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The British Journal of Cancer.... Jun 1978The preliminary details of a randomized clinical trial of misonidazole for the radiotherapy of Grades 3 and 4 cerebral astrocytoma are described. Plasma concentrations... (Clinical Trial)
Clinical Trial Randomized Controlled Trial
The preliminary details of a randomized clinical trial of misonidazole for the radiotherapy of Grades 3 and 4 cerebral astrocytoma are described. Plasma concentrations of misonidazole and its O-demethylated metabolite, determined by high-pressure liquid chromatography analysis, are reported for 8 patients with astrocytoma, 1 with carcinoma of the bronchus and 1 with carcinoma of the breast. In the latter case, tumour concentrations are also presented.
Topics: Adult; Astrocytoma; Brain Neoplasms; Breast Neoplasms; Humans; Nitroimidazoles; Radiation-Sensitizing Agents; Random Allocation; Time Factors
PubMed: 277246
DOI: No ID Found -
Biomedicine & Pharmacotherapy =... Nov 2019The aim of this study was to evaluate the application of F-flortanidazole (F-HX4)/F-fluoromisonidazole (F-FMISO) - based micro positron emission tomography/computed...
OBJECTIVE
The aim of this study was to evaluate the application of F-flortanidazole (F-HX4)/F-fluoromisonidazole (F-FMISO) - based micro positron emission tomography/computed tomography (PET/CT) for imaging of tumor hypoxia and radiotherapy-associated changes in mice.
MATERIALS AND METHODS
Radiotracer-based cellular uptake was performed to explore the correlation between radiotracer uptake and hypoxia state in cells. Animal models were established using subcutaneous injection of the human breast cancer line (MDA-MB-231) in a nude mouse. The effect of radiotherapy on tumor xenograft was assessed by measuring the tumor volume and mouse survival time. Meanwhile, mice with xenograft were imaged with F-FMISO andF-HX4 PET/CT before and after radiotherapy. Tumor-to-normal muscle ratio (T/N) of F-FMISO andF-HX4 maximum uptake was calculated by selecting a region of interest. Changes in tumor biology were assessed with immunohistochemical staining; T/N (F-FMISO) and T/N (F-HX4) were analyzed in relation to tumor volume, survival time, and the expression of tumor biomarkers, including hypoxia-inducible factor (HIF)-1α, glucose transporter (Glut-1) and the proliferation antigen Ki67.
RESULTS
Higher tracer uptake (both F-FMISO and F-HX4) was observed in hypoxic cells compared to oxygenated cell. The in vivo study suggested that both T/N (F-FMISO) and T/N (F-HX4) were positively correlated with tumor hypoxia volume (p = 0.014 and p = 0.009, respectively), but negatively associated with survival time (p = 0.012 and p = 0.007, respectively). HIF-1α, Glut-1 and Ki67 expression in tumors were downregulated after radiotherapy. T/N (F-HX4) was correlated with the expression of hypoxia marker HIF-1α in xenografts (r = 0.768, p = 0.025); while T/N (F-FMISO) was moderately correlated with the expressions of Ki67 (r = 0.412, p = 0.041). No significant correlation was detected between Glut-1 expression and T/N (F-FMISO) or T/N (F-HX4) (r = 0.511, p = 0.097 and r=0.562, p = 0.126, respectively).
CONCLUSIONS
Both F-HX4 and F-FMISO PET/CT can be used as biomarkers for tumor hypoxia and radiotherapy-associated changes. The clinical utilization of these two PET tracers needs to be further validated.
Topics: Animals; Azoles; Biomarkers, Tumor; Cell Line, Tumor; Cell Proliferation; Female; Fluorine Radioisotopes; Humans; Linear Models; Mice, Inbred BALB C; Mice, Nude; Misonidazole; Multivariate Analysis; Positron Emission Tomography Computed Tomography; Tomography, X-Ray Computed; Tumor Burden; Tumor Hypoxia; Xenograft Model Antitumor Assays
PubMed: 31526971
DOI: 10.1016/j.biopha.2019.109454 -
Molecular Oncology May 2016Rationalization of antiangiogenics requires biomarkers. Vascular re-normalization is one widely accepted mechanism of action for this drug class. The interstitium of...
