- Email: [email protected]
Project title small animal multimodality imaging center (sammic)
:~ROJECT TITLE
)ROJECT TITLE
SMALL ANIMAL MULTIMODALITY IMAGING CENTER (SAMMIC)
USE OF NMR TO MEASURE TUMOR AND NORMAL TISSUE METAB DURING TUMOR ACIDIFICATION
Grant Number: PI Name:
Grant Number: PI Name:
1R24CA83105-01 Glickson, Jerry D.
Abstract: DESCRIPTION: (Applicant's Description) Creation of a Small Animal Imaging Resource Program (SAIRP) at the University supporting research by investigators at this institution and also at the Fox Chase Cancer Center and Thomas Jefferson University is proposed. This SAIRP will provide three imaging modalities - - 1) Magnetic Resonance Imaging and Spectroscopy (MRI/S). 2) optical imaging covering the ultraviolet through near infrared (UV-NIR), and positron emission tomography (PET). The MRI/S facilities are now in place; the UV-NIR and PET facilities are now operation on the scale of human patients and will be adapted to studies of small animals (mice and rats) by the end of the first year. The SAIRP will support the research of 13 NIH funded projects dealing with 1) modification of tumor response to radiation and hyperthermia. 2) methods of monitoring tumor hypoxia, 3) gene therapy of brain tumors, 4) immunotherapy of tumors, 5) detection of breast cancer and 6) detection of tumor response to chemotherapy and radiation therapy. Ancillary facilities for redox scannina, NIR time resolved spectroscopoy, electronics, animal management, synthesis of contrast agent and physiological probes, histology, computer resources, biostatistics and MR of perfused cells will be provided. Research and development (R&D) projects will be directed towards the development of novel NMR capabilities that will enhance the research capabilities of the base projects. These R&D projects are: A. MRI of Small Animal Tumors, including: A1. Small Animal Microimaging, A2. Function Imaging of Tumors, B. Multinuclear Spectroscopy, including: B 1. Chemical Shift Selective MR Imaging of 31P in Animal Tumors, B2. 1H 170} MRI of Tumors, B3. In Vivo Imaging of Intra- and Extracelluar Na+ and pH in Tumors, and C. NMR Techniques for Monitoring Gene Therapy of Brain Tumors. Thesaurus Terms: bioimaging/biomedical imaging, biomedical resource magnetic resonance imaging, positron emission tomography
Institution: Fiscal Year Department: Project Start: Project End ICD IRG:
218
University Of Pennsylvania Philadelphia, PA 19104-6380 1999 Radiology 01-SEP-99 31-JUL-04 National Cancer Institute ZCA1
5P01CA56690-060008 Glickson, Jerry
Abstract: This subcontract to Project 4 will examine metabolic
and physiological aspects of acidification of human melanoma xenografts that are amenable to non-invasive measurement by magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MPd). These methods will be applied to animals supplied by Dr. Leeper's laboratory to test the hypothesis that NMR can non-invasively detect tumor specific changes in extracellular and intracellular pH (pile and pHi, respectively) induced by hyperglycemia and by hyperglycemia plus inhibition of oxidative metabolism (with meta- iodobenzylguanidine, MiBG), and/or by hyperglycemia plus inhibition of the Na+/H+ cation exchanger (with Cariporide mesilate, HOE642) and the HCO3-/Cl-anion exchanger (with 4,4-diisothiocyanstilbene 2,2disulphonic acid, DIDS). In addition, it is proposed that NMR can help delineate the underlying mechanism of acidification by hyperglycemia plus regulatory inhibition. To test this hypothesis, 31P MRS will be employed to measure the pHi and pile in the tumor, in host muscle, and brain under conditions of normoglycemia, hyperglycemia plus MIBG and/or HOE642 plus DIDS. Inorganic phosphate (Pi) and 3-aminopropylphosphonate will serve as indicators of pHi and pile, respectively. To test the hypothesis that tumor acidification under conditions of hyperglycemia and hyperglycemia pins respiratory inhibition is mediated by production of lactic acid (i.e., glycolysis), steady state lactate concentrations will be monitored on 1H MRS employing a selective multiple quantum coherence transfer pulse sequence developed by the subcontractor' s laboratory to edit out the lactate resonance from interfering lipid resonances. Further insight into the mechanism of tumor acidification under conditions of hyperglycemia +/- respiratory inhibition will be obtained by measuring flux through the glycolytic pathway and through the TCA cycle from the kinetics of 13C-labeling of lactate and glutamate, respective, following infusion of [1-13C] glucose. The spatial distributions of 13C-labeled glucose and lactate in the tumor at isotope steady state (for glucose) will be imaged by t3C chemical shift imaging at constant concentrations of labeled glucose in the blood (19+/-) mM), and the vascular volume distribution will be imaged by dynamic 1H MRI using Gd-DTPA-albtLmin as a vascular marker. Images will be correlated with histology. Thesaurus Terms: acidity/alkalinity, cellular pathology, glu-
cose metabolism, hyperglycemia, neoplastic cell Krebs' cycle, aerobiosis, blood glucose, cellular respiration, extracetlular, glucose transport, glycolysis, hyperthermia, intraceliular, lactate, melanoma, membrane transport protein SCID mouse, carbon, human tissue, magnetic resonance imaging,nuclear magnetic resonance spectroscopy, stable isotope
)ROJECT TITLE
SMALL ANIMAL MULTIMODALITY IMAGING CENTER (SAMMIC)
USE OF NMR TO MEASURE TUMOR AND NORMAL TISSUE METAB DURING TUMOR ACIDIFICATION
Grant Number: PI Name:
Grant Number: PI Name:
1R24CA83105-01 Glickson, Jerry D.
