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Lancet (London, England) Sep 1978
Topics: Cell Survival; Humans; Hypoxia; Misonidazole; Neoplasms; Nitroimidazoles; Oxygen Consumption; Radiation Tolerance
PubMed: 80536
DOI: No ID Found -
Biochemical Pharmacology May 1983The isolated perfused rat liver was evaluated as a model system for the characterization of misonidazole metabolism under hypoxic conditions. Misonidazole metabolism by...
The isolated perfused rat liver was evaluated as a model system for the characterization of misonidazole metabolism under hypoxic conditions. Misonidazole metabolism by livers perfused under aerobic conditions was also examined. The clearance of misonidazole was more than three times greater under anaerobic compared to aerobic conditions (4.94 +/- 1.56 vs 1.27 +/- 0.22 ml/min; means +/- S.D., N = 3). Misonidazole metabolites were detected only in the bile. Analysis of these metabolites by reverse-phase high performance liquid chromatography (HPLC) demonstrated that misonidazole metabolism was also qualitatively changed when anaerobic conditions were employed. Misonidazole beta-glucuronide was the major metabolite detected under aerobic conditions, but it was a minor metabolite in anaerobically perfused livers. The three major metabolites produced under anaerobic conditions were not characterized, but desmethyl misonidazole (RO-07-9963) and the 2-amino-imidazole derivative of misonidazole (1-[2-aminoimidazol-1-yl]-3-methoxy-2-propanol) were excluded as possible structures.
Topics: Animals; Chromatography, High Pressure Liquid; Hypoxia; Kinetics; Liver; Male; Misonidazole; Nitroimidazoles; Rats
PubMed: 6860347
DOI: 10.1016/0006-2952(83)90335-0 -
Clinical Pharmacology and Therapeutics Mar 1983The kinetics of an oral dose (1.0 gm/m2) of the 2-nitroimidazole radiosensitizer misonidazole were studied in three groups of six healthy subjects before and after a...
The kinetics of an oral dose (1.0 gm/m2) of the 2-nitroimidazole radiosensitizer misonidazole were studied in three groups of six healthy subjects before and after a 1-wk course of phenytoin, phenobarbital, or ascorbic acid. Phenytoin and phenobarbital decreased mean misonidazole half-life by 27% and 23% and the decrease was associated with the respective increases in mean clearance of 42% and 31%. The area under the plasma concentration-time curve for the metabolite O-desmethylmisonidazole increased correspondingly. Volume of distribution of misonidazole was unchanged. After treatment with ascorbic acid there was a very small increase in the mean clearance of misonidazole, but there was no significant change in other kinetic parameters. Induction by phenytoin and phenobarbital of the oxidative metabolism of misonidazole is the most likely mechanism responsible. Deliberate induction of a patient's metabolism may help to reduce the neurotoxicity associated with the use of the drug. The efficacy of the radiosensitizing action of the drug is unlikely to be compromised under these conditions since peak plasma concentrations of misonidazole were not affected by treatment with either phenytoin or phenobarbital. The potentiation of the cytotoxic effects of misonidazole by ascorbic acid is unlikely to be related to a direct effect on the oxidative metabolism of misonidazole.
Topics: Adult; Ascorbic Acid; Drug Interactions; Female; Humans; Kinetics; Male; Misonidazole; Nitroimidazoles; Phenobarbital; Phenytoin; Protein Binding
PubMed: 6825387
DOI: 10.1038/clpt.1983.39 -
The British Journal of Radiology Oct 198314C-misonidazole was injected IP into BALB/C mice bearing EMT-6 tumours. Tumour and normal tissue levels of radioactivity were determined by liquid scintillation...
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.
Topics: Animals; Autoradiography; Carbon Radioisotopes; Female; Injections, Intraperitoneal; Mice; Mice, Inbred BALB C; Misonidazole; Neoplasms, Experimental; Nitroimidazoles; Oxygen Consumption; Time Factors; Tissue Distribution
PubMed: 6616139
DOI: 10.1259/0007-1285-56-670-745 -
The British Journal of Radiology Oct 1980Computer simulations have been made of four radiotherapy fractionation regimes either in current use or proposed for clinical trials of misonidazole. A variety of...
