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Nuclear Medicine Review. Central &... 2011During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by... (Comparative Study)
Comparative Study Review
During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (=FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical.
Topics: Cell Hypoxia; Coordination Complexes; Copper Radioisotopes; Humans; Misonidazole; Neoplasms; Organometallic Compounds; Positron-Emission Tomography; Radiation-Sensitizing Agents; Thiosemicarbazones
PubMed: 22219149
DOI: 10.5603/nmr.2011.00022 -
European Journal of Cancer & Clinical... Jul 1985The toxic side-effects of misonidazole (MISO) have been studied in two strains of mice over a wide weight range. The sensitivity of the mice, determined as the LD50...
The toxic side-effects of misonidazole (MISO) have been studied in two strains of mice over a wide weight range. The sensitivity of the mice, determined as the LD50 within 7 days of administration, varied by almost a factor of two. Differences were seen in the same strain, with heavy mice being most sensitive, and from strain to strain, with CBA mice being more susceptible than WHT albino mice. The toxicity of the MISO was closely related to a change in the peak blood levels, but showed no correlation with biological half-life. The tissue volume available for drug distribution appears to be reduced in large, heavy mice at high drug doses, and cannot be explained simply on the basis of drug exclusion from adipose tissue. For radiobiological studies with MISO doses of more than 0.5 mg/g it is recommended that it should be administered in a dosage that will give a known blood level of the drug, rather than simply by giving a constant dose based on body weight.
Topics: Animals; Body Temperature; Body Weight; Female; Kinetics; Lethal Dose 50; Male; Mice; Mice, Inbred CBA; Mice, Inbred Strains; Misonidazole; Species Specificity; Tissue Distribution
PubMed: 4043172
DOI: 10.1016/0277-5379(85)90224-x -
The British Journal of Radiology Apr 1981Since May 1978 the hypoxic-cell radiosensitizer, misonidazole (MIS), has been under clinical investigation in a phase III trial with multiple doses of the drug in 11... (Clinical Trial)
Clinical Trial
Since May 1978 the hypoxic-cell radiosensitizer, misonidazole (MIS), has been under clinical investigation in a phase III trial with multiple doses of the drug in 11 patients with brain tumours (seven glioblastomas, four recurrent brain tumours) and three patients with oesophageal carcinoma. The doses of MIS administered were usually well tolerated but the principal toxicities observed were peripheral neuropathy as well as nausea and vomiting was completely reversible. The incidence of neuropathy was not related to the pharmacological parameters of plasma level or half-life. Pharmacological assessment by high-pressure liquid chromatography included assays of plasma, urine and cerebrospinal fluid. The demethylated product, Ro-05-9963, was detected as the major metabolite. Peak plasma levels were obtained one to four hours after administration of MIS, with a half-life of five to ten hours. Cerebrospinal fluid levels of MIS correlated well with those of the plasma. MIS was mainly excreted as the demethylated metabolite, but less than 40% of the given dose could be recovered. The results obtained suggest that the present MIS dosage for glioblastoma patients results in a low plasma level with no observable therapeutic effect.
Topics: Adult; Aged; Brain Neoplasms; Clinical Trials as Topic; Esophageal Neoplasms; Female; Glioma; Humans; Kinetics; Male; Middle Aged; Misonidazole; Neoplasm Recurrence, Local; Nitroimidazoles
PubMed: 7013890
DOI: 10.1259/0007-1285-54-640-318 -
The British Journal of Radiology Jun 1984The sensitisation by misonidazole of tail radionecrosis in mice has been assessed using single doses from 0.01 to 1 mg g-1 body weight, for tails in three different...
