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1.
J Transl Med ; 21(1): 576, 2023 08 26.
Artigo em Inglês | MEDLINE | ID: mdl-37633930

RESUMO

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.


Assuntos
Neoplasias de Cabeça e Pescoço , Nimorazol , Humanos , Xenoenxertos , Nimorazol/farmacologia , Nimorazol/uso terapêutico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/radioterapia , Prognóstico , Quimiorradioterapia , Hipóxia/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia
2.
Cancer Treat Res ; 185: 59-77, 2023.
Artigo em Inglês | MEDLINE | ID: mdl-37306904

RESUMO

A crucial element of cancer treatment is radiation therapy that is used to destroy tumors and cancer cells through radiation. Another essential component is immunotherapy that helps immune system to combat cancer. The combination of both radiation therapy and immunotherapy is being focused recently for the treatment of many tumors. Chemotherapy includes the use of some chemical agent to control the growth of cancer, whereas irradiation involves the use of radiations of high energy to kill cancer cells. The union of both became the strongest practice in cancer treatment techniques. Specific chemotherapies are combined with radiation in the treatment of cancer after proper preclinical assessment of their effectiveness. Some classes of compounds include platinum-based drugs, antimicrotubules, antimetabolites (5-Fluorouracil, Capecitabine, Gemcitabine, Pemetrexed), topoisomerase I inhibitors, alkylating agents (Temozolomide), and other agents (Mitomycin-C, Hypoxic Sensitizers, Nimorazole).


Assuntos
Neoplasias , Humanos , Imunoterapia , Gencitabina , Mitomicina , Nimorazol
3.
Molecules ; 27(13)2022 Jun 28.
Artigo em Inglês | MEDLINE | ID: mdl-35807379

RESUMO

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 NO2- 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 (θ ≈ 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.


Assuntos
Elétrons , Nimorazol , Ânions , Transporte de Elétrons , Íons , Potássio/química
4.
J Chem Phys ; 154(7): 074306, 2021 Feb 21.
Artigo em Inglês | MEDLINE | ID: mdl-33607883

RESUMO

A comprehensive investigation of low-energy electron attachment and electron ionization of the nimorazole radiosensitizer used in cancer radiation therapy is reported by means of a gas-phase crossed beam experiment in an electron energy range from 0 eV to 70 eV. Regarding negative ion formation, we discuss the formation of fifteen fragment anions in the electron energy range of 0 eV-10 eV, where the most intense signal is assigned to the nitrogen dioxide anion NO2 -. The other fragment anions have been assigned to form predominantly from a common temporary negative ion state close to 3 eV of the nitroimidazole moiety, while the morpholine moiety seems to act only as a spectator in the dissociative electron attachment event to nimorazole. Quantum chemical calculations have been performed to help interpreting the experimental data with thermochemical thresholds, electron affinities, and geometries of some of the neutral molecules. As far as positive ion formation is concerned, the mass spectrum at the electron energy of 70 eV shows a weakly abundant parent ion and C5H10NO+ as the most abundant fragment cation. We report appearance energy (AE) measurements for six cations. For the intact nimorazole molecular cation, the AE of 8.16 ± 0.05 eV was obtained, which is near the presently calculated adiabatic ionization energy.


Assuntos
Elétrons , Nimorazol/química , Radiossensibilizantes/química , Modelos Moleculares , Conformação Molecular , Temperatura
5.
Eur J Pharm Biopharm ; 161: 29-36, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33567313

RESUMO

Glioblastoma multiforme is the most aggressive and lethal form of brain tumour due to the high degree of cancer cells infiltration into surrounding brain tissue. No form of monotherapy can guarantee satisfactory patient outcomes and is only of palliative importance. To find a potential option of glioblastoma treatment the bioresorbable, layer nonwoven mats for controlled temozolomide and nimorazole release were obtained by classical and coaxial electrospinning. Optimization of fibre structure that enables delayed and controlled drug release was performed. The studied bioresorbable polymers were poly(L-lactide-co-ε-caprolactone) and poly(L-lactide-co-glycolide-co-trimethylene carbonate). The physicochemical properties of polymers were determined as well as drug release profiles of nonwoven mats. A combination of coaxial electrospinning and electrospray technique provided three-phased release profiles of temozolomide and nimorazole: the slow release of very low drug doses followed by accelerated release and saturation phase. Results form the basis for further investigation since both studied polymers possess a great potential as nimorazole and temozolomide delivery systems in the form of layered nonwoven implants.


