metastases from H&N cancers. Different lesions of the same patients underwent different modalities. The clinical results indicate the effectiveness, in respect to a historical series of patients treated with conventional fractionation (200 rads/day, five days/week), of either MDF alone (200 + 150 + 150 rads/day, five days/week) or MDF + hyperthermia (500 MHz, 42-43 C, 45 min., after 2nd daily fraction, on day 1, 3, and 5 of each week) or MDF + misonidazole (1.2 g/m2 daily, 2 hours before 1st fraction, up to a maximum dose of 12 g/m2), or MDF + hyperthermia + misonidazole. The latter modality appears to be possibly the most effective at inducing a complete local tumor response lasting longer in time (follow-up to a minimum of four months). The pharmacology of misonidazole has been monitored in the patients to avoid undesired excessive drug plasma level. No neurological symptoms have been observed. Oropharyngeal mucositis has been observed only in patients treated with misonidazole and radiation through two cross-firing portals. The problem of selecting individual patients for a particular modality is discussed.
Topics: Animals; Drug Administration Schedule; Head and Neck Neoplasms; Humans; Hyperthermia, Induced; Lymphatic Metastasis; Mice; Misonidazole; Neoplasms, Experimental; Nitroimidazoles; Radiation Dosage; Radiotherapy; Time Factors
PubMed: 7379004
DOI: 10.1002/1097-0142(19800601)45:11<2707::aid-cncr2820451102>3.0.co;2-6 -
International Journal of Radiation... Jun 1985The distribution of misonidazole and its terminal reduction product 1-(2-amino-1-imidazolyl)-3-methoxy-2-propanol (miso-amine) were compared in female Swiss Webster mice... (Comparative Study)
Comparative Study
The distribution of misonidazole and its terminal reduction product 1-(2-amino-1-imidazolyl)-3-methoxy-2-propanol (miso-amine) were compared in female Swiss Webster mice to determine if either misonidazole or miso-amine is distributed to peripheral nerves. Female Swiss Webster mice received a 100 mg/kg (5 microCi/mumole) i.p. dose of either 3H-misonidazole or 3H-miso-amine and the distribution of radioactivity was determined in various tissues including sciatic nerves and other myelinated nerves. Urine from misonidazole treated animals contained both miso-amine and misonidazole (8.4 and 20.4%, respectively, of the total radioactivity in the urine). Misonidazole produced higher initial tissue concentrations of radioactivity than did miso-amine. The relative tissue concentrations of radioactivity produced by misonidazole or miso-amine were similar, although not identical, 48 hours after administration of the drugs. Both sciatic and other myelinated nerves were found to retain radioactivity following the administration of either misonidazole or miso-amine.
Topics: Animals; Female; Mice; Misonidazole; Nitroimidazoles; Tissue Distribution; Tritium
PubMed: 3997598
DOI: 10.1016/0360-3016(85)90064-1 -
International Journal of Radiation... 1982Metabolism-induced binding of misonidazole was shown previously to be enhanced in hypoxic regions of V79 spheroids. Data are presented to show that the binding of...
Metabolism-induced binding of misonidazole was shown previously to be enhanced in hypoxic regions of V79 spheroids. Data are presented to show that the binding of misonidazole to EMT6 spheroids is similar to V79 in some respects and different in others. The binding rate in nitrogen was constant in all cells in EMT6 spheroids, whereas a 5-fold rise was found in binding rate across the outer 100 micrometers of V79 spheroids. A small enhancement of binding to the cells near the necrotic center in EMT6 spheroids in air was found, which was similar to the binding to chronically hypoxic cells in aerobic V79 spheroids. The binding rate in 1--5% oxygen was similar in EMT6 and V79 spheroids. Both showed a large rise in binding rate across the outer 120 micrometers and a constant binding rate to healthy cells interior to this. Since 1.5 oxygen should supply only the outer 40 micrometers of a typical spheroid, something beyond a simple oxygen diffusion limitation is required to explain the data. One possible explanation is the diffusion of some of the reactive product away from the hypoxic cells which produce it. This was tested by incubating a single cell suspension in misonidazole at 0.5% oxygen in the presence of absence of V79 spheroids. No evidence was found for an appreciable loss of reactive product from the spheroids.