The sensitisation by misonidazole of tail radionecrosis in mice has been assessed using single doses from 0.01 to 1 mg g-1 body weight, for tails in three different states of oxygenation affecting sensitivity. The levels of sensitisation after different injected doses of misonidazole could be described reasonably well by the Alper -Howard-Flanders relationship, originally applied to the sensitisation of cells by oxygen, and hence the relationship could be used for interpolation. With clamped tails gassed with nitrogen at room temperature, 21-25 degrees C, the injected dose giving half the maximum sensitisation (defined as K inj ) was about 0.12-0.17 mg g-1 (0.6-0.8 mM). Unclamped tails in air demonstrated a value for K inj of about 0.14 mg g-1, indicating that the background level of oxygen and the injected misonidazole were not additive regarding sensitisation. With clamped tails gassed with nitrogen warmed to 37 degrees C (near body-core temperature) the sensitivity was slightly increased compared with clamped tails at 21-25 degrees C, and the additional increase in sensitivity following injections of misonidazole ( K inj of about 0.22 mg g-1) was less than at 21-25 degrees. With tails in air at 37 degrees C the increase in sensitivity following misonidazole was much more marked ( K inj of about 0.05 mg g-1) than expected. When eight "daily" fractions were given using 0.67 mg g-1 misonidazole and with the target cells well oxygenated at 37 degrees C (effective OER of about 2.0), the amount of sensitisation was less than for single doses, but it was similar (i.e. dose-modifying) for radiation doses per fraction between 2.6 and 6.3 Gy. At a dose of 0.1 mg g-1, giving a serum level corresponding to about the maximum tolerable in humans, the dose reduction factor would be only about 1.03 which corresponds roughly to a doubling in the tail necrosis rate from 5% to 10%. With future less neurotoxic drugs, higher serum levels may be expected to be tolerated and hence the dose reduction factor could be greater. This aspect, applicable to some but not all tissues tested in mice, should not be neglected in the design of future clinical trials with hypoxic-cell radiosensitisers .
Topics: Animals; Dose-Response Relationship, Radiation; Female; Mice; Misonidazole; Necrosis; Nitroimidazoles; Radiation Dosage; Radiation Injuries, Experimental; Skin
PubMed: 6722448
DOI: 10.1259/0007-1285-57-678-507 -
International Journal of Radiation... Feb 1989A randomized prospective trial was performed to study the toxicity and efficacy of the hypoxic cell sensitizer, misonidazole (MISO), used as an adjunct to high... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
A phase I/II study of the hypoxic cell sensitizer misonidazole as an adjunct to high fractional dose radiotherapy in patients with unresectable squamous cell carcinoma of the head and neck: a RTOG randomized study (#79-04).
A randomized prospective trial was performed to study the toxicity and efficacy of the hypoxic cell sensitizer, misonidazole (MISO), used as an adjunct to high fractional dose radiotherapy in the management of unresectable Stage III and IV squamous cell carcinomas of the oral cavity, oropharynx and hypopharynx. From June 1979 to February 1983, 42 patients were randomized with 40 patients available for analysis. In the radiotherapy (RT) only group, 19 patients received a short course of high fractional dose radiotherapy with 400 rad per day, 5 days per week, to a total of 4400 to 5200 rad. In the radiotherapy plus misonidazole group (RT + MISO) 21 patients received the same radiotherapy plus 1.5 gm/m2 of misonidazole 3 times a week for a total of 7 doses. The observed side effects associated with misonidazole were: persistent numbness and paresthesia (1 patient), transient peripheral nerve paresis and persistent paresthesia (1 patient), and nausea and vomiting (2 patients). The treatment related morbidities were similar in both groups. Acute mucositis was seen in 4 of 19 patients in the RT group and 3 of 21 patients in the RT + MISO group. Acute airway obstruction requiring tracheotomy was seen in 2 patients with massive tumor in the base of tongue (1 in each group). Severe dysphagia requiring NG tube feeding was seen in 3 patients in the RT + MISO group and 3 patients in the RT group. The initial complete response rate in the RT group was 53%, versus 48% in the RT + MISO group. The estimated 2-year loco-regional control rates were 10% for RT alone and 17% for RT + MISO (no significancy). These results indicate that the addition of misonidazole does not improve the efficacy of high fractional dose radiotherapy for management of unresectable head and neck carcinomas. However, high fractional dose radiotherapy can be administered for the management of advanced head and neck carcinomas with acceptable morbidity and thus, is a useful regimen for future clinical trials of hyperbaric oxygen or new hypoxic cell sensitizers.
