-
Radiotherapy and Oncology : Journal of... May 1989Nitroaromatic radiosensitizers are effective chemosensitizers in vitro and in vivo. We have used EMT6 tumour cells grown as multicellular spheroids to try and further...
Nitroaromatic radiosensitizers are effective chemosensitizers in vitro and in vivo. We have used EMT6 tumour cells grown as multicellular spheroids to try and further understand the role that hypoxia plays in this process. Our results show that the cell killing produced in whole spheroids following a 1-h exposure to melphalan (L-PAM) was enhanced by a 3-h pre-exposure to 5 mM misonidazole (MISO), an enhancement ratio of 1.3-1.7 being obtained. Sequentially disaggregating spheroids we also found that both L-PAM toxicity and MISO chemosensitization were relatively constant as a function of depth within the spheroid. The binding of 14C-MISO to spheroid cells, measured by scintillation counting of disaggregated cells and by autoradiography analysis of sectioned spheroids, demonstrated that binding increased with depth. However, cells in the outer layers of the spheroid bound more 14C-MISO than expected with fully aerobic cells, while in the innermost viable cells the binding was less than that measured in cells which were fully radiobiologically hypoxic. This suggests that the majority of viable spheroid cells were at oxygen tensions intermediate between those found in either fully aerobic or radiobiologically hypoxic cells, yet their levels of oxygenation were sufficiently low for MISO chemosensitization to occur.
Topics: Animals; Cell Line; Cell Survival; Drug Synergism; In Vitro Techniques; Melphalan; Mice; Misonidazole; Oxygen; Tumor Cells, Cultured
PubMed: 2748937
DOI: 10.1016/0167-8140(89)90123-0 -
The British Journal of Radiology Jan 1980
Topics: Humans; Lymphatic Metastasis; Misonidazole; Mouth Mucosa; Nitroimidazoles; Radiotherapy, High-Energy
PubMed: 6766338
DOI: 10.1259/0007-1285-53-625-44 -
International Journal of Radiation... Feb 1982From August 1978 through December 1979, 51 patients with advanced non-oat cell carcinoma of the lung were enrolled in a Phase I/II trial sponsored by the Radiation...
From August 1978 through December 1979, 51 patients with advanced non-oat cell carcinoma of the lung were enrolled in a Phase I/II trial sponsored by the Radiation Therapy Oncology Group (RTOG) employing misonidazole (a 2-nitroimidazole) as a hypoxic cell sensitizer and radiation. The purpose of this study was to test drug and radiation tolerance and to assess the short term efficacy of this unconventional treatment. Tumor doses of 600 rad wer given twice weekly for three weeks for a total of 3600 rad, preceded four to six hours by misonidazole in a dose of 2 gm/m2 or 1.75 gm/m2, administered orally. Forty-nine patients were evaluable. Serious toxicity from this treatment was rare. Grade 2 or 3 peripheral neuro-toxicity occurred in eight of 24 patients (33%) with drug doses of 2 gm/m2 and in four of 26 patients (15%) who received 1.75 gm/m2. Grade 3 or 4 central nervous system toxicity occurred in two patients. Two patients developed serious late radiation complications: one patient had a transverse myelitis that appeared one year following delivery of 3600 rad to the spinal cord; a second patient developed a tracheoesophageal fistula and pericarditis eight months following treatment. Objective responses were reported in 67% of patients (complete in 18%); 70% of the patients died with a median survival time of nine months. Of 32 patients eligible for 12 month follow-up, 34% survived more than one year. Patterns of relapse after initial treatment and comparison with results from other RTOG trials using conventional fractionation are discussed.
Topics: Adenocarcinoma; Adult; Aged; Carcinoma, Squamous Cell; Drug Evaluation; Female; Humans; Lung Neoplasms; Male; Middle Aged; Misonidazole; Nitroimidazoles; Radiotherapy; Radiotherapy Dosage
PubMed: 7085386
DOI: 10.1016/0360-3016(82)90532-6 -
PloS One 2017Mapping brain hypoxia is a major goal for stroke diagnosis, pathophysiology and treatment monitoring. 18F-fluoro-misonidazole (FMISO) positron emission tomography (PET)...
