Browsing by Subject "Bioluminescent imaging"

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    Dynamic Bioluminescence Imaging: Development of a Physiological Pharmacokinetic Model of Tumor Metabolism
    (Office of the Vice Chancellor for Research, 2013-04-05) Territo, P. R.; Shannon, H. E.; Freise, K. J.; Riley, A. A.; McCarthy, B. P.; Bailey, B. J.; Cai, S.; Cai, W.; Sinn, T. L.; Wang, H.; Wiek, C.; Hanenberg, H.; Pollok, Karen E.; Hutchins, Gary D.
    Bioluminescent imaging (BLI) has proven to be a valuable tool for the study of cellular biology and therapeutic response in a wide array of tumor types. Several BLI analytical approaches have been developed to assess tumor function and growth, all with the primary assumption that substrate concentrations saturate the luciferase enzyme. Recent work suggests that when D-luciferin is administered over the range from 75-600mg/kg, target tissue concentrations of D-luciferin are well below the Km of luciferase for the reaction, and, that the pharmacokinetics of D-luciferin significantly impact observed emission rates. To address the concentration and PK concerns, we developed a three compartment physiologically based pharmacokinetic (PhPK) model for D-luciferin including oxidation by luciferase via Michaelis-Menten kinetics. The model was applied to dynamically acquired BLI in NOD/SCID mice with ectopic luciferase-transfected SF767 tumors. The current PhPK model estimates tumor volume, tumor substrate metabolism (M ̅), tumor blood flow (Vb) and substrate extraction from the blood (Er). Studies were conducted using intraperitoneal, subcutaneous and intravenous routes of administration of 150 mg/kg of D-luciferin, where dynamic BLI was conducted weekly for four weeks. The D-luciferin concentration in tumor tissue, determined immediately after the last imaging session, was found to be approximately 8-fold below the reported Km for the reaction across all routes of administration, supporting the need for a PhPK modeling approach for analyzing BLI data. The model-predicted tumor volumes increased over time and were highly correlated with caliper-measured tumor volumes (y=1.984x, R2=0.980, p<0.0001). Tumor D-luciferin metabolism was found to increase exponentially over the 4 weeks, while blood flow decreased over this same interval, a finding which is consistent with the interpretation of a Warburg effect. When tumor M ̅ was compared with the traditional measures of peak emission (Cmax) and area under the curve (AUC), it was found that metabolism increased exponentially with increases in either Cmax (y=92.7exp(8E-11x), R2= 0.997) or AUC ( y=86.4exp(5E-14x), R2= 0.989), suggesting that Cmax and AUC may substantially underestimate the magnitude of tumor metabolism. The present PhPK model of D-luciferin distribution and metabolism overcomes limitations in the Cmax and AUC approaches caused by incorrect substrate: enzyme concentration assumptions, and thus provides a more reliable estimate of tumor burden, growth, and therapeutic response.
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    Small Molecule Functional Converter of B-Cell Lymphoma-2 (Bcl-2) Suppresses Breast Cancer Lung Metastasis
    (ACS, 2024-05-01) Kopparapu, Prasad R.; Löhr, Christiane V.; Pearce, Martin C.; Tyavanagimatt, Shanthakumar; Nakshatri, Harikrishna; Kolluri, Siva K.; Surgery, School of Medicine
    The B-cell lymphoma-2 (Bcl-2) family of proteins plays a vital role in tumorigenesis. Cancer cells utilize the expression of Bcl-2 to evade therapy and develop resistance. Bcl-2 overexpression also causes cancer cells to be more invasive and metastatic. About 80% of cancer deaths are due to metastases, and yet targeted therapies for metastatic cancers are scarce. We discovered a small molecule, BFC1103, which changes the conformation of Bcl-2 to convert the antiapoptotic protein to a proapoptotic protein. BFC1103-induced apoptosis is dependent on the expression levels of Bcl-2, with higher levels causing more apoptosis. BFC1103 suppressed the growth of breast cancer lung metastasis. BFC1103 has the potential for further optimization and development for clinical testing in metastatic cancers that express Bcl-2. This study demonstrates a new approach to target Bcl-2 using a small molecule, BFC1103, to suppress metastatic disease.