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Cancer May 1985The rationale for hypoxic cell radiosensitizers, of which misonidazole (MISO) is the most widely used drug, is based on the premise that hypoxic cells limit the cure... (Clinical Trial)
Clinical Trial Review
The rationale for hypoxic cell radiosensitizers, of which misonidazole (MISO) is the most widely used drug, is based on the premise that hypoxic cells limit the cure rate of tumors to conventional radiotherapy. There is evidence that this is the case for tumors of the head and neck and possibly also for carcinoma of the cervix and lung. Despite numerous trials, however, MISO has not shown a significant clinical benefit. However, it can be demonstrated that little or no effect would have been expected at the doses of MISO used. New and more efficient radiosensitizers are now available which are more likely to produce significant improvements in local control with radiotherapy. The sulfhydryl radioprotector WR-2721 protects normal more than malignant tissues in animals from damage by radiation and chemotherapy agents. Evidence for protection of bone marrow and kidney has now been obtained for cyclophosphamide and cisplatin, respectively, in Phase I clinical trials. Sensitizers and protectors demonstrate that chemical modification of the therapeutic index is possible for both radiation and chemotherapy treatment of cancer.
Topics: Amifostine; Animals; Aziridines; Clinical Trials as Topic; Drug Evaluation; Etanidazole; Glutathione; Humans; Misonidazole; Neoplasms; Neoplasms, Experimental; Nitroimidazoles; Oxygen; Radiation-Protective Agents; Radiation-Sensitizing Agents; Radiotherapy
PubMed: 2983876
DOI: 10.1002/1097-0142(19850501)55:9+<2222::aid-cncr2820551426>3.0.co;2-k -
Archiv Der Pharmazie Mar 2014Racemic misonidazole, a radiosensitizer formally used in radiation therapy of cancer and to date still applied, was once reported to exhibit strong inhibitory effects on...
Racemic misonidazole, a radiosensitizer formally used in radiation therapy of cancer and to date still applied, was once reported to exhibit strong inhibitory effects on mouse glutathione peroxidases (GPX). This appeared to qualify misonidazole as a lead structure for the development of novel GPX inhibitors to cause oxidative stress in chemotherapy-resistant tumors. A unique feature of misonidazole as an inhibitor of GPX is the absence of a thiol functionality. Therefore, it was expected to selectively target inhibition devoid of promiscuous interactions with cations and sulfhydryl groups. We synthesized the isomers of misonidazole and analyzed the ability of chiroptical high-performance liquid chromatography (HPLC) to identify the particular enantiomers. Due to the chiral pool synthesis, the assignment of the correct configuration could be verified. Finally, we evaluated both isomers for their inhibitory activities on bovine erythrocyte GPx-1, which is 87% homologous to the human enzyme. Despite the previously reported inhibition of racemic misonidazole on the less homologous mouse GPx-1, we did not find any significant inhibitory activity on the bovine enzyme for either isomer. Though misonidazole appears unlikely to be an inhibitor of human GPx-1 activity, we still spotlight misonidazole as a promising fragment-like lead structure in general.
Topics: Amino Acid Sequence; Animals; Cattle; Chromatography, High Pressure Liquid; Circular Dichroism; Drug Discovery; Enzyme Inhibitors; Glutathione Peroxidase; Isomerism; Misonidazole; Molecular Sequence Data; Oxidants; Glutathione Peroxidase GPX1
PubMed: 24375829
DOI: 10.1002/ardp.201300285 -
Cancer Clinical Trials 1980The data from 44 patients with documented glioblastoma who received 1.5 g/m2 of misonidazole twice weekly in conjunction with whole brain radiotherapy (total dose 6000...
The data from 44 patients with documented glioblastoma who received 1.5 g/m2 of misonidazole twice weekly in conjunction with whole brain radiotherapy (total dose 6000 rad) was analyzed for factors associated with the development of peripheral neuropathy. The average total cumulative dose of misonidazole was 16.9 g/m2 and mild to moderate reversible peripheral neuropathy developed in 18% of patients. Peripheral neuropathy was positively associated with: 1) evidence of residual misonidazole in pretreatment plasma samples (> 10 microgram/ml), 2) elevated plasma concentrations of misonidazole on the day following treatment (> 25% of 4-hour plasma concentration), and 3) a prolonged plasma half-life (an average of 25% greater in patients developing peripheral neuropathy). The use of corticosteriods was negatively associated with the development of peripheral neuropathy and appeared to confer some protection. Age, sex, total dose of misonidazole, 4-hour plasma concentration (namely, at the time of radiotherapy), or the receipt of phenytoin or barbiturates was not related to the development of peripheral neuropathy. Monitoring of plasma misonidazole concentrations during treatment in conjunction with careful examination of the patient may result in a reduction of the incidence or severity of peripheral neuropathy.
