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The British Journal of Radiology Jan 2019The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured... (Review)
Review
The concept of tumour hypoxia as a cause of radiation resistance has been prevalent for over 100 years. During this time, our understanding of tumour hypoxia has matured with the recognition that oxygen tension within a tumour is influenced by both diffusion and perfusion mechanisms. In parallel, clinical strategies to modify tumour hypoxia with the expectation that this will improve response to radiation have been developed and tested in clinical trials. Despite many disappointments, meta-analysis of the data on hypoxia modification confirms a significant impact on both tumour control and survival. Early trials evaluated hyperbaric oxygen followed by a generation of studies testing oxygen mimetics such as misonidazole, pimonidazole and etanidazole. One highly significant result stands out from the use of nimorazole in advanced laryngeal cancer with a significant advantage seen for locoregional control using this radiosensitiser. More recent studies have evaluated carbogen and nicotinamide targeting both diffusion related and perfusion related hypoxia. A significant survival advantage is seen in muscle invasive bladder cancer and also for locoregional control in hypopharygeal cancer associated with a low haemoglobin. New developments include the recognition that mitochondrial complex inhibitors reducing tumour oxygen consumption are potential radiosensitising agents and atovaquone is currently in clinical trials. One shortcoming of past hypoxia modifying trials is the failure to identify oxygenation status and select those patient with significant hypoxia. A range of biomarkers are now available including histological necrosis, immunohistochemical intrinsic markers such as CAIX and Glut 1 and hypoxia gene signatures which have been shown to predict outcome and will inform the next generation of hypoxia modifying clinical trials.
Topics: Animals; Cell Hypoxia; Female; Humans; Male; Misonidazole; Neoplasms; Niacinamide; Oxygen Consumption; Radiation-Sensitizing Agents; Randomized Controlled Trials as Topic; Risk Assessment; Survival Analysis; Treatment Outcome; Tumor Hypoxia
PubMed: 29979089
DOI: 10.1259/bjr.20170966 -
Journal of Translational Medicine Aug 2023Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined...
BACKGROUND
Tumor hypoxia is associated with resistance to radiotherapy and chemotherapy. In head and neck squamous cell carcinoma (HNSCC), nimorazole, an oxygen mimic, combined with radiotherapy (RT) enabled to improve loco-regional control (LRC) in some patients with hypoxic tumors but it is unknown whether this holds also for radiochemotherapy (RCTx). Here, we investigated the impact of nimorazole combined with RCTx in HNSCC xenografts and explored molecular biomarkers for its targeted use.
METHODS
Irradiations were performed with 30 fractions in 6 weeks combined with weekly cisplatin. Nimorazole was applied before each fraction, beginning with the first or after ten fractions. Effect of RCTx with or without addition of nimorazole was quantified as permanent local control after irradiation. For histological evaluation and targeted gene expression analysis, tumors were excised untreated or after ten fractions. Using quantitative image analysis, micromilieu parameters were determined.
RESULTS
Nimorazole combined with RCTx significantly improved permanent local control in two tumor models, and showed a potential improvement in two additional models. In these four models, pimonidazole hypoxic volume (pHV) was significantly reduced after ten fractions of RCTx alone. Our results suggest that nimorazole combined with RCTx might improve TCR compared to RCTx alone if hypoxia is decreased during the course of RCTx but further experiments are warranted to verify this association. Differential gene expression analysis revealed 12 genes as potential for RCTx response. When evaluated in patients with HNSCC who were treated with primary RCTx, these genes were predictive for LRC.
CONCLUSIONS
Nimorazole combined with RCTx improved local tumor control in some but not in all HNSCC xenografts. We identified prognostic biomarkers with the potential for translation to patients with HNSCC.
Topics: Humans; Heterografts; Nimorazole; Squamous Cell Carcinoma of Head and Neck; Prognosis; Chemoradiotherapy; Hypoxia; Head and Neck Neoplasms
PubMed: 37633930
DOI: 10.1186/s12967-023-04439-2 -
Angewandte Chemie (International Ed. in... Feb 2021Nimorazole belongs to the imidazole-based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for...
