Radiographic assessment of tissue after exposure to a compound

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Reexamination Certificate

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Reexamination Certificate

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06751290

ABSTRACT:

BACKGROUND OF THE INVENTION
A. Field of the Invention
This invention relates to a radiographic system and method for assessing the response of tissue in vivo to compounds, including therapeutic compounds.
B. Description of the Related Art
The ability to accurately assess the effects of compounds in vivo is essential in a wide range of pharmacological and related studies. Assessment of tissue response to compounds is particularly important in each stage of drug discovery, development, and clinical application. Noninvasive studies of tissue response may be particularly useful in the early validation of lead compounds during the drug discovery process, in clinical trials of potential therapeutic compounds, and in monitoring the efficacy of therapeutic compounds already used in clinical practice. These studies may include evaluation of therapeutic efficacy and detection of toxicity and other adverse side effects.
Evaluation of tissue response to compounds in vivo may initially be useful in the lead validation phase of the drug discovery process. Data that must be acquired during this early phase of drug discovery may be classified into three categories: pharmacodynamics, pharmacokinetics and toxicology. Pharmacodynamic studies include the evaluation of therapeutic efficacy in a targeted disease process, the relationship between compound dosage and therapeutic effect, and the duration of action of administered compounds. Pharmacokinetic studies include quantitative measurements of compound absorption, distribution, metabolism, and excretion (ADME). Toxicological studies include determination of gross systemic toxicity, damage to individual organs, and other adverse effects that may be caused by test compounds.
Pharmacodynamic, pharmacokinetic, and toxicological data are now frequently obtained by administering one or multiple doses of a test compound to an animal; killing the animal; and performing anatomical examination of body organs, histological examination of tissue, and analysis of body fluids. This approach to characterization of pharmacological activity has several significant limitations. First, anatomical and histological studies may not precisely reflect significant changes in the activity of relevant biochemical pathways in normal and abnormal tissue after administration of test compounds. Second, because animals must be killed for anatomical and histological studies, serial measurements cannot be performed on an individual animal during and after repeated administration of a test compound. Finally, processing of tissue for histological examination is labor-intensive, time consuming, and expensive, and often represents a serious rate-limiting step in applications such as high-throughput drug discovery.
For these reasons, a rapid, noninvasive method for assessment of tissue response to lead compounds during the early phases of the drug discovery process is highly desirable. The method may desirably enable quantitative measurements of changes in the activity of normal and abnormal biochemical pathways in tissue in response to administered compounds. The method may also desirably permit repeated, noninvasive measurements of the activity of these biochemical pathways in individual animals over long periods of time and over the course of multiple administrations of lead compounds. The method may also desirably allow data to be rapidly acquired and analyzed.
A second area of application for noninvasive assessment of tissue response in vivo is in clinical trials of new pharmaceutical compounds. A rapid, inexpensive method for assessment of tissue response might provide prompt accurate feedback on both efficacy and toxicity of test compounds in patients. Direct noninvasive assessment of tissue response might also provide data complementary to that obtained using measurements such as clinical chemistry studies of blood and urine.
A third application in which noninvasive assessment of tissue response to compounds should prove valuable is in the evaluation of efficacy and toxicity of therapeutic compounds already used in clinical practice. In many diseases processes, the response of abnormal or diseased tissue to therapeutic compounds may vary widely between individual patients. A noninvasive method that could provide prompt accurate feedback on the clinical efficacy of therapeutic compounds in individual patients should be of great value in selecting appropriate therapeutic agents, planning treatment regimens, and predicting outcome.
A number of approaches have been developed for noninvasive measurements of tissue response in vivo. These approaches have generally used techniques of nuclear medicine to generate images of a variety of tissue biochemical pathways. These imaging methods include positron emission tomography (PET) and single photon emission computed tomography (SPECT). A wide variety of radiopharmaceuticals have been successfully employed in PET and SPECT imaging studies. However, certain practical limitations of these modalities have reduced their economic feasibility and restricted their widespread use. These limitations include very high procedure costs, limited availability, need for dedicated imaging devices, and relatively low spatial resolution.
The spatial limitations of radiopharmaceutical-based imaging modalities are particularly problematic for lead validation studies in small animals. In these experimental models, the problem of low spatial resolution is more serious because of the small size of the subject relative to the fixed spatial resolution of the imaging modality. Alternative, relatively time-consuming and labor-intensive non-imaging-based methods have therefore been devised for metabolic measurements in small animals [Green L A et al.: J. Nucl. Med. 39: 729-734 (1998)].
The development and clinical use of anti-cancer chemotherapeutic agents is an exemplary pharmacological application that illustrates the potential utility of a method for inexpensive noninvasive assessment of tissue response in each stage of the process of drug discovery, clinical trials, and therapeutic use. In cancer chemotherapy, compounds are systemically administered to destroy or inhibit the growth of malignant cells in the body. Chemotherapeutic compounds are used to treat both primary malignancies and secondary metastases that may occur at distant sites in the body.
In the typical drug discovery process, initial lead validation in vivo of new potential chemotherapeutic compounds is now generally performed by means of manual anatomical measurements of implanted tumors in animals. Tumors or tumor cell suspensions are implanted or injected into the flanks of test animals. The tumors are often obtained from a foreign species, such as humans. After a variable period of growth, the size of the implanted tumor is determined. One or a combination of potential chemotherapeutic agents is then administered in a selected dosage protocol and serial measurements of changes in tumor size are performed over time. Tumor volume is estimated using two-dimensional measurements of tumor size which are manually obtained with calipers or a ruler. Shrinkage of the tumor is considered to reflect therapeutic efficacy of the test compound. [Geran R I et al.: Cancer Chemother. Res. 3: 51-61 (1972)]. Disadvantages of this method include the limited sensitivity and reproducibility of manual measurements, the difficulty of accurately determining tumor volume from two-dimensional surface measurements, the confounding effects of necrotic and scar tissue on tumor dimensions, and the inability to use tumor models that are typically localized deep within internal organs.
A rapid, noninvasive method for assessment of the response of malignant tissue to potential chemotherapeutic compounds should therefore provide significant advantages over methods currently used for evaluating therapeutic efficacy. Measurement of changes in biochemical pathways specifically associated with malignancy might provide a much more sensitive and rapid indicator of therapeutic efficacy than gross anatomical measu

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