Computer simulations have been made of four radiotherapy fractionation regimes either in current use or proposed for clinical trials of misonidazole. A variety of cell-survival parameters and reoxygenation patterns have been used. The models allow the relative importance of repair capacity, reoxygenation rate, and dose per fraction to be assessed for these four schedules in the presence or absence of misonidazole. Unlike hyperbaric oxygen, the dose of misonidazole and the fractionation scheme to be used are critically interdependent, because the total drug dose is limited to 12 g/m2 by its neurotoxicity, regardless of the extent to which it is fractionated. The largest sensitizing effect is always demonstrated with six fractions, each given with 2 g/m2 of misonidazole. In the absence of reoxygenation a sensitizer enhancement ratio of 1.7 is predicted, but this falls to 1.1--1.2 if extensive reoxy-generation occurs. Less sensitization is observed with 30 fractions, each with 0.4 g/m2 of drug. However, for clinical use, the important question is which treatment kills the maximum number of tumour cells. Many of the simulations predict a marked disadvantage of reducing the fraction number for X rays alone. The circumstances in which this disadvantage is offset by the large SER values with a six-fraction schedule are few. The model calculations suggest that many small fractions, each with a low drug dose, are safest unless the clinician has some prior knowledge that a change in fraction number is not disadvantageous.
Topics: Animals; Cell Survival; Drug Administration Schedule; Female; Male; Misonidazole; Models, Biological; Neoplasms; Nitroimidazoles; Oxygen; Radiotherapy Dosage
PubMed: 7426922
DOI: 10.1259/0007-1285-53-634-981 -
British Journal of Cancer Apr 2017Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical... (Review)
Review
Pathological angiogenesis involves complex and dynamic interactions between tumour cells and other lineages existing in the microenvironment of the tumour. Preclinical and clinical data suggest that tumours can show dual, different adaptive responses against antiangiogenic agents: one successful adaptation is vascular normalisation, whereas the second adaptation is elicited through vascular trimming and increased hypoxia. These phenomena depend on the type of tumour and the type of agent. The classical approach for investigating acquired resistance against antiangiogenic agents is to identify compensatory signalling pathways emerging in response to VEGF blockade, which has led to the development of highly effective drugs; however, ultimately these drugs fail. Here we review how the dual stromal adaptive patterns determine the mechanisms of escape that go beyond the reprogramming of signal transduction pathways, which obliges us to investigate the tumour as an ecosystem and to develop uni- and multicompartmental models that explain drug resistance involving metabolic and immune reprogramming. We also propose a method for facilitating personalised therapeutic decisions, which uses 18F-fluoromisonidazole-positron emission tomography to monitor the dual stromal response in tumours of individual patients.
Topics: Angiogenesis Inhibitors; Cell Hypoxia; Drug Resistance, Neoplasm; Humans; Misonidazole; Neovascularization, Pathologic; Precision Medicine; Stromal Cells; Tumor Microenvironment; Vascular Endothelial Growth Factor A
PubMed: 28301873
DOI: 10.1038/bjc.2017.69 -
Journal of Nuclear Medicine : Official... Mar 1989Fluoromisonidazole, a member of a class of compounds referred to as "hypoxic sensitizers," accumulates in hypoxic, viable tumor cells. We hypothesized that it might...
Fluoromisonidazole, a member of a class of compounds referred to as "hypoxic sensitizers," accumulates in hypoxic, viable tumor cells. We hypothesized that it might therefore accumulate also in ischemic, but non-necrotic myocardium potentially salvageable by interventional therapy. To evaluate the myocardial kinetics of [18F]fluoromisonidazole (FM), 20 isolated perfused rabbit hearts were used to characterize the uptake and binding of tracer under control conditions (n = 6), or with ischemia (flow 10% of control, n = 5), hypoxia without low flow (control flow rates with hypoxic medium, n = 5), or with reperfusion (n = 4). Myocardial retention of tracer detected externally with gamma scintillation probes after 20 min of constant [18F]FM infusion followed by 20 min of washout with nonradioactive buffer was 41 +/- 7% and 46 +/- 8% of peak activity in hearts subjected to ischemia or hypoxia, respectively, and significantly higher than in hearts subjected to either control perfusion or to ischemia followed by reperfusion (18 +/- 6 and 16 +/- 5% of peak activity, respectively, p less than 0.01). The biologic half-time of retained tracer was 40 hr in all hearts indicating essentially irreversible binding. Based on these findings, we measured uptake of [18F]FM using positron emission tomography in five dogs subjected to acute coronary occlusion. Five to thirteen millicuries of tracer were injected within 3 hr of occlusion. Within 30 min after administration of tracer, 18F accumulation in ischemic myocardium was greater than that observed in normal myocardium. The results indicate that [18F]FM accumulates in ischemic myocardium in relation to diminished tissue oxygen content and not simply because of diminished flow. Thus, this class of compounds may be potentially useful to help identify hypoxic myocardium.