Nimorazole belongs to the imidazole-based family of antibiotics to fight against anaerobic bacteria. Moreover, nimorazole is now in Phase 3 clinical trial in Europe for potential use as a hypoxia radiosensitizer for treatment of head and neck cancers. We envision the use of [ N ]nimorazole as a theragnostic hypoxia contrast agent that can be potentially deployed in the next-generation MRI-LINAC systems. Herein, we report the first steps to create long-lasting (for tens of minutes) hyperpolarized state on three N sites of [ N ]nimorazole with T of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000-fold at 1.4 T (corresponding to P of 3.2 %) by N- N spin-relayed SABRE-SHEATH hyperpolarization technique, relying on simultaneous exchange of [ N ]nimorazole and parahydrogen on polarization transfer Ir-IMes catalyst. The presented results pave the way to efficient spin-relayed SABRE-SHEATH hyperpolarization of a wide range of imidazole-based antibiotics and chemotherapeutics.
Topics: Anti-Bacterial Agents; Humans; Hydrogen; Magnetic Fields; Magnetic Resonance Spectroscopy; Nimorazole
PubMed: 33063407
DOI: 10.1002/anie.202011698 -
Journal of Radiation Research Dec 2005Sanazole (AK-2123, 3-nitrotriazole derivative, N1-(3-methoxypropyl)-2-(3-nitro-1 H-1,2,4-triazol-1-yl)acetamide) and nimorazole (5-nitroimidazole derivative,... (Comparative Study)
Comparative Study
Sanazole (AK-2123, 3-nitrotriazole derivative, N1-(3-methoxypropyl)-2-(3-nitro-1 H-1,2,4-triazol-1-yl)acetamide) and nimorazole (5-nitroimidazole derivative, 4-(2-(5-nitro-1H-1-imidazolyl)ethyl)morpholine) have been tested clinically as hypoxic cell radiosensitizers, mainly outside Japan. To determine if these sensitizers deserve clinical investigation in Japan, we reevaluated the radiosensitizing effects of these compounds in vitro and in vivo, in comparison with a fluorinated 2-nitroimidazole derivative KU-2285 (N1-(2-hydroxyethyl)-1,2-difluoro-3-(2-nitro-1 H-1-midazolyl)propanamide). KU-2285 is a known and established radiosensitizer, but is not suitable for clinical studies because of the high cost of synthesis. In vitro, the radiosensitizing effects of the three compounds on SCCVII (squamous cell carcinoma line in C3H mice) tumor cells were examined at 0.5 and 1 mM under aerobic or hypoxic conditions, using a colony assay. In vivo, SCCVII tumors grown subcutaneously in the hind legs of C3H/HeN mice were irradiated with or without prior intraperitoneal administration of 100, 200 or 400 mg/kg of the drugs. Thereafter, tumor growth delay was measured. In vitro, no sensitizing effect was observed under aerobic conditions at 1 mM. Under hypoxic conditions, the sensitizer enhancement ratio (SER) determined at 1% cell survival level for sanazole, nimorazole and KU-2285 was 1.55, 1.45 and 1.95, respectively, at 1 mM, and 1.40, 1.40 and 1.75, respectively, at 0.5 mM. In vivo, all three compounds had significant radiosensitizing effects; their effects appeared to decrease in the order of KU-2285, sanazole, and nimorazole. It was suggested that sanazole may be more suitable for clinical trials than nimorazole.
Topics: Animals; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Survival; Dose-Response Relationship, Drug; Dose-Response Relationship, Radiation; Drug Evaluation, Preclinical; Female; Mice; Nimorazole; Nitroimidazoles; Radiation Tolerance; Radiation-Sensitizing Agents; Treatment Outcome; Triazoles
PubMed: 16394636
DOI: 10.1269/jrr.46.453 -
The Journal of Physical Chemistry. A Jul 2020We study gas-phase photodissociation of radiosensitizer molecules nimorazole and metronidazole with the focus on the yield of the oxygen mimics nitrogen oxides and...
We study gas-phase photodissociation of radiosensitizer molecules nimorazole and metronidazole with the focus on the yield of the oxygen mimics nitrogen oxides and nitrous acid. Regardless of photon energy, we find the nimorazole cation to split the intramolecular bridge with little NO or NO production, which makes the molecule a precursor of dehydrogenated methylnitroimidazole. Metronidazole cation, on the contrary, has numerous fragmentation pathways with strong energy dependence. Most notably, ejection of NOOH and NO takes place within 4 eV from the valence ionization energy. Whereas the NO ejection is followed by further fragmentation steps when energy so allows, we find emission of NOOH takes place in microsecond time-scales and as a slow process that is relevant only when no other competing reaction is feasible. These primary dissociation characteristics of the molecules are understood by applying the long-known principle of rapid internal conversion of the initial electronic excitation energy and by studying the energy minima and the saddle points on the potential energy surface of the electronic ground state of the molecular cation.