Topics: Aged; Carcinoma, Squamous Cell; Clinical Trials as Topic; Combined Modality Therapy; Female; Head and Neck Neoplasms; Humans; Male; Middle Aged; Misonidazole; Multicenter Studies as Topic; Prospective Studies; Radiotherapy; Radiotherapy Dosage; Random Allocation
PubMed: 2646255
DOI: 10.1016/0360-3016(89)90343-x -
Radiotherapy and Oncology : Journal of... Apr 1985As the radiation field used in the radiation therapy of malignancies in the thoracic cavity often exposes the trachea to ionizing irradiation, it is important to...
As the radiation field used in the radiation therapy of malignancies in the thoracic cavity often exposes the trachea to ionizing irradiation, it is important to ascertain the effects of radiation on this tissue either as a single therapy or in combination with radiosensitizers. In the study reported here the vascular area in the subepithelial layer of the trachea has been calculated in 160 rabbits treated in four ways: (1) 10 rabbits received no treatment and served as controls; (2) 50 rabbits were given 100 mg misonidazole daily on consecutive days, with the individual total dose ranging from 100 to 1000 mg; (3) 50 rabbits were treated with misonidazole in the same way, but were also exposed to radiation (2 Gy/F) at 15-30 min later; (4) 50 rabbits received only fractionated radiation (2 Gy/F). The total radiation dose in the irradiated animals ranged from 2 to 20 Gy. In the treated groups, an oedema was observed in both the ciliary cell layer and in the subepithelial area. In the group given only irradiation, this oedema was dose-dependent, but no such dose-dependency was observed in the two groups treated with misonidazole. The vascular area in the groups treated with misonidazole was significantly increased as compared with the group given only irradiation and the control group; this was valid both with and without correction for the oedema. There was a significant correlation between the oedema and the vascular area in the groups treated with misonidazole, which was not found in the group irradiated without the drug.
Topics: Animals; Blood Vessels; Misonidazole; Nitroimidazoles; Rabbits; Trachea
PubMed: 4001445
DOI: 10.1016/s0167-8140(85)80035-9 -
International Journal of Radiation... Jun 1985The effect of extracellular pH (pHe) on the radiosensitization of hypoxic Chinese hamster V79 cells in vitro by the 2-nitroimidazole, misonidazole, and analogues...
The effect of extracellular pH (pHe) on the radiosensitization of hypoxic Chinese hamster V79 cells in vitro by the 2-nitroimidazole, misonidazole, and analogues substituted with basic or acid functions has been studied. Misonidazole (1 mmol dm-3) gave an enhancement ratio (e.r.) of 1.6 which remained unchanged over the pHe range of 3.8-9.5. Control hypoxic survival curves in the absence of sensitizer also remained essentially unchanged over this pHe range. These results contrast with those seen for 0.1 mmol dm-3 Ro 03-8799 (1-(2-nitro-1-imidazolyl)-3-N-piperidino-2-propanol), a base with pKa = 8.9): the ER increased from 1.4 to 2.1 as pHe increased from 5.6 to 8.4. However, with the weaker bases, Ro 03-8800 and nimorazole (morpholino derivatives with pKa = 6.3 and 5.2 respectively) the e.r. remained constant over a wide pHe range. Nitroimidazoles substituted with acidic functions gave decreasing sensitization with increasing pHe. For azomycin (pKa = 7.2) at 1 mmol dm-3 the e.r. decreased from 1.9 at pHe 4 to 1.0 at pHe 9. The effect of the proton conductor carbonyl cyanide-3-chlorophenylhydrazone (CCCP, 10 mumol dm-3) on radiosensitization by Ro 03-8799 (0.1 mmol dm-3) and misonidazole (1.0 mmol dm-3) was also studied. At pHe 6.67 the e.r. for Ro 03-8799 was increased from 1.36 to 1.76 by the presence of CCCP, whereas at pHe 7.33 the e.r. was unchanged. In contrast the e.r. for misonidazole was unchanged at pHe 6.65 and 7.33. These results are consistent with pH differentials across the cell membrane creating intracellular:extracellular concentrations gradients for radiosensitizers with acidic or basic functions.