BACKGROUND
Rationalization of antiangiogenics requires biomarkers. Vascular re-normalization is one widely accepted mechanism of action for this drug class. The interstitium of tumors with abnormal vasculature is hypoxic. We sought to track vascular normalization with (18)F-misonidazole ([18F]-FMISO, a probe that detects hypoxia) PET, in response to window-of-opportunity (WoO) treatment with the antiangiogenic dovitinib.
METHODS
Two patient-derived pancreas xenografts (PDXs; Panc215 and Panc286) and the spontaneous breast cancer model MMTV-PyMT were used. Animals were treated during 1 week of WoO treatment with vehicle or dovitinib, preceded and followed by [18F]-FMISO-PET, [18F]-FDG-PET, and histologic assessment (dextran extravasation, hypoxia and microvessel staining, and necrosis, cleaved caspase-3 and Ki67 measurements). After WoO treatment, gemcitabine (pancreas)/adriamycin (breast) or vehicle was added and animals were treated until the humane endpoint. Tumor growth inhibition (TGI) and survival were the parameters studied.
RESULTS
[18F]-FMISO SUV did not change after dovitinib-WoO treatment compared to vehicle-WoO (0.54 vs. 0.6) treatment in Panc215, but it decreased significantly in Panc286 (0.58 vs. 1.18; P < 0.05). In parallel, 10-KDa perivascular dextran extravasation was not reduced with dovitinib or vehicle-WoO treatment in Panc215, but it was reduced in Panc286. Whereas the addition of dovitinib to gemcitabine was indifferent in Panc215, it increased TGI in Panc286 (TGI switched from -59% to +49%). [18F]-FMISO SUV changes were accompanied by an almost 100% increase in interstitial gemcitabine delivery (665-1260 ng/mL). The results were validated in the PyMT model.
CONCLUSIONS
[18F]-FMISO accurately monitored vascular re-normalization and improved interstitial chemotherapy delivery.
Topics: Angiogenesis Inhibitors; Animals; Antimetabolites, Antineoplastic; Benzimidazoles; Breast; Breast Neoplasms; Cell Hypoxia; Cell Line, Tumor; Deoxycytidine; Female; Fluorine Radioisotopes; Humans; Mice; Mice, Nude; Misonidazole; Neovascularization, Pathologic; Pancreas; Pancreatic Neoplasms; Positron-Emission Tomography; Quinolones; Gemcitabine
PubMed: 26778791
DOI: 10.1016/j.molonc.2015.12.011 -
The British Journal of Cancer.... Jun 1978Misonidazole has been given to a total of 87 patients. Neurotoxicity has occurred--convulsions with the higher doses and peripheral neuropathy with the lowern ones. The...
Misonidazole has been given to a total of 87 patients. Neurotoxicity has occurred--convulsions with the higher doses and peripheral neuropathy with the lowern ones. The data from 34 patients receiving 4--7 doses has been analysed. Peripheral neuropathy is related to the total tissue exposure. By monitoring serum levels and controlling the total dose given, convulsions are avoidable and peripheral neuropathy restricted to a low and acceptable level.
Topics: Drug Administration Schedule; Half-Life; Humans; Neoplasms; Nitroimidazoles; Peripheral Nervous System Diseases; Radiation-Sensitizing Agents
PubMed: 209808
DOI: No ID Found -
Oncology (Williston Park, N.Y.) Mar 2007The role of hypoxia as a key determinant of outcome for human cancers has encouraged efforts to noninvasively detect and localize regions of poor oxygenation in tumors.... (Review)
Review
The role of hypoxia as a key determinant of outcome for human cancers has encouraged efforts to noninvasively detect and localize regions of poor oxygenation in tumors. In this review, we will summarize existing and developing techniques for imaging tumoral hypoxia. A brief review of the biology of tumor oxygenation and its effect on tumor cells will be provided initially. We will then describe existing methods for measurement of tissue oxygenation status. An overview of emerging molecular imaging techniques based on radiolabeled hypoxic markers such as misonidazole or hypoxia-related genes and proteins will then be given, and the usefulness of these approaches toward targeting hypoxia directly will be assessed. Finally, we will evaluate the clinical potential of oxygen- and molecular-specific techniques for imaging hypoxia, and discuss how these methods will individually and collectively advance oncology.