Assuntos
Implantes Absorvíveis , Portadores de Fármacos/química , Nimorazol/administração & dosagem , Temozolomida/administração & dosagem , Antineoplásicos Alquilantes/administração & dosagem , Antineoplásicos Alquilantes/química , Neoplasias Encefálicas/tratamento farmacológico , Química Farmacêutica , Preparações de Ação Retardada , Dioxanos/química , Liberação Controlada de Fármacos , Glioblastoma/tratamento farmacológico , Nimorazol/química , Poliésteres/química , Copolímero de Ácido Poliláctico e Ácido Poliglicólico/química , Polímeros/química , Radiossensibilizantes/administração & dosagem , Radiossensibilizantes/química , Temozolomida/química
6.
Angew Chem Int Ed Engl ; 60(5): 2406-2413, 2021 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-33063407

RESUMO

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 [15 N3 ]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 15 N sites of [15 N3 ]nimorazole with T1 of up to ca. 6 minutes. The nuclear spin polarization was boosted by ca. 67000-fold at 1.4 T (corresponding to P15N of 3.2 %) by 15 N-15 N spin-relayed SABRE-SHEATH hyperpolarization technique, relying on simultaneous exchange of [15 N3 ]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.


Assuntos
Antibacterianos/uso terapêutico , Hidrogênio/química , Espectroscopia de Ressonância Magnética/métodos , Nimorazol/uso terapêutico , Antibacterianos/farmacologia , Humanos , Campos Magnéticos , Nimorazol/farmacologia
7.
Radiother Oncol ; 148: 65-72, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32335364

RESUMO

BACKGROUND: A phase I-II study to evaluate the feasibility and efficacy of intensified, primary radiotherapy (RT) for Locally Advanced Head and Neck Squamous Cell Carcinoma (LAHNSCC) employing dose escalation by hyperfractionation, acceleration of treatment time, concomitant chemotherapy and hypoxic modification. METHODS: Patients with HPV/p16- LAHNSCC receiving primary hyperfractionated, accelerated RT, 76 Gy/56 fx, 10 fx/week for 5½ weeks, concomitant weekly cisplatin (40 mg/m2) and nimorazole (HART-CN) were included. Primary endpoint was locoregional failure (LRF). Secondary endpoints were overall survival (OS) and toxicity. RESULTS: 50 patients received HART-CN from 2013 to 2017. Median age was 60 years. Most patients had stage IV hypo- or oropharynx cancer with a heavy smoking history. All oropharyngeal cancers were HPV/p16-negative. Ninety-eight percent of patients completed RT, but compliance to cisplatin and nimorazole was lower. Median observation time was 44 months. LRF was diagnosed in 10 patients. All LRFs were in the high-dose CTV. The 3-year actuarial LRF was 21%, and OS was 74%. The peak incidence of acute toxicity showed that 67% of patients experienced severe dysphagia, 61% severe mucositis, and 78% were equipped with feeding tubes. Late severe morbidity was seen in 7 of 29 recurrence-free patients with at least 3 years of followup, who presented with either severe dysphagia (n = 2), severe xerostomia (n = 1), severe fibrosis of the neck (n = 3) or osteoradionecrosis (n = 1). Three were still tube dependent. CONCLUSION: HART-CN is feasible in patients with HPV/p16- LAHNSCC in good health. Although acute toxicity was pronounced, the proportion of patients with late toxicity was acceptable and outcome at 3 years encouraging.


Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Laringe , Infecções por Papillomavirus , Carcinoma de Células Escamosas/terapia , Cisplatino/efeitos adversos , Fracionamento da Dose de Radiação , Estudos de Viabilidade , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Hipofaringe , Pessoa de Meia-Idade , Boca , Recidiva Local de Neoplasia , Nimorazol , Orofaringe , Infecções por Papillomavirus/complicações
8.
BMJ Case Rep ; 13(4)2020 Apr 14.
Artigo em Inglês | MEDLINE | ID: mdl-32295798

RESUMO

Phlegmasia cerulea dolens (PCD) is a rare, fulminant, potentially lethal and often debilitating presentation of deep venous thrombosis (DVT). Mortality and amputations rates are high. We present a rare case of bilateral PCD in the lower extremities. A 67-year-old woman presented with newly diagnosed squamous cell cancer of unknown primary origin with lymph node metastases to the neck. The patient started curatively intended treatment, consisting of removal of one lymph node on the neck, radiotherapy with concomitant carboplatin and nimorazol. The patient developed bilateral DVT in the legs. Despite treatment with low-molecular-weight heparins, the patient developed thrombosis in the inferior vena cava and lungs. Due to developing painful discolouration and necrosis on the legs, the patient underwent acute and extensive surgery. PCD is a severe and potentially lethal form of DVT. There are several known risk factors for developing DVT, including active cancer and the use of chemotherapy.


Assuntos
Carboplatina/efeitos adversos , Quimiorradioterapia/efeitos adversos , Neoplasias de Cabeça e Pescoço/terapia , Perna (Membro)/cirurgia , Tromboflebite/induzido quimicamente , Trombose Venosa/induzido quimicamente , Idoso , Feminino , Fibrinolíticos/uso terapêutico , Neoplasias de Cabeça e Pescoço/secundário , Heparina de Baixo Peso Molecular/uso terapêutico , Humanos , Perna (Membro)/irrigação sanguínea , Neoplasias de Células Escamosas , Neoplasias Primárias Desconhecidas , Nimorazol/efeitos adversos , Procedimentos Cirúrgicos Operatórios
9.
Nat Commun ; 10(1): 2388, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31160602

RESUMO

While matter is irradiated with highly-energetic particles, it may become chemically modified. Thereby, the reactions of free low-energy electrons (LEEs) formed as secondary particles play an important role. It is unknown to what degree and by which mechanism LEEs contribute to the action of electron-affinic radiosensitisers applied in radiotherapy of hypoxic tumours. Here we show that LEEs effectively cause the reduction of the radiosensitiser nimorazole via associative electron attachment with the cross-section exceeding most of known molecules. This supports the hypothesis that nimorazole is selectively cytotoxic to tumour cells due to reduction of the molecule as prerequisite for accumulation in the cell. In contrast, dissociative electron attachment, commonly believed to be the source of chemical activity of LEEs, represents only a minor reaction channel which is further suppressed upon hydration. Our results show that LEEs may strongly contribute to the radiosensitising effect of nimorazole via associative electron attachment.


Assuntos
Quimiorradioterapia , Elétrons , Neoplasias/terapia , Nimorazol/química , Radiossensibilizantes/química , Humanos , Nimorazol/uso terapêutico , Oxirredução , Radiossensibilizantes/uso terapêutico
10.
Br J Radiol ; 92(1093): 20170843, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29436847

RESUMO

Tumour hypoxia is a well-recognised barrier to anti-cancer therapy and represents one of the best validated targets in oncology. Previous attempts to tackle hypoxia have focussed primarily on increasing tumour oxygen supply; however, clinical studies using this approach have yielded only modest clinical benefit, with often significant toxicity and practical limitations. Therefore, there are currently no anti-hypoxia treatments in widespread clinical use. As an emerging alternative strategy, we discuss the relevance of inhibiting tumour oxygen metabolism to alleviate hypoxia and highlight recently initiated clinical trials using this approach.


Assuntos
Nimorazol/uso terapêutico , Carga Tumoral/efeitos dos fármacos , Carga Tumoral/efeitos da radiação , Hipóxia Tumoral/efeitos dos fármacos , Hipóxia Tumoral/efeitos da radiação , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/efeitos da radiação , Progressão da Doença , Sistemas de Liberação de Medicamentos , Feminino , Humanos , Masculino , Avaliação das Necessidades , Invasividade Neoplásica/prevenção & controle , Consumo de Oxigênio/efeitos dos fármacos , Consumo de Oxigênio/efeitos da radiação , Prognóstico , Radioterapia/métodos , Ensaios Clínicos Controlados Aleatórios como Assunto
11.
Radiat Oncol ; 13(1): 39, 2018 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-29514673

RESUMO

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 18F-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. 18F-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 18F-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 18F-FAZA PET/CT is predictive for RT response in an EAC xenograft model. The radiosensitizing effect of nimorazole was questionable and requires further investigation.