Topics: Adrenal Cortex Hormones; Barbiturates; Brain Neoplasms; Drug Interactions; Female; Glioma; Half-Life; Humans; Male; Middle Aged; Misonidazole; Nitroimidazoles; Peripheral Nervous System Diseases; Phenytoin
PubMed: 6253094
DOI: No ID Found -
European Journal of Nuclear Medicine... Sep 2017
Topics: Humans; Misonidazole; Neoplasms; Oxygen; Positron-Emission Tomography; Radiopharmaceuticals; Tumor Hypoxia
PubMed: 28634683
DOI: 10.1007/s00259-017-3754-9 -
Lancet (London, England) Oct 1978
Comparative Study
Topics: Dose-Response Relationship, Drug; Drug Evaluation; Humans; Hypoxia; Metronidazole; Misonidazole; Neoplasms; Nitroimidazoles
PubMed: 81431
DOI: 10.1016/s0140-6736(78)91592-1 -
The New England Journal of Medicine Dec 1979
Review
Topics: Animals; Female; Glioblastoma; Humans; Metronidazole; Misonidazole; Neoplasms; Oxygen Consumption; Radiation-Sensitizing Agents; Recurrence; Uterine Cervical Neoplasms
PubMed: 229413
DOI: 10.1056/NEJM197912273012606 -
International Journal of Cancer May 1995To correlate misonidazole concentrations and oxygen pressures (Po2) at identical locations within EMT6/Ro multi-cell spheroids (mean diameters +/- SD: 867 +/- 20... (Comparative Study)
Comparative Study
To correlate misonidazole concentrations and oxygen pressures (Po2) at identical locations within EMT6/Ro multi-cell spheroids (mean diameters +/- SD: 867 +/- 20 microns), Po2 measurements were performed with oxygen-sensitive microelectrodes during incubation of these spheroids with tritiated misonidazole (10 mg/I; 445 microCi/mg). In each individual spheroid, Po2 profiles were correlated with the corresponding spatial distribution of misonidazole as quantified by conventional autoradiography and grain counting. To compare the oxygenation status of spheroids in the measuring chamber with that of spheroids in spinner culture, misonidazole labeling was performed in both environments following the same protocol. All experiments were conducted in 20% oxygen and BME or in 5% oxygen and DMEM to obtain spheroids with different degrees of oxygenation. Labeled misonidazole was fairly evenly distributed in the outer, better oxygenated regions of EMT6 spheroids. In contrast, there was an accumulation of the labeled substance near central necrosis where low oxygen tensions were measured. Grain densities were similar at corresponding oxygen pressures under both environmental conditions. Except for some scatter, grain density as a function of oxygen pressure showed little variation in the Po2 range of 20-60 mm Hg, but exhibited a steep increase below 10 mm Hg. The findings imply that a substantial rise in local misonidazole labeling indicates a metabolically active tissue region at low Po2 that is not necessarily identical with the radiobiologically hypoxic cell fraction. A comparison of the labeling densities of spheroids in spinner flasks and in the Po2 measuring chamber indicates that oxygenation of spheroids is better in rotation culture than during microelectrode measurements.
Topics: Animals; Autoradiography; Calibration; Cell Division; Cell Hypoxia; Feasibility Studies; Mammary Neoplasms, Experimental; Mice; Microelectrodes; Misonidazole; Oxygen; Partial Pressure; Tritium; Tumor Cells, Cultured
PubMed: 7759162
DOI: 10.1002/ijc.2910610422 -
International Journal of Radiation... 1982This is a report on Radiation Therapy Oncology Group (RTOG) Protocol No. 78-32, a Phase I/II prospective study aimed at determining tolerance, tumor response, and...
This is a report on Radiation Therapy Oncology Group (RTOG) Protocol No. 78-32, a Phase I/II prospective study aimed at determining tolerance, tumor response, and survival of squamous cell carcinoma of the esophagus treated with unorthodox fractionation radiotherapy combined with misonidazole. Misonidazole was administered by mouth 4 to 6 hr prior to radiation, at a dose of 1.0 to 1.25 Gm/.m2; blood levels were measured at about 4 hr after intake of the drug and reported in micrograms/ml. Radiotherapy was administered at 4 to 6 hr post-misonidazole dose and given with 400 rad fractions, alternating 2 or 3 times/week, up to 4,800 rad. A total of 43 patients were entered; 26 are evaluable for survival at 1 year post accession. Thirty patients (88%) received the planned radiation course. Twenty-eight patients (78%) received the planned misonidazole dosage. Tumor response, evaluable in 18 patients, showed a complete regression (C.R.) in only 2 patients (11%); and partial response (P.R.) in 6 patients (33%). Eight patients (44%) showed no tumor response to planned therapy. Toxicity was acceptable and in 38 evaluable patients only 4 reported (11%) nausea and vomiting, 7 reported mild paresthesias (18%). The median survival was only five months. In 26 patients evaluable for 1 year survival determination, only 1 survived (3.8%) this period. In view of the poor tumor response and low survival observed, we do not recommend that this particular fractionation regimen with misonidazole be used in a Phase III randomized trial in squamous cell carcinoma of the esophagus.