Abstract: DESCRIPTION: (Applicant's Description) Creation of a Small Animal Imaging Resource Program (SAIRP) at the University supporting research by investigators at this institution and also at the Fox Chase Cancer Center and Thomas Jefferson University is proposed. This SAIRP will provide three imaging modalities - - 1) Magnetic Resonance Imaging and Spectroscopy (MRI/S). 2) optical imaging covering the ultraviolet through near infrared (UV-NIR), and positron emission tomography (PET). The MRI/S facilities are now in place; the UV-NIR and PET facilities are now operation on the scale of human patients and will be adapted to studies of small animals (mice and rats) by the end of the first year. The SAIRP will support the research of 13 NIH funded projects dealing with 1) modification of tumor response to radiation and hyperthermia. 2) methods of monitoring tumor hypoxia, 3) gene therapy of brain tumors, 4) immunotherapy of tumors, 5) detection of breast cancer and 6) detection of tumor response to chemotherapy and radiation therapy. Ancillary facilities for redox scannina, NIR time resolved spectroscopoy, electronics, animal management, synthesis of contrast agent and physiological probes, histology, computer resources, biostatistics and MR of perfused cells will be provided. Research and development (R&D) projects will be directed towards the development of novel NMR capabilities that will enhance the research capabilities of the base projects. These R&D projects are: A. MRI of Small Animal Tumors, including: A1. Small Animal Microimaging, A2. Function Imaging of Tumors, B. Multinuclear Spectroscopy, including: B 1. Chemical Shift Selective MR Imaging of 31P in Animal Tumors, B2. 1H 170} MRI of Tumors, B3. In Vivo Imaging of Intra- and Extracelluar Na+ and pH in Tumors, and C. NMR Techniques for Monitoring Gene Therapy of Brain Tumors. Thesaurus Terms: bioimaging/biomedical imaging, biomedical resource magnetic resonance imaging, positron emission tomography
Institution: Fiscal Year Department: Project Start: Project End ICD IRG:
218
University Of Pennsylvania Philadelphia, PA 19104-6380 1999 Radiology 01-SEP-99 31-JUL-04 National Cancer Institute ZCA1
5P01CA56690-060008 Glickson, Jerry
Abstract: This subcontract to Project 4 will examine metabolic
and physiological aspects of acidification of human melanoma xenografts that are amenable to non-invasive measurement by magnetic resonance spectroscopy (MRS) and magnetic resonance imaging (MPd). These methods will be applied to animals supplied by Dr. Leeper's laboratory to test the hypothesis that NMR can non-invasively detect tumor specific changes in extracellular and intracellular pH (pile and pHi, respectively) induced by hyperglycemia and by hyperglycemia plus inhibition of oxidative metabolism (with meta- iodobenzylguanidine, MiBG), and/or by hyperglycemia plus inhibition of the Na+/H+ cation exchanger (with Cariporide mesilate, HOE642) and the HCO3-/Cl-anion exchanger (with 4,4-diisothiocyanstilbene 2,2disulphonic acid, DIDS). In addition, it is proposed that NMR can help delineate the underlying mechanism of acidification by hyperglycemia plus regulatory inhibition. To test this hypothesis, 31P MRS will be employed to measure the pHi and pile in the tumor, in host muscle, and brain under conditions of normoglycemia, hyperglycemia plus MIBG and/or HOE642 plus DIDS. Inorganic phosphate (Pi) and 3-aminopropylphosphonate will serve as indicators of pHi and pile, respectively. To test the hypothesis that tumor acidification under conditions of hyperglycemia and hyperglycemia pins respiratory inhibition is mediated by production of lactic acid (i.e., glycolysis), steady state lactate concentrations will be monitored on 1H MRS employing a selective multiple quantum coherence transfer pulse sequence developed by the subcontractor' s laboratory to edit out the lactate resonance from interfering lipid resonances. Further insight into the mechanism of tumor acidification under conditions of hyperglycemia +/- respiratory inhibition will be obtained by measuring flux through the glycolytic pathway and through the TCA cycle from the kinetics of 13C-labeling of lactate and glutamate, respective, following infusion of [1-13C] glucose. The spatial distributions of 13C-labeled glucose and lactate in the tumor at isotope steady state (for glucose) will be imaged by t3C chemical shift imaging at constant concentrations of labeled glucose in the blood (19+/-) mM), and the vascular volume distribution will be imaged by dynamic 1H MRI using Gd-DTPA-albtLmin as a vascular marker. Images will be correlated with histology. Thesaurus Terms: acidity/alkalinity, cellular pathology, glu-
cose metabolism, hyperglycemia, neoplastic cell Krebs' cycle, aerobiosis, blood glucose, cellular respiration, extracetlular, glucose transport, glycolysis, hyperthermia, intraceliular, lactate, melanoma, membrane transport protein SCID mouse, carbon, human tissue, magnetic resonance imaging,nuclear magnetic resonance spectroscopy, stable isotope