Assuntos
Adenocarcinoma/patologia , Neoplasias Esofágicas/patologia , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Tolerância a Radiação , Animais , Hipóxia Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Humanos , Camundongos , Camundongos Nus , Nimorazol/farmacologia , Nitroimidazóis , Compostos Radiofarmacêuticos , Ensaios Antitumorais Modelo de Xenoenxerto
12.
Radiother Oncol ; 127(1): 12-19, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-29523409

RESUMO

PURPOSE: To evaluate if correction of low hemoglobin (Hb) levels by means of darbepoetin alfa improves the outcomes of radiotherapy in patients with squamous cell carcinoma of the head and neck (HNSCC). PATIENTS AND METHODS: Patients eligible for primary radiotherapy and who had Hb values below 14.0 g/dl were randomized to receive accelerated fractionated radiotherapy with or without darbepoetin alfa. Patients also received the hypoxic radiosensitizer nimorazole. Darbepoetin alfa was given weekly during radiotherapy or until the Hb value exceeded 15.5 g/dl. RESULTS: Following a planned interim analysis which showed inferiority of the experimental treatment the trial was stopped after inclusion of 522 patients (of a planned intake of 600). Of these, 513 were eligible for analysis (254 patients treated with darbepoetin alfa and 259 patients in the control group). Overall, the patients were distributed according to the stratification parameters (gender, T and N staging, tumor site). Treatment with darbepoetin alfa increased the Hb level to the planned value in 81% of the patients. The compliance was good without excess serious adverse events. The results showed a poorer outcome with a 5-year cumulative loco-regional failure rate of 47% vs. 34%, Hazard Ratio (HR): 1.53 [1.16-2.02], for the darbepoetin alfa vs. control arm, respectively. This was also seen for the endpoints of event-free survival (HR: 1.36 [1.09-1.69]), disease-specific death (HR: 1.43 [1.08-1.90]), and overall survival (HR: 1.30 [1.02-1.64]). There was no enhanced risk of cardio-vascular events observed in the experimental arm or any significant differences in acute or late radiation related morbidity. All univariate analyses were confirmed in a multivariate setting. CONCLUSION: Correction of the Hb level with darbepoetin alfa during radiotherapy of patients with HNSCC resulted in a significantly poorer tumor control and survival.


Assuntos
Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/radioterapia , Darbepoetina alfa/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/radioterapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patologia , Intervalo Livre de Doença , Fracionamento da Dose de Radiação , Feminino , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/patologia , Hemoglobinas/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Nimorazol/administração & dosagem , Oxigênio/metabolismo , Cooperação do Paciente , Radiossensibilizantes/administração & dosagem , Carcinoma de Células Escamosas de Cabeça e Pescoço
13.
J Colloid Interface Sci ; 505: 1193-1201, 2017 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-28738516

RESUMO

We described a three-dimensional Mn3O4 microcubes (3D-Mn3O4MCs) synthesised via a facile hydrothermal route for the determination of nimorazole (NMZ), an important drug that used in the treatment of head and neck cancer. The 3D-Mn3O4 MCs possess large active area and high conductivity, and 3D-Mn3O4 MCs film modified screen-printed carbon electrode (3D-Mn3O4MCs/SPCE) was fabricated which displayed excellent electrocatalytic ability towards NMZ. Under optimised working conditions, the modified electrode responded linearly to NMZ in the 0.025-8060µM concentration range and the detection limit was 6nM. A rapid, sensitive, selective, reproducible, and durable sensor was described. The practical feasibility of the sensor was demonstrated in human serum and NMZ tablet samples. The obtained results revealed the potential real-time applicability of the sensing device in biological analysis and pharmaceutical formulations.


