Investigation of hypoxia and carbonic anhydrase IX expression in a renal cell carcinoma xenograft model with oxygen tension measurements and I-124-cG250 PET/CT

Lawrentschuk, N; Lee, FT; Jones, G; Rigcpoulos, A; Mountain, A; O&#39;Keefe, G; Papenfuss, AT; Bolton, DM; Davis, ID; Scott, AM

Author(s): Lawrentschuk, N; Lee, FT; Jones, G; Rigcpoulos, A; Mountain, A; O'Keefe, G; Papenfuss, AT; Bolton, DM; Davis, ID; Scott, AM;
Details: Publication Year 2011-07,Volume 29,Issue #4,Page 411-420
Journal Title: UROLOGIC ONCOLOGY-SEMINARS AND ORIGINAL INVESTIGATIONS
Publication Type: Journal Article
Abstract: Objectives: In tumors, hypoxia stimulates angiogenesis and correlates with treatment resistance and poor prognosis. We have previously demonstrated hypoxia in human renal cell carcinoma (RCC) via direct oxygen probe measurements. Carbonic anhydrase IX (CA IX) is a protein stimulated by hypoxia and involved in angiogenesis, and is a potential tumor target for imaging and therapies using cG250, monoclonal antibody that recognizes CAIN. Our objectives were to characterize intratumoral hypoxia in a human RCC xenograft model using oxygen probe measurements; investigate if I-124-cG250 targets RCC correlating uptake on noninvasive positron emission tomography-computerized tomography (PET-CT) against traditional biodistribution studies, and investigate CAIX expression in this RCC model. Methods: BALB/c nude mice had human RCC (SK-RC-52) subcutaneously xenografted with oxygen levels measured by probe. Positron emission tomography (PET/CT) and biodistribution studies (I-124-cG250) were correlated with oxygen measurements. Immunohistochemistry and autorachography were performed on selected tumors to confirm CAIN expression Results: Oxygen tension in normal tissue (muscle) was 35.08 +/- 2.41 mmHg (mean +/- 95% CI), significantly greater compared to xenograft SK-RC-52 tumors at 5.02 +/- 1.12 mmHg. Biodistribution studies of I-124-cG250 demonstrated isotope uptake in SK-RC-52 xenografts peaking at 23.45 +/- 5.07% ID/g (mean +/- SD) 48 hours after antibody injection, which was maintained for a further 2 days (19.43 +/- 4.31 and 10.64 +/- 5.64 % ID/g, respectively). PET studies demonstrated excellent localization of I-124-cG250 in tumor, and a significant correlation between SUVmean, SUVmax, and %/ID I-124-cG250. CAIN expression was present in all groups studied but there was no significant correlation between it and any oxygen parameter studied. Conclusion: Intraturnoral hypoxia does exist within a human RCC xenograft model using invasive oxygen probe measurements. I-124-cG250 targets RCC with correlation between uptake on noninvasive PET-CT studies and traditional biodistribution studies opening the possibility of using PET/CT in future studies. Finally, CAIX expression was not related to hypoxia in this model, supporting the hypothesis that cell lines may subvert known hypoxia mechanisms in hypoxic environments. (C) 2011 Elsevier Inc. All rights reserved.
Publisher: ELSEVIER SCIENCE INC
Keywords: MONOCLONAL-ANTIBODY G250; PREDICTS RADIATION RESPONSE; ENDOTHELIAL GROWTH-FACTOR; TUMOR OXYGENATION; CA-IX; BREAST-CANCER; NUDE-MICE; SURVIVAL; MARKER; CERVIX
Publisher's Version: https://doi.org/10.1016/j.urolonc.2009.03.028
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2011-07-01 12:00:00