Topics: Animals; Carbonyl Cyanide m-Chlorophenyl Hydrazone; Cell Line; Cell Survival; Cricetinae; Extracellular Space; Fibroblasts; Hydrogen-Ion Concentration; In Vitro Techniques; Misonidazole; Nimorazole; Nitroimidazoles; Radiation Tolerance; Radiation-Sensitizing Agents
PubMed: 3873434
DOI: 10.1080/09553008514550881 -
Cancer Clinical Trials 1980Clinical experience at Mount Vernon from November 1974 has now extended to over 200 patients. Neurotoxicity is the dominant dose-limiting toxic effect and was seen in... (Clinical Trial)
Clinical Trial Comparative Study
Clinical experience at Mount Vernon from November 1974 has now extended to over 200 patients. Neurotoxicity is the dominant dose-limiting toxic effect and was seen in 28% of those given two or more doses. Randomized clinical trials in carcinoma of bronchus, bladder, and breast have so far shown no advantage to those in patients with carcinoma of the cervix. Although misonidazole may be shown to be of benefit in certain situations, it is unlikely to be a drug of general use in radiotherapy. The promise of an increase in local tumor control in radiotherapy with use of an effective hypoxic cell sensitizer remains. New more effective hypoxic cell sensitizers are needed.
Topics: Adult; Clinical Trials as Topic; Dose-Response Relationship, Drug; Female; Half-Life; Humans; Male; Misonidazole; Nitroimidazoles
PubMed: 7000388
DOI: No ID Found -
International Journal of Radiation... Oct 1985Between February 1979 and January 1982, a Phase II study of misonidazole as a radiosensitizer was performed in 34 patients with advanced carcinoma of the uterine cervix....
Between February 1979 and January 1982, a Phase II study of misonidazole as a radiosensitizer was performed in 34 patients with advanced carcinoma of the uterine cervix. Twenty-nine patients were treated with conventional fractionated radiation and five patients with a twice daily fractionation schedule, 3 days a week. The total dose to the whole pelvis was 5000 cGy delivered in 5.5 weeks. Intracavitary curietherapy delivered an additional boost to the tumor. Misonidazole was given to all patients during external radiation and to 25 patients during intracavitary treatment for a total dose of 11 to 14 g/m2. All patients were followed for at least 28 months after treatment with a median follow-up of 52 months. Misonidazole toxicity included peripheral neuropathy (18%) and central nervous system toxicity (3%). The 3-year survival rate is 74% and the 3-year disease-free survival is 57%. When compared to our historical group survival, 42 and 12% for Stage III and IV, respectively, our data suggest that there is a probable advantage from using misonidazole in advanced carcinoma of the cervix.
Topics: Female; Humans; Lymph Nodes; Misonidazole; Radiotherapy Dosage; Uterine Cervical Neoplasms
PubMed: 4044341
DOI: 10.1016/0360-3016(85)90032-x -
British Journal of Cancer Apr 1982A quantitative, cytochemical assay for measuring lysosomal enzymes in the peripheral nerves of mice has been developed. That the time course of lysosomal enzyme changes...
A quantitative, cytochemical assay for measuring lysosomal enzymes in the peripheral nerves of mice has been developed. That the time course of lysosomal enzyme changes after misonidazole (MISO) treatment reflects the degree of neurotoxicity of this agent in the mouse, has been confirmed by the use of two known neurotoxic compounds: methyl mercury and acrylamide. This effect is specific to the peripheral nerves and was not found in liver, kidney, heart or cerebral cortex. Enzyme activities varied with mouse strain and sex, as did the response to MISO treatment. Of the mice studied, female C57 gave the greatest increase in beta-glucuronidase activity. With the MISO dose of 0.6 mg/g/dose the increased enzyme activity was independent of the route of administration and appeared to approach a plateau after 5 daily doses.
Topics: Acrylamide; Acrylamides; Animals; Female; Glucuronidase; Male; Methylmercury Compounds; Mice; Mice, Inbred Strains; Misonidazole; Nitroimidazoles; Sex Factors; Tibial Nerve
PubMed: 7073948
DOI: 10.1038/bjc.1982.95