PubMed: 32513004
DOI: 10.1021/acs.jpca.0c03045 -
Molecules (Basel, Switzerland) Jun 2022This novel work reports nimorazole (NIMO) radiosensitizer reduction upon electron transfer in collisions with neutral potassium (K) atoms in the lab frame energy range...
This novel work reports nimorazole (NIMO) radiosensitizer reduction upon electron transfer in collisions with neutral potassium (K) atoms in the lab frame energy range of 10-400 eV. The negative ions formed in this energy range were time-of-flight mass analyzed and branching ratios were obtained. Assignment of different anions showed that more than 80% was due to the formation of the non-dissociated parent anion NIMO at 226 u and nitrogen dioxide anion NO at 46 u. The rich fragmentation pattern revealed that significant collision induced the decomposition of the 4-nitroimidazole ring, as well as other complex internal reactions within the temporary negative ion formed after electron transfer to neutral NIMO. Other fragment anions were only responsible for less than 20% of the total ion yield. Additional information on the electronic state spectroscopy of nimorazole was obtained by recording a K energy loss spectrum in the forward scattering direction ( ≈ 0°), allowing us to determine the most accessible electronic states within the temporary negative ion. Quantum chemical calculations on the electronic structure of NIMO in the presence of a potassium atom were performed to help assign the most significant lowest unoccupied molecular orbitals participating in the collision process. Electron transfer was shown to be a relevant process for nimorazole radiosensitisation through efficient and prevalent non-dissociated parent anion formation.
Topics: Anions; Electron Transport; Electrons; Ions; Nimorazole; Potassium
PubMed: 35807379
DOI: 10.3390/molecules27134134 -
Cell Death Discovery 2020The hypoxic tumour is a chaotic landscape of struggle and adaption. Against the adversity of oxygen starvation, hypoxic cancer cells initiate a reprogramming of... (Review)
Review
The hypoxic tumour is a chaotic landscape of struggle and adaption. Against the adversity of oxygen starvation, hypoxic cancer cells initiate a reprogramming of transcriptional activities, allowing for survival, metastasis and treatment failure. This makes hypoxia a crucial feature of aggressive tumours. Its importance, to cancer and other diseases, was recognised by the award of the 2019 Nobel Prize in Physiology or Medicine for research contributing to our understanding of the cellular response to oxygen deprivation. For cancers with limited treatment options, for example those that rely heavily on radiotherapy, the results of hypoxic adaption are particularly restrictive to treatment success. A fundamental aspect of this hypoxic reprogramming with direct relevance to radioresistance, is the alteration to the DNA damage response, a complex set of intermingling processes that guide the cell (for good or for bad) towards DNA repair or cell death. These alterations, compounded by the fact that oxygen is required to induce damage to DNA during radiotherapy, means that hypoxia represents a persistent obstacle in the treatment of many solid tumours. Considerable research has been done to reverse, correct or diminish hypoxia's power over successful treatment. Though many clinical trials have been performed or are ongoing, particularly in the context of imaging studies and biomarker discovery, this research has yet to inform clinical practice. Indeed, the only hypoxia intervention incorporated into standard of care is the use of the hypoxia-activated prodrug Nimorazole, for head and neck cancer patients in Denmark. Decades of research have allowed us to build a picture of the shift in the DNA repair capabilities of hypoxic cancer cells. A literature consensus tells us that key signal transducers of this response are upregulated, where repair proteins are downregulated. However, a complete understanding of how these alterations lead to radioresistance is yet to come.
PubMed: 32864165
DOI: 10.1038/s41420-020-00311-0 -
Radiation Oncology (London, England) Mar 2018Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to...
BACKGROUND
Esophageal cancer is an aggressive disease with poor survival rates. A more patient-tailored approach based on predictive biomarkers could improve outcome. We aimed to predict radiotherapy (RT) response by imaging tumor hypoxia with F-FAZA PET/CT in an esophageal adenocarcinoma (EAC) mouse model. Additionally, we investigated the radiosensitizing effect of the hypoxia modifier nimorazole in vitro and in vivo.