Assuntos
Técnicas Biossensoriais/métodos , Técnicas Eletroquímicas/métodos , Eletrodos , Neoplasias de Cabeça e Pescoço , Compostos de Manganês/química , Nimorazol/sangue , Óxidos/química , Comprimidos/metabolismo , Antitricômonas/sangue , Carbono/química , Humanos
14.
Radiother Oncol ; 123(3): 424-430, 2017 06.
Artigo em Inglês | MEDLINE | ID: mdl-28478912

RESUMO

BACKGROUND AND PURPOSE: The phase III EORTC 1219-DAHANCA 29 intergroup trial evaluates the influence of nimorazole in patients with locally advanced head and neck cancer when treated with accelerated radiotherapy (RT) in combination with chemotherapy. This article describes the results of the RT Benchmark Case (BC) performed before patient inclusion. MATERIALS AND METHODS: The participating centers were asked to perform a 2-step BC, consisting of (1) a delineation and (2) a planning exercise according to the protocol guidelines. Submissions were prospectively centrally reviewed and feedback was given to the submitting centers. Sørensen-Dice similarity index (DSI) and the 95th percentile Hausdorff distance (HD) were retrospectively used to evaluate the agreement between the centers and the expert contours. RESULTS: Fifty-four submissions (34 delineation and 20 planning exercises) from 19 centers were reviewed. Nine (47%) centers needed to perform the delineation step twice and three (16%) centers 3 times before receiving an approval. An increase in DSI-value and a decrease in HD, in particular for the prophylactic Clinical Target Volume (pCTV), could be found for the resubmitted cases. No unacceptable variations could be found for the planning exercise. CONCLUSIONS: These BC-results highlight the need for effective and prospective RTQA in clinical trials. Even with clearly defined protocol guidelines, delineation and not planning remain the main reason for unacceptable protocol variations. The introduction of more objective quantitative analysis methods, such as the HD and DSI, in future trials might strengthen the evaluation by experts.


Assuntos
Benchmarking , Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Garantia da Qualidade dos Cuidados de Saúde , Carcinoma de Células Escamosas/virologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Nimorazol/uso terapêutico , Órgãos em Risco , Estudos Prospectivos , Planejamento da Radioterapia Assistida por Computador , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço
15.
Acta Oncol ; 55(9-10): 1091-1098, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-27161763

RESUMO

BACKGROUND: In head and neck squamous cell carcinomas (HNSCC) hypoxic radioresistance can be reduced by use of the hypoxic modifier nimorazole, as shown in the DAHANCA 5 trial. Recently, a 15-gene hypoxia classifier has shown predictive impact for the effect of nimorazole by identifying 'more' and 'less' hypoxic tumors in the DAHANCA 5 cohort. A prospective multicentre EORTC-1219 study is initiated, where nimorazole and prospective use of the classifier as a predictor is tested in relation to the most recent accelerated chemoradiotherapy treatment. Validation of the gene expression classification procedures is described here. MATERIAL AND METHODS: Formalin-fixed paraffin-embedded (FFPE) tumor material from three recent HNSCC cohorts [DAHANCA 18 (n = 96), 24 (n = 40), and IAEA Hypo (n = 55)] was used to establish and validate procedures for prospective classification of patients. Repeatability was tested for the different steps in the gene expression analysis, and reproducibility was tested with xenograft tumors (FaDuDD, UTSCC33), where gene expression in complementary sections was compared after fixation and embedding locally and at international institutions, respectively. Intra-tumor heterogeneity was addressed by classifying biopsy samples from HNSCC tumors, where 2-4 biopsies from each tumor was accessible. RESULTS: Procedures were successfully established for individual classification of HNSCC patients in retrospective and prospective cohorts. Measurements of gene expression levels were reproducible between different international institutions. CONCLUSION: Technical validation of the 15-gene hypoxia classifier demonstrated that it is suitable for implementation in prospective clinical trials.