Topics: Adolescent; Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Esophageal Neoplasms; Female; Humans; Male; Middle Aged; Misonidazole; Nitroimidazoles; Radiotherapy, High-Energy
PubMed: 6809704
DOI: 10.1016/0360-3016(82)90639-3 -
Current Drug Delivery 2019The use of Misonidazole (MISO), the first and a potential hypoxic tumor cell radiosensitizer, has been limited by peripheral neurotoxicity, thus discouraging phase III...
BACKGROUND
The use of Misonidazole (MISO), the first and a potential hypoxic tumor cell radiosensitizer, has been limited by peripheral neurotoxicity, thus discouraging phase III clinical trials.
OBJECTIVE
To develop a targeted drug delivery and tracing System with pH-sensitive liposomes (SpHLs) and Superparamagnetic Iron Oxide Nanoparticles (SPIONs) to counter MISO-related adverse effects and to enable tracing under magnetic resonance.
METHODS
SPION-MISO-SpHLs were prepared by a reverse evaporation and freeze-thawing method. HPLC and phenanthroline spectrophotometry were established for MISO and Fe determination. The characterization and in vitro pH-sensitivity of SPION-MISO-SpHLs were evaluated.
RESULTS
The maximal entrapment efficiencies of MISO and SPIONs in SPION-MISO-SpHLs were 30.2% and 23.7%, respectively. The cumulative release rates of MISO and SPIONs were respectively 2.49 and 2.47 times higher in pH 5.5 than in pH 7.4 buffer. The mean particle size of SPION-MISOSpHLs was 950 nm. The zeta potential was -58.9 mV in pH 7.4 buffer and 36.3 mV in pH 5.5 buffer. SEM imaging showed that SPION-MISO-SpHLs had similar spherical morphologies. SPIONs were packed in the center of liposomes and were well dispersed in a TEM graph. Magnetization curve showed that SPION-MISO-SpHLs retained superparamagnetic properties. SPION-MISO-SpHLs were compared with MISO+SPION+blank liposome in hypoxia and control groups of A549 cells. MISO and SPION concentrations in culture medium showed significant differences between the same concentration groups (P < 0.0001) and at different times (P < 0.0001).
CONCLUSION
SPION-MISO-SpHLs possess pH-dependent release ability and superparamagnetism, and thus provides a system for targeted delivery and tracing under magnetic resonance.
Topics: A549 Cells; Antineoplastic Agents; Drug Compounding; Drug Delivery Systems; Ferric Compounds; Humans; Hydrogen-Ion Concentration; Liposomes; Magnetic Phenomena; Metal Nanoparticles; Misonidazole
PubMed: 30426901
DOI: 10.2174/1567201816666181114124333 -
British Journal of Cancer Oct 1983A review of misonidazole pharmacokinetics in 83 consecutive patients treated for tumours other than glioma has shown that among patients not receiving enzyme-inducing...
A review of misonidazole pharmacokinetics in 83 consecutive patients treated for tumours other than glioma has shown that among patients not receiving enzyme-inducing agents the plasma elimination half life is lower in patients taking steroids. Such a difference is not seen if patients already taking enzyme inducers are given steroids. Five further patients with carcinoma of the lung, treated with radiation over a period of 3 weeks, have been studied in greater detail. Misonidazole, in oral dose of 1 gm-2, was given in conjunction with the first and last radiotherapy fractions, and dexamethasone, in a divided daily dose of 8 mg, was given throughout the radiation treatment, commencing after the first treatment. Misonidazole pharmacokinetics were studied at each administration. Following the dexamethasone treatment period there was a 25% reduction in misonidazole plasma elimination half life, a 24% reduction in plasma AUC0-00, and a 38% increase in 24 h urinary excretion (all changes being statistically significant--P less than 0.005). No changes were observed in the plasma AUC0-24 and urinary excretion of the major metabolite desmethylmisonidazole. Glomerular filtration rates in one patient, before and after treatment with dexamethasone, remained unchanged. These results suggest that the effect of dexamethasone on misonidazole kinetics is not related to an enhancement of demethylation.
Topics: Adult; Aged; Dexamethasone; Drug Interactions; Female; Humans; Kinetics; Lung Neoplasms; Male; Metabolic Clearance Rate; Middle Aged; Misonidazole; Nitroimidazoles; Phenobarbital; Phenytoin
PubMed: 6626454
DOI: 10.1038/bjc.1983.228