METHODS
In vitro MTS cell proliferation assays (OACM5 1.C SC1, human EAC cell line) were performed under normoxic and hypoxic (< 1%) conditions: control (100 μL PBS), nimorazole, irradiation (5, 10 or 20 Gy) with or without nimorazole. In vivo, subcutaneous xenografts were induced in nude mice (OACM5 1.C SC1). Treatment was given daily for 5 consecutive days: (A) control (600 μl NaCl 0.9% intraperitoneally (IP)) (N = 5, n = 7), (B) RT (5 Gy/d) (N = 11, n = 20), (C) combination (nimorazole (200 mg/kg/d IP) 30 min before RT) (N = 13, n = 21). N = number of mice, n = number of tumors. F-FAZA PET/CT was performed before treatment and tumor to background (T/B) ratios were calculated. Relative tumor growth was calculated and tumor sections were examined histologically (hypoxia, proliferation).
RESULTS
A T/B ≥ 3.59 on pre-treatment F-FAZA PET/CT was predictive for worse RT response (sensitivity 92.3%, specificity 71.4%). Radiation was less effective in hypoxic tumors (T/B ≥ 3.59) compared to normoxic tumors (T/B < 3.59) (P = 0.0025). In vitro, pre-treatment with nimorazole significantly decreased hypoxic radioresistance (P < 0.01) while in vivo, nimorazole enhanced the efficacy of RT to suppress cancer cell proliferation in hypoxic tumor areas (Ki67, P = 0.064), but did not affect macroscopic tumor growth.
CONCLUSIONS
Tumor tissue hypoxia as measured with F-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.
Topics: Adenocarcinoma; Animals; Cell Hypoxia; Cell Line, Tumor; Esophageal Neoplasms; Humans; Mice; Mice, Nude; Nimorazole; Nitroimidazoles; Positron Emission Tomography Computed Tomography; Radiation Tolerance; Radiopharmaceuticals; Xenograft Model Antitumor Assays
PubMed: 29514673
DOI: 10.1186/s13014-018-0984-3 -
International Journal of Radiation... Dec 2023Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the...
Randomized Phase 3 Trial of the Hypoxia Modifier Nimorazole Added to Radiation Therapy With Benefit Assessed in Hypoxic Head and Neck Cancers Determined Using a Gene Signature (NIMRAD).
PURPOSE
Tumor hypoxia is an adverse prognostic factor in head and neck squamous cell carcinoma (HNSCC). We assessed whether patients with hypoxic HNSCC benefited from the addition of nimorazole to definitive intensity modulated radiation therapy (IMRT).
METHODS AND MATERIALS
NIMRAD was a phase 3, multicenter, placebo-controlled, double-anonymized trial of patients with HNSCC unsuitable for concurrent platinum chemotherapy or cetuximab with definitive IMRT (NCT01950689). Patients were randomized 1:1 to receive IMRT (65 Gy in 30 fractions over 6 weeks) plus nimorazole (1.2 g/m daily, before IMRT) or placebo. The primary endpoint was freedom from locoregional progression (FFLRP) in patients with hypoxic tumors, defined as greater than or equal to the median tumor hypoxia score of the first 50 patients analyzed (≥0.079), using a validated 26-gene signature. The planned sample size was 340 patients, allowing for signature generation in 85% and an assumed hazard ratio (HR) of 0.50 for nimorazole effectiveness in the hypoxic group and requiring 66 locoregional failures to have 80% power in a 2-tail log-rank test at the 5% significance level.
RESULTS
Three hundred thirty-eight patients were randomized by 19 centers in the United Kingdom from May 2014 to May 2019, with a median follow-up of 3.1 years (95% CI, 2.9-3.4). Hypoxia scores were available for 286 (85%). The median patient age was 73 years (range, 44-88; IQR, 70-76). There were 36 (25.9%) locoregional failures in the hypoxic group, in which nimorazole + IMRT did not improve FFLRP (adjusted HR, 0.72; 95% CI, 0.36-1.44; P = .35) or overall survival (adjusted HR, 0.96; 95% CI, 0.53-1.72; P = .88) compared with placebo + IMRT. Similarly, nimorazole + IMRT did not improve FFLRP or overall survival in the whole population. In total (N = 338), 73% of patients allocated nimorazole adhered to the drug for ≥50% of IMRT fractions. Nimorazole + IMRT caused more acute nausea compared with placebo + IMRT (Common Terminology Criteria for Adverse Events version 4.0 G1+2: 56.6% vs 42.4%, G3: 10.1% vs 5.3%, respectively; P < .05).
CONCLUSIONS
Addition of the hypoxia modifier nimorazole to IMRT for locally advanced HNSCC in older and less fit patients did not improve locoregional control or survival.
PubMed: 38072326
DOI: 10.1016/j.ijrobp.2023.11.055 -
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