PURPOSE
Mapping brain hypoxia is a major goal for stroke diagnosis, pathophysiology and treatment monitoring. 18F-fluoro-misonidazole (FMISO) positron emission tomography (PET) is the gold standard hypoxia imaging method. Normobaric hyperoxia (NBO) is a promising therapy in acute stroke. In this pilot study, we tested the straightforward hypothesis that NBO would markedly reduce FMISO uptake in ischemic brain in Wistar and spontaneously hypertensive rats (SHRs), two rat strains with distinct vulnerability to brain ischemia, mimicking clinical heterogeneity.
METHODS
Thirteen adult male rats were randomized to distal middle cerebral artery occlusion under either 30% O2 or 100% O2. FMISO was administered intravenously and PET data acquired dynamically for 3hrs, after which magnetic resonance imaging (MRI) and tetrazolium chloride (TTC) staining were carried out to map the ischemic lesion. Both FMISO tissue uptake at 2-3hrs and FMISO kinetic rate constants, determined based on previously published kinetic modelling, were obtained for the hypoxic area. In a separate group (n = 9), tissue oxygen partial pressure (PtO2) was measured in the ischemic tissue during both control and NBO conditions.
RESULTS
As expected, the FMISO PET, MRI and TTC lesion volumes were much larger in SHRs than Wistar rats in both the control and NBO conditions. NBO did not appear to substantially reduce FMISO lesion size, nor affect the FMISO kinetic rate constants in either strain. Likewise, MRI and TTC lesion volumes were unaffected. The parallel study showed the expected increases in ischemic cortex PtO2 under NBO, although these were small in some SHRs with very low baseline PtO2.
CONCLUSIONS
Despite small samples, the apparent lack of marked effects of NBO on FMISO uptake suggests that in permanent ischemia the cellular mechanisms underlying FMISO trapping in hypoxic cells may be disjointed from PtO2. Better understanding of FMISO trapping processes will be important for future applications of FMISO imaging.
Topics: Animals; Brain; Hyperoxia; Kinetics; Magnetic Resonance Imaging; Middle Cerebral Artery; Misonidazole; Oxygen; Pilot Projects; Positron-Emission Tomography; Rats; Rats, Wistar
PubMed: 29091934
DOI: 10.1371/journal.pone.0187087 -
The British Journal of Radiology Nov 1983In a series of studies, we have shown that phenytoin, 300 mg daily for one week, produces consistent hepatic microsomal enzyme induction, resulting in a decrease of 25%...
In a series of studies, we have shown that phenytoin, 300 mg daily for one week, produces consistent hepatic microsomal enzyme induction, resulting in a decrease of 25% in misonidazole half-life, without causing any toxicity per se. A longer period of administration gives only a slightly greater induction. Phenobarbitone in a daily dose of 90 mg causes a reduction of 18% and 23% in misonidazole half-life after 1 and 2 weeks' pre-treatment respectively, but is less suitable clinically because of its sedative effect. A further series of studies using phenytoin as the inducing agent has shown that, despite adequate enzyme induction and increased misonidazole metabolism, it is impossible to increase the total dose of misonidazole beyond the usually accepted value of 12 g/m2 because of unacceptable neuropathy (a rate of 50% at a dose of 14 g/m2 over three weeks). In single doses of above 3.0-4.0 g of misonidazole, severe nausea and vomiting are prominent, so that this side effect is a determining factor in the treatment fractionation. Audiometric studies show no correlation between the incidence of peripheral neuropathy and abnormal audiograms, and have no value in the early prediction of neurotoxicity. It seems that despite causing increased metabolism, enzyme induction does not protect against neurotoxicity and thus will not permit the use of higher doses of misonidazole for increased radiosensitisation.