Topics: Animals; Cells, Cultured; Cricetinae; Kinetics; Misonidazole; Neoplasms, Experimental; Nitroimidazoles; Oxygen
PubMed: 7107407
DOI: 10.1016/0360-3016(82)90724-6 -
Cancer Aug 1981
Review
Topics: Animals; Cell Line; Cell Survival; Cricetinae; Cricetulus; Dose-Response Relationship, Drug; Electrons; Humans; Melphalan; Mice; Misonidazole; Neoplasms; Oxygen; Radiation-Sensitizing Agents; Radiotherapy Dosage; Structure-Activity Relationship; Technology, Pharmaceutical
PubMed: 7018662
DOI: 10.1002/1097-0142(19810801)48:3<696::aid-cncr2820480307>3.0.co;2-v -
British Journal of Cancer May 1983We have investigated the effect of misonidazole (MISO) on the pharmacokinetics of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in mice. CCNU and its...
We have investigated the effect of misonidazole (MISO) on the pharmacokinetics of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) in mice. CCNU and its monohydroxylated metabolites were measured using a high performance liquid chromatography (HPLC) method. In the absence of MISO the plasma disappearance of CCNU was biphasic with a t 1/2 alpha of 2.3 min and a t 1/2 beta of 53 min. The monohydroxylated metabolites of CCNU also followed biphasic clearance kinetics. A large single dose of MISO (0.5 mg g-1), given i.p. 30 min prior to CCNU, prolonged the t 1/2 alpha by a factor of 2.6 but had no effect on t 1/2 beta. In addition, the apparent volume of distribution was decreased by a factor of 1.6. Consequently, the plasma area under the curve (AUC0 - infinity) was increased by a factor of 1.7 for CCNU and by a factor of 2.0 for total nitrosourea (CCNU + monohydroxylated metabolites). The effects of MISO on CCNU kinetics were dependent on MISO dose and plasma concentration and on the interval between MISO and CCNU administration. The concentration of CCNU was measured in 4 tumours: the KHT, RIF-1 and EMT6 mouse tumours, and the HT29 xenograft. For all 4 tumours, 0.5 mg g-1 MISO raised the tumour concentrations of CCNU and total nitrosourea by a considerable amount (2-2.5 times). More detailed studies in the KHT tumour demonstrated that there was a significant lag period before peak tumour CCNU concentrations were reached, and that MISO increased the peak concentrations by a factor of about 2.4. In contrast, there was no such lag period for the plasma and MISO did not increase the plasma peak CCNU concentrations. These data strongly suggest that modification of the pharmacokinetics may be a major contributory factor in the enhancement of CCNU cytotoxicity by large single doses of MISO in vivo.
Topics: Animals; Blood Proteins; Cell Line; Chromatography, High Pressure Liquid; Dose-Response Relationship, Drug; Drug Interactions; Female; Half-Life; Kinetics; Lomustine; Male; Mice; Mice, Inbred Strains; Misonidazole; Neoplasms, Experimental; Nitroimidazoles; Nitrosourea Compounds
PubMed: 6849803
DOI: 10.1038/bjc.1983.104 -
Radiation Research May 1981
Topics: Chromatography, High Pressure Liquid; Free Radicals; Misonidazole; Nitroimidazoles; Oxidation-Reduction; Spectrum Analysis
PubMed: 7232695
DOI: No ID Found -
International Journal of Radiation... 1982Reductive activation of misonidazole and misondiazole acetate, a simple derivative, in the presence of xanthine oxidase causes inactivation of the enzyme. The...
Reductive activation of misonidazole and misondiazole acetate, a simple derivative, in the presence of xanthine oxidase causes inactivation of the enzyme. The inactivation is not accompanied by binding of the misonidazole to the enzyme. The nitroreductase activity of xanthine oxidase is inhibited as measured by the reduction of 3,5-dinitrobenzonitrile (DNBN). Cysteine does not appear to protect against the enzyme inactivation by misonidazole but, by itself, cysteine has a strong stimulating effect on the reduction of DNBN. The possible significance of these reactions to the toxicity of misonidazole are discussed.
Topics: Biotransformation; Misonidazole; Nitro Compounds; Nitroimidazoles; Oxidation-Reduction; Xanthine Oxidase
PubMed: 6896706
DOI: 10.1016/0360-3016(82)90716-7