Assuntos
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/terapia , Quimiorradioterapia/métodos , Perfilação da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Tolerância a Radiação/efeitos dos fármacos , Radiossensibilizantes/uso terapêutico , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Biomarcadores Tumorais/genética , Biópsia , Carcinoma de Células Escamosas/patologia , Hipóxia Celular/efeitos dos fármacos , Hipóxia Celular/genética , Ensaios Clínicos como Assunto , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Camundongos , Camundongos Nus , Pessoa de Meia-Idade , Nimorazol/uso terapêutico , Tolerância a Radiação/fisiologia , Reprodutibilidade dos Testes , Carcinoma de Células Escamosas de Cabeça e Pescoço , Ensaios Antitumorais Modelo de Xenoenxerto
17.
J Phys Chem A ; 119(39): 9986-95, 2015 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-26344652

RESUMO

Soft X-ray photoelectron spectroscopy has been used to investigate the radiosensitizer nimorazole and related model compounds. We report the valence and C, N, and O 1s photoemission spectra and K-edge NEXAFS spectra of gas-phase nimorazole, 1-methyl-5-nitroimidazole, and 4(5)-nitroimidazole in combination with theoretical calculations. The valence band and core level spectra are in agreement with theory. We determine the equilibrium populations of the two tautomers in 4(5)-nitroimidazole and find a ratio of 1:0.7 at 390 K. The NEXAFS spectra of the studied nitroimidazoles show excellent agreement with spectra of compounds available in the literature that exhibit a similar chemical environment. By comparing 1-methyl-5-nitroimidazole (single tautomer) with 4(5)-nitroimidazole, we are able to disentangle the photoemission and photoabsorption spectra and identify features due to each single tautomer.


Assuntos
Modelos Teóricos , Nimorazol/química , Espectroscopia Fotoeletrônica/métodos , Radiossensibilizantes/química , Modelos Moleculares , Estrutura Molecular
18.
Acta Oncol ; 54(9): 1385-92, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26329662

RESUMO

BACKGROUND: Hypoxia is a characteristic feature of solid tumours that significantly reduces the efficacy of conventional radiation therapy. In this study we investigated the role of hypoxia in a stereotactic radiation schedule by using a variety of hypoxic modifiers in a preclinical tumour model. MATERIAL AND METHODS: C3H mammary carcinomas were irradiated with 3 × 15 Gy during a one-week period, followed three days later by a clamped top-up dose to produce a dose response curve; the endpoint was tumour control. The hypoxic modifiers were nimorazole (200 mg/kg), nicotinamide (120 mg/kg) and carbogen (95% O2 + 5% CO2) breathing, OXi4503 (10 mg/kg), and hyperthermia (41.5°C; 1 h). RESULTS: The radiation dose controlling 50% of clamped tumours (TCD50) following 3 × 15 Gy was 30 Gy. Giving nimorazole or nicotinamide+ carbogen prior to the final 15 Gy fraction non-significantly (χ(2)-test; p < 0.05) reduced this TCD50 to 20-23 Gy; when administered with each 3 × 15 Gy fraction these values were significantly reduced to ≤ 2.5 Gy. Injecting OXi4503 or heating after irradiating significantly reduced the TCD50 to 9-12 Gy regardless of whether administered with one or all three 15 Gy fractions. Combining OXi4503 and heat with the final 15 Gy had a significantly larger effect (TCD50 = 2 Gy). CONCLUSIONS: Clinically relevant modifiers of hypoxia effectively enhanced an equivalent stereotactic radiation treatment confirming the importance of hypoxia in such schedules.


Assuntos
Hipóxia Celular , Neoplasias Mamárias Experimentais/terapia , Radiocirurgia , Administração por Inalação , Animais , Dióxido de Carbono/administração & dosagem , Difosfatos/farmacologia , Feminino , Hipertermia Induzida , Neoplasias Mamárias Experimentais/metabolismo , Camundongos Endogâmicos C3H , Niacinamida/farmacologia , Nimorazol/farmacologia , Oxigênio/administração & dosagem , Oxigênio/metabolismo , Radiossensibilizantes/administração & dosagem , Dosagem Radioterapêutica , Estilbenos/farmacologia , Complexo Vitamínico B/farmacologia
19.
Radiother Oncol ; 116(1): 15-20, 2015 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-25913070