Topics: Adult; Aged; Drug Administration Schedule; Drug Interactions; Enzyme Induction; Half-Life; Humans; Kinetics; Microsomes, Liver; Middle Aged; Misonidazole; Nervous System Diseases; Nitroimidazoles; Phenobarbital; Phenytoin
PubMed: 6626878
DOI: 10.1259/0007-1285-56-671-865 -
Radiotherapy and Oncology : Journal of... Feb 1985The clinical work with chemical agents to restore the radiosensitivity of hypoxic cells began in 1973 with metronidazole, misonidazole was first given in 1974. The... (Clinical Trial)
Clinical Trial Review
The clinical work with chemical agents to restore the radiosensitivity of hypoxic cells began in 1973 with metronidazole, misonidazole was first given in 1974. The results so far recorded of the clinical trials with misonidazole have been generally disappointing. Only in 5 of 32 studies analyzed have significant benefits been shown to suggest real advantage with the use of misonidazole. Hypoxic cells must exist in all human tumours presenting for treatment and it is, however, probable that the oxygen effect is an important one at all dose fractionation regimes employed in radiotherapy but, after conventional fractionated radiotherapy, hypoxia may be a reason for failure in only a proportion of cases. The most important factor underlying the failure of misonidazole to achieve useful advantage is undoubtedly the low radiosensitizing concentrations achievable with the permitted dose of this neurotoxic drug. New drugs are under development and some have different dose-limiting toxicity. Those showing promise at this time are the Stanford compound, SR-2508, which is being extensively studied in the United States and the Roche compound, Ro 03-8799, which is being studied in the United Kingdom. It is possible that the greatest sensitization with the greatest tolerance will be achieved by a combination of drugs.
Topics: Adrenal Cortex Hormones; Clinical Trials as Topic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Etanidazole; Humans; Metronidazole; Misonidazole; Neoplasms; Nimorazole; Nitroimidazoles; Oxygen; Radiation-Sensitizing Agents
PubMed: 3157206
DOI: 10.1016/s0167-8140(85)80015-3 -
International Journal of Radiation... 1982With a view to modifying misonidazole (MISO) neurotoxicity, we initiated a randomized clinical study to assess a possible drug interaction and toxicity protection when... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
With a view to modifying misonidazole (MISO) neurotoxicity, we initiated a randomized clinical study to assess a possible drug interaction and toxicity protection when dexamethasone (DXM) is administered concomittantly with MISO. The ongoing study consists of: 1. Pharmacokinetic evaluation; 2. Assessment of toxicity. Fourteen patients undergoing radiation therapy for different types of malignant neoplasia (excluding brain tumors) have been randomized to receive either MISO alone, or DXM one week prior and during treatment with MISO. Five of seven patients receiving MISO alone developed peripheral neuropathies while only one out of 7 patients that received MISO with DXM coverage developed a transient and mild neuropathy. Pharmacokinetic evaluation of MISO in plasma and urine of those patients receiving DXM has shown no evidence of drug interaction. It is postulated that the mechanism of action of DXM is at the nerve cell membrane level, restoring and stabilizing cell surface properties. In future studies we will investigate the use of DXM with increasing doses of MISO above the recommended maximum dose of 12 gm/m2, hoping to achieve a higher tumor tissue level of MISO while avoiding unacceptable toxicity. The effect of Allopurinol on the plasma kinetics of MISO was studied in four additional patients, observing also no evidence of drug interaction.
Topics: Allopurinol; Dexamethasone; Drug Interactions; Humans; Misonidazole; Neoplasms; Nervous System Diseases; Nitroimidazoles; Time Factors
PubMed: 7107353
DOI: 10.1016/0360-3016(82)90641-1 -
Mutation Research Nov 1994Cytogenetic effects produced in bone marrow of mice by various doses of misonidazole (MISO, 100 to 1000 mg/kg bodyweight) were studied by assaying the induction of...
