Radiation Biology of EPR Oxygen Images

EPR 氧气图像的放射生物学

• 批准号: 9891015
• 负责人: HOWARD J HALPERN
• 金额: $ 30.78万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-06-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9891015
• 关键词: 3D Print; Achievement; Animal Model; Animals; Applications Grants; Area; Breast Carcinoma; Carcinoma; Cell Line; Classification; Clinical; Conformal Radiotherapy; Data; Dependence; Development; Dose; Dose Fractionation; Electron Spin Resonance Spectroscopy; Elements; Failure; Fatty acid glycerol esters; Female; Fractionation; Funding; Gastrocnemius Muscle; Gender; HIF1A gene; Human; Hypoxia; Image; Immunologics; Leg; Life; Location; Magnetic Resonance Imaging; Malignant neoplasm of prostate; Mammals; Mammary Duct; Mammary gland; Measurement; Measures; Miso; Misonidazole; Modeling; Molecular; Monitor; Mus; Nitroimidazoles; Nude Mice; Organ; Oxygen; PC3 cell line; Partial Pressure; Patients; Positron-Emission Tomography; Prostate carcinoma; Proteins; Radiation; Radiation Dose Unit; Radiation Tolerance; Radiation therapy; Radiobiology; Reporting; Research Project Grants; Resistance; Resolution; Roentgen Rays; Short Interspersed Nucleotide Elements; Solid Neoplasm; System; Technology; Time; Tissues; Tumor Tissue; Tumor Volume; Tungsten; Validation; Variant; Vascular Endothelial Growth Factors; Work; Xenograft procedure; base; cancer imaging; expectation; experimental study; fibrosarcoma; fractionated radiation; human imaging; human subject; immunogenic; immunogenicity; improved; in vivo; innovative technologies; male; novel; pre-clinical; preclinical imaging; programs; radiation delivery; radiation resistance; radiation response; sarcoma; side effect; single fraction radiation; subcutaneous; success; tumor; tumor hypoxia

For over a century, resistance of radiation to living tissues has been associated with hypoxia, a local lack of molecular oxygen, or low pO₂. The focus of the past funding cycle has been to validate the hypothesis that has been assumed, but not proven over the past century, that treatment focused specifically on regions of tumors with low pO₂, voxels less than 10 torr, hypoxia boosts, would improve tumor curability. This research grant has used Electron Paramagnetic Resonance (EPR) imaging to provide absolute pO₂ images in volume elements or voxels of murine tumors with 1 torr pO₂ resolution and 0.5 mm spatial resolution in FSa carcinomas in the legs of C₃H mice. The voxel pO₂ correlates with local Oxylite measurements. EPR pO₂ image based hypoxic fractions, HF10 (fraction of tumor voxels with pO₂ less than 10 torr) correlates with hypoxia proteins VEGF, CAIX, and HIF1α, and with the curability of tumors given a dose of radiation sufficient to cure 50% of 450 µl tumors (TCD50). This established EPR pO₂ imaging as a reliable locator of relevant radiobiologically relevant hypoxia. To determine if pO₂ based dose painting improves tumor cure, we implemented the XRAD₂₂₅Cx system to deliver gantry based x-ray treatments to mouse tumors accurately registered with EPR pO2 images. We implemented rapid 3D printing Tungsten loaded, conformal plastic blocks to compare treating ~100% of hypoxic tumor voxels with hypoxia avoidance. Only then did we observe significant (p=0.02) tumor control differences between hypoxic boosts and anti-boosts. This is the first validation of hypoxia based dose painting in mammalian tumors. The systematics of the differences between hypoxic and normal pO₂ tumor tissue now need to be determined in several animal models with different immunologic conditions and with fractionation to guide eventual human use, possibly based on reductive retention of ¹⁸F-nitroimidazole PET images. We propose the following program investigating the systematics of EPR pO₂ image based dose painting: 1) Determine the in vivo hypoxic and separate normally oxygenated tumor tissue pO₂ control doses (TCD₅₀Hypox and TCD₅₀Ox), an in vivo oxygen enhancement ratios (OER) for orthotopic FSa and RIF1 fibrosarcomas, MCa4 mammary carcinomas grown orthotopically and, to determine the immunogenic status dependence, in human PC3 prostate carcinoma xenografts in athymic nude mice. 2) Determine the influence of three dose fractionation on hypoxic tumor control and oxygen enhancement ratios (₃fTCD₅₀Hypox, ₃fTCD₅₀Ox: ₃fOER) These experiments will provide ranges of in vivo variation from which to estimate in vivo oxygen enhancement ratios to guide early human trials of hypoxic boost/dose painting treatment. The success of preclinical determination of OER in multiple model tumors may suggest means by which to correct PET based human hypoxic tumor imaging. We also show technology suggesting EPR imaging in human subjects.

世纪以来，对活组织的辐射抗性一直与缺氧有关，缺氧是一种局部的损伤。 缺乏分子氧或低pO_2。上一个供资周期的重点是验证这一假设 在过去的世纪中，人们一直认为， 具有低pO_（max）、体素小于10 μ m、缺氧增强的肿瘤将提高肿瘤的治愈性。这 一项研究基金使用电子顺磁共振（EPR）成像提供绝对pO图像， 在FSa中具有1 μ p0 μ m分辨率和0.5 mm空间分辨率的鼠肿瘤的体积元素或体素 C型肝炎小鼠腿部的癌。体素p0与局部Oxylite测量相关。EPR pO图像 基于缺氧分数，HF 10（pO <10 μ g的肿瘤体素分数）与缺氧相关 VEGF、CAIX和HIF 1 α蛋白，以及给予足以治愈肿瘤的放射剂量的可治愈性 450 µl肿瘤的50%（TCD 50）。这建立了EPR pO成像作为相关的可靠定位器， 放射生物学相关缺氧。为了确定基于pO 2的剂量描绘是否改善肿瘤治愈，我们 实施了XRAD X射线造影机Cx系统，以准确地将基于机架的X射线治疗输送到小鼠肿瘤 与EPR pO 2图像配准。我们实现了快速3D打印钨装载，保形塑料 以比较处理~100%的低氧肿瘤体素与低氧避免。直到那时我们才发现 低氧加强和抗加强之间的肿瘤控制差异显著（p=0.02）。这是第一 在哺乳动物肿瘤中基于缺氧的剂量涂抹的验证。系统的差异之间 现在需要在几种动物模型中测定缺氧和正常pO肿瘤组织， 免疫条件下，并与分馏，以指导最终的人类使用，可能基于还原 保留12 F-硝基咪唑PET图像。我们提出了以下计划调查的系统学 基于EPR pO图像的剂量绘制： 1)确定体内缺氧和单独的正常氧合肿瘤组织pO-对照剂量 (TCD原位FSa和RIF 1的体内氧增强比（OER） 纤维肉瘤、原位生长的MCa 4乳腺癌，以确定免疫原性状态 依赖性，在无胸腺裸鼠中的人PC 3前列腺癌异种移植物中。 2)确定三个剂量分割对低氧肿瘤控制和氧增强的影响 比值（TCD血氧饱和度，TCD血氧饱和度：OER） 这些实验将提供体内变化的范围，由此估计体内氧增强 比率，以指导低氧增强/剂量涂抹治疗的早期人体试验。临床前的成功 在多种模型肿瘤中测定OER可提示校正基于PET的人类肿瘤的方法。 乏氧肿瘤显像我们还展示了人类受试者的EPR成像技术。