Topics: Animals; Diagnostic Imaging; Humans; Hypoxia; Neoplasms; Oxygen
PubMed: 17447439
DOI: No ID Found -
BMC Cancer Sep 2014Radiotherapy is an important treatment strategy for head and neck cancers. Tumor hypoxia and repopulation adversely affect the radiotherapy outcome. Accordingly,...
Dual tracer evaluation of dynamic changes in intratumoral hypoxic and proliferative states after radiotherapy of human head and neck cancer xenografts using radiolabeled FMISO and FLT.
BACKGROUND
Radiotherapy is an important treatment strategy for head and neck cancers. Tumor hypoxia and repopulation adversely affect the radiotherapy outcome. Accordingly, fractionated radiotherapy with dose escalation or altered fractionation schedule is used to prevent hypoxia and repopulation. 18F-fluoromisonidazole (FMISO) and 18F-fluorothymidine (FLT) are noninvasive markers for assessing tumor hypoxia and proliferation, respectively. Thus, we evaluated the dynamic changes in intratumoral hypoxic and proliferative states following radiotherapy using the dual tracers of 18F-FMISO and 3H-FLT, and further verified the results by immunohistochemical staining of pimonidazole (a hypoxia marker) and Ki-67 (a proliferation marker) in human head and neck cancer xenografts (FaDu).
METHODS
FaDu xenografts were established in nude mice and assigned to the non-radiation-treated control and two radiation-treated groups (10- and 20-Gy). Tumor volume was measured daily. Mice were sacrificed 6, 24, and 48 hrs and 7 days after radiotherapy. 18F-FMISO, and 3H-FLT and pimonidazole were injected intravenously 4 and 2 hrs before sacrifice, respectively. Intratumoral 18F-FMISO and 3H-FLT levels were assessed by autoradiography. Pimonidazole and Ki-67 immunohistochemistries were performed.
RESULTS
In radiation-treated mice, tumor growth was significantly suppressed compared with the control group, but the tumor volume in these mice gradually increased with time. Visual inspection showed that intratumoral 18F-FMISO and 3H-FLT distribution patterns were markedly different. Intratumoral 18F-FMISO level did not show significant changes after radiotherapy among the non-radiation-treated control and radiation-treated groups, whereas 3H-FLT level markedly decreased to 59 and 45% of the non-radiation-treated control at 6 hrs (p<0.0001) and then gradually increased with time in the 10- and 20-Gy-radiation-treated groups. The pimonidazole-positive hypoxic areas were visually similar in both the non-radiation-treated control and radiation-treated groups. No significant differences were observed in the percentage of pimonidazole-positive cells and Ki-67 index.
CONCLUSION
Intratumoral 18F-FMISO level did not change until 7 days, whereas 3H-FLT level markedly decreased at 6 hrs and then gradually increased with time after a single dose of radiotherapy. The concomitant monitoring of dynamic changes in tumor hypoxia and proliferation may provide important information for a better understanding of tumor biology after radiotherapy and for radiotherapy planning, including dose escalation and altered fractionation schedules.
Topics: Animals; Cell Proliferation; Disease Models, Animal; Head and Neck Neoplasms; Heterografts; Humans; Hypoxia; Male; Mice; Misonidazole; Radionuclide Imaging; Radiopharmaceuticals; Tumor Burden
PubMed: 25245041
DOI: 10.1186/1471-2407-14-692 -
Journal of Nuclear Medicine : Official... Mar 2016(18)F-fluoromisonidazole dynamic PET (dPET) is used to identify tumor hypoxia noninvasively. Its routine clinical implementation, however, has been hampered by the long...
UNLABELLED
(18)F-fluoromisonidazole dynamic PET (dPET) is used to identify tumor hypoxia noninvasively. Its routine clinical implementation, however, has been hampered by the long acquisition times required. We investigated the feasibility of kinetic modeling using shortened acquisition times in (18)F-fluoromisonidazole dPET, with the goal of expediting the clinical implementation of (18)F-fluoromisonidazole dPET protocols.