RESUMO

PURPOSE: To test the hypothesis that radiotherapy (RT) of head and neck squamous cell carcinoma (HNSCC) can be improved by hypoxic modification using nimorazole (NIM) in association with accelerated fractionation. MATERIALS AND METHODS: The protocol was activated in March 2012 as an international multicenter randomized trial in patients with HNSCC. Tumors were treated to a dose of 66-70Gy, 33-35 fractions, 6 fractions per week. NIM was administered in a dose of 1.2gperm(2), 90min before the first daily RT fraction. The primary endpoint was loco-regional failure. The trial was closed prematurely by June 2014 due to poor recruitment. An associated quality assurance program was performed to ensure the consistency of RT with the protocol guidelines. RESULTS: The trial was dimensioned to include 600 patients in 3years, but only 104 patients were randomized between March 2012 and May 2014 due to the inability to involve three major centers and the insufficient recruitment rate from the other participating centers. Twenty patients from two centers had to be excluded from the analysis due to the unavailability of the follow-up data. Among the remaining 84 patients, 82 patients were evaluable (39 and 43 patients in the RT+NIM and the RT-alone arms, respectively). The treatment compliance was good with only six patients not completing the full planned RT course, and 31 patients (79%) out of 39 allocated for NIM, achieving at least 90% of the prescribed drug dose. At the time of evaluation, 40 patients had failed to achieve persistent loco-regional tumor control, and a total of 45 patients had died. The use of NIM improved the loco-regional tumor control with an 18month post-randomization cumulative failure rate of 33% versus 51% in the control arm, yielding a risk difference of 18% (CI -3% to 39%; P=0.10). The corresponding values for overall death was 43% versus 62%, yielding a risk difference of 19% (CI -3% to 42%; P=0.10). Sixteen patients, out of 55 patients analyzed for hypoxic gene expression, were classified as having more hypoxic tumors. Such patients, if treated with RT alone, had a higher loco-regional tumor failure rate as compared to the rest of the patients with known hypoxic status (P=0.05). CONCLUSION: Although the trial was incomplete and suffered from a small number of patients, the results suggested an improvement in loco-regional tumor control and overall survival in patients with advanced HNSCC given the hypoxic modifier NIM in addition to accelerated fractionation RT. However, the trial also revealed that conducting multicenter and multinational study combining drug and RT in developing countries may suffer from uncontrolled and unsolvable problems.


Assuntos
Carcinoma de Células Escamosas/radioterapia , Neoplasias de Cabeça e Pescoço/radioterapia , Nimorazol/uso terapêutico , Radiossensibilizantes/uso terapêutico , Adulto , Idoso , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Fracionamento da Dose de Radiação , Feminino , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Hipóxia/genética , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Cooperação do Paciente , Carcinoma de Células Escamosas de Cabeça e Pescoço
20.
Biomed Chromatogr ; 29(10): 1575-80, 2015 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-25845449

RESUMO

A highly sensitive, accurate and robust LC-MS/MS method was developed and validated for determination of nimorazole (NMZ) in rat plasma using metronidazole (MNZ) as internal standard (IS). The analyte and IS were extracted from plasma by precipitating protein with acetonitrile and were chromatographed using an Agilent Poroshell 120, EC-C18 column. The mobile phase was composed of a mixture of acetonitrile and 0.1 % formic acid (85:15 v/v). The total run time was 1.5 min and injection volume was 5 µL. Multiple reaction monitoring mode using the transitions of m/z 227.1 → m/z 114.0 for MNZ and m/z 172.10 → m/z 128.1 for IS were monitored on a triple quadrupole mass spectrometer, operating in positive ion mode. The calibration curve was linear in the range of 0.25-200 ng/mL (r(2) > 0.9996) and the lower limit of quantification was 0.25 ng/mL in the rat plasma samples. Recoveries of NMZ ranged between 88.05 and 95.25%. The precision (intra-day and inter-day) and accuracy of the quality control samples were 1.25-8.20% and -2.50-3.10, respectively. The analyte and IS were found to be stable during all sample storage and analysis procedures. The LC-MS/MS method described here was validated and successfully applied to pharmacokinetic study in rats.


Assuntos
Cromatografia Líquida/métodos , Nimorazol/sangue , Nimorazol/farmacocinética , Espectrometria de Massas em Tandem/métodos , Animais , Área Sob a Curva , Calibragem , Fracionamento Químico/métodos , Estabilidade de Medicamentos , Masculino , Metronidazol/sangue , Radiossensibilizantes/farmacocinética , Ratos Wistar , Reprodutibilidade dos Testes , Sensibilidade e Especificidade
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