Cytogenetic effects produced in bone marrow of mice by various doses of misonidazole (MISO, 100 to 1000 mg/kg bodyweight) were studied by assaying the induction of micronuclei (MN) and chromosomal aberrations. Misonidazole increased the frequency of both micronuclei and chromosomal aberrations over normal at 24 h after treatment, however, the values were statistically significant from normal only at drug doses above 250 mg/kg. The increase was proportional to the drug dose with a best fit to linear quadratic model for MN induction. For chromosomal aberrations the data fitted equally well to linear as well as linear quadratic models.
Topics: Animals; Bone Marrow; Chromosome Aberrations; Dose-Response Relationship, Drug; Male; Mice; Mice, Inbred Strains; Micronuclei, Chromosome-Defective; Misonidazole
PubMed: 7523932
DOI: 10.1016/0165-7992(94)90002-7 -
International Journal of Radiation... Sep 1984Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, we reported a preliminary... (Clinical Trial)
Clinical Trial
Neurotoxicity induced by misonidazole (MISO) and desmethylmisonidazole (DMM) has become the dose limiting factor in clinical work. In 1981, we reported a preliminary study suggestive that Dexamethasone (DEXA) does have a protective effect against peripheral neuropathies (PN) resulting from toxicity of misonidazole. Furthermore, in that study we have observed that DEXA did not alter the plasma pharmacokinetics of misonidazole. We are presently investigating the use of DEXA (2 mg t.i.d. during treatment), with escalating doses of MISO in an attempt to modify its neurotoxicity. To date, 16 patients have been registered to receive total doses of MISO ranging from 13.5 to 17.5 gm/M2 given in 9 equally divided doses over 3 weeks. DEXA, 2 mg t.i.d. is given 3 days prior to the first dose and continues for the duration of therapy. All patients receive palliative radiation. No toxicity was seen at the total dose of 13.5 gm/M2. One grade I PN occurred in the first four patients receiving 15.5 gm/M2. Six additional patients were entered at this dose level and no further incidence of PN was observed. Patients are being entered at the next step of 17.5 gm/M2.
Topics: Adolescent; Adult; Aged; Dexamethasone; Dose-Response Relationship, Drug; Humans; Middle Aged; Misonidazole; Neoplasms; Nervous System Diseases; Nitroimidazoles; Radiation-Sensitizing Agents
PubMed: 6480455
DOI: 10.1016/0360-3016(84)90539-x -
British Journal of Cancer Dec 1982The hypoxic cell radiosensitizing properties of nimorazole have been investigated in a C3H mammary carcinoma transplanted to the feet of C3D2F1. The results have been... (Comparative Study)
Comparative Study
The hypoxic cell radiosensitizing properties of nimorazole have been investigated in a C3H mammary carcinoma transplanted to the feet of C3D2F1. The results have been compared with those obtained with misonidazole (MISO) in the same animal tumour system. For single-dose irradiation in air, nimorazole gives an enhancement ratio (ER) of approximately 1.4, independent of the dose of drug administered over the range 0.1-1.0 mg/g. MISO yields a similar ER at the 0.1 mg/g level but, unlike nimorazole, shows a steep dose-response curve with an ER of 2.2 when given in a concentration of 1.0 mg/g. No such dose-response relationship is seen with nimorazole despite the fact that tumour and plasma concentrations of the 2 drugs have an identical dose relationship. With irradiation given in 5 daily fractions, nimorazole and MISO at a dose of 0.3 mg/g per fraction both show an ER of approximately 1.3. The high drug doses used in single-fraction radiation experiments in animals bear little relation to those applicable to clinical practice since these would result in unacceptable toxicity. The results of the present studies are therefore of interest as nimorazole is potentially less toxic than MISO in humans but demonstrates similar radiosensitizing properties at clinically relevant dose levels.
Topics: Animals; Cell Survival; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Female; Male; Mammary Neoplasms, Experimental; Mice; Mice, Inbred Strains; Misonidazole; Nimorazole; Nitroimidazoles; Oxygen; Radiation-Sensitizing Agents
PubMed: 7150484
DOI: 10.1038/bjc.1982.300