Topics: Animals; Coronary Disease; Dogs; Fluorine Radioisotopes; Hypoxia; Male; Misonidazole; Myocardium; Rabbits; Radionuclide Imaging
PubMed: 2738664
DOI: No ID Found -
American Journal of Clinical Oncology Aug 1983Between October 1979 and January 1982, a total of 39 cases were entered on a nonrandomized phase I-II protocol for the evaluation of misonidazole combined with radiation...
Misonidazole combined with large-fraction pelvic irradiation in the treatment of patients with advanced pelvic malignancies. Preliminary report of an ongoing RTOG phase I-II study.
Between October 1979 and January 1982, a total of 39 cases were entered on a nonrandomized phase I-II protocol for the evaluation of misonidazole combined with radiation in the treatment of patients with advanced pelvic malignancies of multiple gynecological and gastrointestinal origin. Patients were treated with pelvic irradiation using a dose of 1000 rad in one fraction every 4 weeks for a total of three treatments. Oral misonidazole at a dose of 4 g/m2, was administered 4-6 hours prior to the radiation treatment (total dose, 12 g/m2). Of the 39 patients entered, 25 have completed the three doses of radiation and have had at least one follow-up after the third treatment. Eight patients have had insufficient follow-up information for evaluation and five patients did not complete three doses of radiation but have follow-up. One patient was excluded from the study. Among the 30 patients with follow-up, there were four complete responses (13.3%) and seven partial responses (23.3%). Two patients showed no response, and 17 experienced progression of disease. Follow-up time ranged from 2 to 16 months. The most frequent toxicity in the study has been nausea and vomiting. There were eight cases of neurotoxicity reported: ototoxicity grade 1 (one patient), peripheral neuropathy grades 1 and 2 (six patients), and C.N.S. toxicity grade 2 (one patient). Toxicity from radiation was difficult to separate from the presenting symptomatology. In the 30 patients with follow-up information, eight cases of abdominal sequelae were seen with five of them major complications (perforation, obstruction, and abscess). Early information from the study indicates the following: The most frequent morbidity at this point is acute nausea and vomiting. This level of nausea is consistent with the protocol dose of misonidazole. From the evaluable patients, 5/30 (17%) have developed major bowel problems requiring surgery. At the time of this report, this protocol remains open for case accession.
Topics: Adolescent; Adult; Aged; Dose-Response Relationship, Drug; Drug Evaluation; Female; Humans; Middle Aged; Misonidazole; Nitroimidazoles; Palliative Care; Pelvic Neoplasms; Radiotherapy; Radiotherapy, High-Energy
PubMed: 6191560
DOI: 10.1097/00000421-198308000-00005 -
International Journal of Radiation... Mar 1987
Comparative Study
Topics: Animals; Humans; Hyperbaric Oxygenation; Mice; Mice, Inbred CBA; Misonidazole; Neoplasms; Neoplasms, Experimental
PubMed: 3558036
DOI: 10.1016/0360-3016(87)90025-3 -
Cancer Treatment Reports Jan 1980Following iv administration of misonidazole, evidence of decreased plasma half-life (3.8 hours versus 9.1 hours +/- 0.8 [SD] in eight other patients studied) and...
Following iv administration of misonidazole, evidence of decreased plasma half-life (3.8 hours versus 9.1 hours +/- 0.8 [SD] in eight other patients studied) and increased metabolism was observed in a patient receiving continuous phenytoin therapy.
Topics: Drug Evaluation; Drug Interactions; Half-Life; Humans; Infusions, Parenteral; Liver; Misonidazole; Nitroimidazoles; Phenytoin
PubMed: 7379050
DOI: No ID Found