METHODS
Six patients with squamous cell carcinoma of the head and neck and 10 HT29 colorectal carcinoma-bearing nude rats were studied. In addition to an (18)F-FDG PET scan, each patient underwent a 45-min (18)F-fluoromisonidazole dPET scan, followed by 10-min acquisitions at 96 ± 4 and 163 ± 17 min after injection. Ninety-minute (18)F-fluoromisonidazole dPET scans were acquired in animals. Intratumor voxels were classified into 4 clusters based on their kinetic behavior using k-means clustering. Kinetic modeling was performed using the foregoing full datasets (FD) and repeated for each of 2 shortened datasets corresponding to the first approximately 100 min (SD1; patients only) or the first 45 min (SD2) of dPET data. The kinetic rate constants (KRCs) as calculated with a 2-compartment model for both SD1 and SD2 were compared with those derived from FD by correlation (Pearson), regression (Passing-Bablok), deviation (Bland-Altman), and classification (area-under-the-receiver-operating characteristic curve) analyses. Simulations were performed to assess uncertainties due to statistical noise.
RESULTS
Strong correlation (r ≥ 0.75, P < 0.001) existed between all KRCs deduced from both SD1 and SD2, and from FD. Significant differences between KRCs were found only for FD-SD2 correlations in patient studies. K1 and k3 were reproducible to within approximately 6% and approximately 30% (FD-SD1; patients) and approximately 4% and approximately 75% (FD-SD2; animals). Area-under-the-receiver-operating characteristic curve values for classification of patient clusters as hypoxic, using a tumor-to-blood ratio greater than 1.2, were 0.91 (SD1) and 0.86 (SD2). The percentage SD in estimating K1 and k3 from 45-min shortened datasets due to noise was less than 1% and between 2% and 12%, respectively.
CONCLUSION
Using single-session 45-min shortened (18)F-fluoromisonidazole dPET datasets appears to be adequate for the identification of intratumor regions of hypoxia. However, k3 was significantly overestimated in the clinical cohort. Further studies are necessary to evaluate the clinical significance of differences between the results as calculated from full and shortened datasets.
Topics: Algorithms; Animals; Carcinoma, Squamous Cell; Cohort Studies; Colorectal Neoplasms; HT29 Cells; Head and Neck Neoplasms; Humans; Hypoxia; Image Processing, Computer-Assisted; Misonidazole; Neoplasm Transplantation; Perfusion; ROC Curve; Radionuclide Imaging; Radiopharmaceuticals; Rats; Reproducibility of Results; Retrospective Studies
PubMed: 26609178
DOI: 10.2967/jnumed.115.160168 -
Journal of Nuclear Medicine : Official... Oct 2017Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena...
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor. This aggressiveness is in part attributed to the closely interrelated phenomena tumor hypoxia and angiogenesis, although few in vivo data exist in human brain tumors. This work aimed to study hypoxia and angiogenesis, in vivo and in situ, in patients admitted with GBM using multimodal imaging. Twenty-three GBM patients were assessed by F-fluoromisonidazole (F-FMISO) PET and conventional and perfusion MRI before surgery. The level and location of hypoxia (F-FMISO uptake, evaluated by tumor-to-blood [T/B] ratio), vascularization (cerebral blood volume [CBV]), and vascular permeability (contrast enhancement after gadolinium injection) were analyzed. The spatial relationship between tumor hypoxia and angiogenesis was assessed by an overlap analysis of the volume of F-FMISO uptake and the volumes of the high CBV regions and the contrast-enhancement regions. A significant correlation was found between hypoxia and hypervascularization, especially for their maximum values (volume of maximal tumor hypoxia vs. relative CBV: = 0.61, = 0.002) and their volumes (hypoxia vs. hypervascularization: = 0.91, < 0.001). A large proportion of the high CBVs collocated with hypoxia (81.3%) and with contrast enhancement (46.5%). These results support the hypothesis of a tight association between hypoxia and angiogenesis. Our results suggest that there is insufficient tumor oxygenation in human GBM, despite increased tumor vascularization.
