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.

一个多世纪以来，对活组织的辐射抵抗一直与缺氧有关，这是一种局部的 分子氧缺乏，或Po₂低。过去资金周期的重点一直是验证这一假设 在过去的一个世纪里，人们一直认为，治疗主要集中在 Po₂低、体素小于10Torr、低氧促进的肿瘤，可提高肿瘤的治愈率。这 研究基金已使用电子顺磁共振成像技术提供绝对Po₂图像 1 Torr Po₂分辨率和0.5 mm空间分辨率的小鼠肿瘤的体积元素或体素 C₃H小鼠腿部的癌症。体素Po₂与当地的草岩测量结果相关联。EPR Po₂图像 基于低氧部分，Hf10(Po₂小于10Torr的肿瘤体素部分)与低氧相关 蛋白血管内皮生长因子、cax和hif1α，并与肿瘤的可治性给予足够的辐射剂量治愈 50%的L肿瘤(TCD50)。这使EPR Po₂成像成为相关疾病的可靠定位器 与放射生物学相关的低氧。为了确定基于Po₂的剂量涂装是否提高了肿瘤的治愈率，我们 实施了Xrad₂₂₅CX系统，以准确地向小鼠肿瘤提供基于龙门的X射线治疗 注册了EPR PO2图像。我们实现了快速3D打印，装载钨，保形塑料 方块比较治疗~100%低氧肿瘤体素和避免缺氧。直到那时我们才观察到 低氧强化疗法和抗强化疗法之间的肿瘤控制差异显著(p=0.02)。这是第一次 哺乳动物肿瘤中基于缺氧的剂量绘画的有效性。从系统学的角度来分析 现在需要在几个不同的动物模型中确定缺氧和正常的Po₂肿瘤组织 免疫学条件和分级以指导人类最终使用，可能基于还原 ⁸F-硝基咪唑正电子发射体层摄影图像的保留。我们建议进行以下项目的研究： 基于EPR Po₂图像的剂量绘制： 1)确定体内低氧和单独常氧肿瘤组织Po₂控制剂量 (Tcd₅₀Hypox和Tcd₅₀Ox)，一种原位FSA和Rif1的体内氧增强比 纤维肉瘤、MCa4乳腺癌原位生长及免疫原性测定 人PC3前列腺癌裸鼠移植瘤的依赖性。 2)确定三剂量分割对低氧肿瘤控制和氧增强的影响 比率(₃fTCD₅₀Hypox，₃fTCD₅₀Ox：₃Foer) 这些实验将提供体内变异的范围，以此来估计体内的氧气增强。 指导低氧强化/剂量涂抹治疗的早期人体试验的比率。临床前研究的成功 多模型肿瘤中OER的测定可能提示校正基于PET的人类的方法 低氧肿瘤成像。我们还展示了在人类受试者中进行EPR成像的技术。