Non-invasive nuclear imaging techniques are increasingly becoming an important tool in preclinical research. The need to reduce the number of animal subjects used in experimentation, the capability for in-vivo tracking, and the increasing availability of such systems has meant that these novel nuclear imaging techniques are increasingly being explored in preclinical models of cancer-induced bone disease such as that associated with multiple myeloma. While sensitivity, resolution, field of view, and animal gating have been at the forefront of technical development, increased throughput and consistency in animal positioning during multi-modal scanning have not kept pace with the technology. Therefore, there is a need to develop custom apparatus for multi-modality image fusion. Combining animal models of multiple myeloma with preclinical Micro-Single photon computed tomography/Micro-Computed Tomography, and optical imaging allows the creation of a novel preclinical cross-modality imaging standard to investigate impaired bone remodeling changes associated with multiple myeloma in vivo. Knowledge accumulated using Technetium-99m Methylene Diphosphonate in clinical assessment of bone-related diseases over the past five decades and in preclinical research over the last 25 years will provide a platform that can guide optimization of the imaging modalities. The correlations and standards created will aid in quantitatively assessing the efficacy of a wide range of drugs with potential anti-myeloma and bone anabolic effects. Bortezomib—a first-in-class proteasome inhibitor—has been shown to facilitate a return of normal bone remodeling function, independent of its anti-myeloma properties. The overall hypothesis is Micro-Single photon computed tomography imaging with Technetium-99m Methylene Diphosphonate will enable accurate tracking of temporal changes in skeletal tissues induced by multiple myeloma in a mouse model. The notion is that Technetium-99m Methylene Diphosphonate skeletal uptake in mice bearing multiple myeloma tumors will be reduced consistent with known skeletal remodeling changes and osteoblast impairment induced by multiple myeloma. Furthermore, treatment with bortezomib will restore osteoblast function in tumor-bearing mice. This will manifest as a reversal of the decreased Technetium-99m Methylene Diphosphonate uptake.
The specific aims proposed to test the hypothesis are: 1) Design, test, and implement an animal bed adapter for reproducible and accurate positioning of mice in preclinical Micro-Single photon computed tomography/Micro-Computed Tomography scanner to improve throughput and increase quantitative image analysis accuracy. 2) Develop noninvasive Technetium-99m Methylene Diphosphonate and Micro-Computed Tomography imaging techniques and analysis procedures to assess osteoblast activity in normal non-tumor bearing mice and mice with multiple myeloma bone disease over a 28-day period of disease progression. 3) Validate the Technetium-99m Methylene Diphosphonate Micro-Single photon computed tomography imaging protocol to assess therapy-induced changes in osteoblast activity in a myeloma mouse model following treatment with the bone anabolic drug, bortezomib. The results suggest a purpose designed holder that facilitated not only higher throughput of image analysis results, with greater consistency, but also increased the throughput and ease at the time of imaging. Further, Technetium-99m Methylene Diphosphonate was useful in assessing changes in skeletal and select non-skeletal anatomy. A significant decrease in skeletal uptake of Technetium-99m Methylene Diphosphonate in subjects with multiple myeloma was observed over the time course of the disease. Quantitative Micro-Single photon computed tomography imaging techniques provided the best agreement with gamma counter results, as compared to planar imaging protocols. Subjects treated with bortezomib demonstrated increased uptake of Technetium-99m Methylene Diphosphonate as compared to untreated multiple myeloma subjects and untreated, non-tumor control subjects, and implying bortezomib does interact with mechanisms responsible for skeletal Technetium-99m Methylene Diphosphonate uptake.
|Commitee:||Oyajobi, Babatunde, Iwata, Koji, Clarke, Geoffery, Philips, William|
|School:||The University of Texas Health Science Center at San Antonio|
|School Location:||United States -- Texas|
|Source:||DAI-B 81/1(E), Dissertation Abstracts International|
|Subjects:||Medical imaging, Oncology, Public health|
|Keywords:||99mTc MDP, Bortezomib, micro-SPECT, Multiple Myeloma, Planar, Technetium-99m Methylene Diphosphonate|
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