Topics: Adult; Aged; Brain Neoplasms; Female; Glioblastoma; Humans; Magnetic Resonance Imaging; Male; Middle Aged; Misonidazole; Multimodal Imaging; Neovascularization, Pathologic; Positron-Emission Tomography; Tumor Hypoxia
PubMed: 28596159
DOI: 10.2967/jnumed.116.188557 -
Cancers Aug 2021Hypoxic areas are typically resistant to treatment. However, the fluorine-18-fluoroazomycin-arabinoside (FAZA) and fluorine 18 misonidazole (FMISO) tracers have never...
Hypoxic areas are typically resistant to treatment. However, the fluorine-18-fluoroazomycin-arabinoside (FAZA) and fluorine 18 misonidazole (FMISO) tracers have never been compared in non small cell lung cancer (NSCLC). This study compares the capability of 18F-FAZA PET/CT with that of 18F-FMISO PET/CT for detecting hypoxic tumour regions in early and locally advanced NSCLC patients. We prospectively evaluated patients who underwent preoperative PET scans before surgery for localised NSCLC (i.e., fluorodeoxyglucose (FDG)-PET, FMISO-PET, and FAZA-PET). The PET data of the three tracers were compared with each other and then compared to immunohistochemical analysis (GLUT-1, CAIX, LDH-5, and HIF1-Alpha) after tumour resection. Overall, 19 patients with a mean age of 68.2 ± 8 years were included. There were 18 lesions with significant uptake (i.e., SUVmax >1.4) for the F-MISO and 17 for FAZA. The mean SUVmax was 3 (±1.4) with a mean volume of 25.8 cc (±25.8) for FMISO and 2.2 (±0.7) with a mean volume of 13.06 cc (±13.76) for FAZA. The SUVmax of F-MISO was greater than that of FAZA ( = 0.0003). The SUVmax of F-MISO shows a good correlation with that of FAZA at 0.86 (0.66-0.94). Immunohistochemical results are not correlated to hypoxia PET regardless of the staining. The two tracers show a good correlation with hypoxia, with FMISO being superior to FAZA. FMISO, therefore, remains the reference tracer for defining hypoxic volumes.
PubMed: 34439254
DOI: 10.3390/cancers13164101 -
Scientific Reports Dec 2018This study aimed to explore the application of two radiotracers (F-fluorodeoxyglucose (FDG) and F-fluoromisonidazole (FMISO)) in monitoring hepatic metastases of human...
This study aimed to explore the application of two radiotracers (F-fluorodeoxyglucose (FDG) and F-fluoromisonidazole (FMISO)) in monitoring hepatic metastases of human colorectal cancer (CRC). Mouse models of CRC hepatic metastases were established by implantation of the human CRC cell lines LoVo and HT29 by intrasplenic injection. Wound healing and Transwell assays were performed to examine cell migration and invasion abilities. Radiotracer-based cellular uptake in vitro and micro-positron emission tomography imaging of liver metastases in vivo were performed. The incidence of liver metastases in LoVo-xenografted mice was significantly higher than that in HT29-xenografted ones. The SUVmax/mean values of F-FMISO, but not F-FDG, in LoVo xenografts were significantly greater than in HT29 xenografts. In vitro, LoVo cells exhibited stronger metastatic potential and higher radiotracer uptake than HT29 cells. Mechanistically, the expression of HIF-1α and GLUT-1 in LoVo cells and LoVo tumor tissues was remarkably higher than in HT29 cells and tissues. Linear regression analysis demonstrated correlations between cellular F-FDG/F-FMISO uptake and HIF-1α/GLUT-1 expression in vitro, as well as between F-FMISO SUVmax and GLUT-1 expression in vivo. F-FMISO uptake may serve as a potential biomarker for the detection of liver metastases in CRC, whereas its clinical use warrants validation.
Topics: Animals; Cell Line, Tumor; Colorectal Neoplasms; Female; Fluorodeoxyglucose F18; Heterografts; Humans; Liver Neoplasms; Mice, Inbred BALB C; Mice, Nude; Misonidazole; Neoplasm Metastasis; Neoplasm Transplantation; Positron-Emission Tomography
PubMed: 30546057
DOI: 10.1038/s41598-018-36238-x