[en] The noninvasive assessment of tumor hypoxia in vivo is under active investigation because hypoxia has been shown to be an important prognostic factor for therapy resistance. Various nuclear medicine imaging modalities are being used, including PET imaging of 18F-containing compounds. In this study, we report the development of 18F-labeled EF1 for noninvasive imaging of hypoxia. EF1 is a 3-monofluoro analog of the well-characterized hypoxia marker EF5, 2(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetami de, which has been used to detect hypoxia in tumor and nontumor systems using immunohistochemical methods. METHODS: We have studied 2 rat tumor types: the hypoxic Morris 7777 (Q7) hepatoma and the oxic 9LF glioma tumor, each grown in subcutaneous sites. PET studies were performed using a pharmacological dose of nonradioactive carrier in addition to [18F]EF1 to optimize and assess drug biodistribution. After PET imaging of the tumor-bearing rats, tissues were obtained for gamma-counting of the 18F in various tissues and immunohistochemical detection of intracellular drug adducts in tumors. In one pair of tumors, Eppendorf needle electrode studies were performed. RESULTS: [18F]EF1 was excreted dominantly through the urinary tract. The tumor-to-muscle (T/M) ratio of [18F]EF1 in the Q7 tumors was 2.7 and 2.4 based on PET studies and 2.1, 2.5, and 3.0 based on gamma-counting of the tissues (n = 3). In contrast, the T/M ratio of [18F]EF1 in the 9LF glioma tumor was 0.8 and 0.5 based on PET studies and 1.0, 1.2, and 1.4 based on gamma-counting of the tissues (n = 3). Immunohistochemical analysis of drug adducts for the two tumor types agreed with the radioactivity analysis. In the Q7 tumor, substantial heterogeneous binding was observed throughout the tumor, whereas in the 9LF tumor minimal binding was found. CONCLUSION: [18F]EF1 is an excellent radiotracer for noninvasive imaging of tumor hypoxia.
Disciplines :
Radiology, nuclear medicine & imaging
Author, co-author :
Evans, S. M.
Kachur, A. V.
Shiue, C. Y.
Hustinx, Roland ; Université de Liège - ULiège > Département des sciences cliniques > Médecine nucléaire
Jenkins, W. T.
Shive, G. G.
Karp, J. S.
Alavi, A.
Lord, E. M.
Dolbier, W R Jr
Koch, C. J.
Language :
English
Title :
Noninvasive detection of tumor hypoxia using the 2-nitroimidazole [18F]EF1.
Publication date :
2000
Journal title :
Journal of Nuclear Medicine
ISSN :
0161-5505
eISSN :
1535-5667
Publisher :
Society of Nuclear Medicine, Reston, United States - Virginia
Hockel M, Schlenger K, Aral B, Mitze M, Schaffer U, Vaupel P. Association between tumor hypoxia and malignant progression in advanced cancer of the uterine cervix. Cancer Res. 1996;56:4509-4515.
Brizel DM, Sibley GS, Prosnitz LR, Scher RL, Dewhirst MW. Tumor hypoxia adversely affects the prognosis of carcinoma of the head and neck. Int J Radiat Oncol Biol Phys. 1997;38:285-289.
Reynolds TY, Rockwell S, Glazer PM. Genetic instability induced by the tumor microenvironment. Cancer Res. 1996;56:5754-5757.
Waleh N, Brody M, Knapp M, et al. Mapping of the vascular endothelial growth factor-producing hypoxic cells in multicellular tumor spheroids using a hypoxia-specific marker. Cancer Res. 1995;55:6222-6226.
Brizel DM, Scully SP, Harrelson JM, et al. Tumor oxygenation predicts for the likelihood of distant metastases in human soft tissue sarcoma. Cancer Res. 1996;56:941-943.
Olive PL, Durand RE, LeRiche J, Jackson SM. Gel electrophoresis of individual cells to quantify hypoxic fraction in human breast cancers. Cancer Res. 1993;53:733-736.
Evans SM, Jenkins WT, Joiner B, Lord EM, Koch CJ. 2-Nitroimidazole (EF5) binding predicts radiation resistance in individual 9L s.c. tumors. Cancer Res. 1996;56:405-411.
Koch CJ, Evans SM, Lord EM. Oxygen dependence of cellular uptake of EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl)acetamide]: analysis of drug adducts by fluorescent antibodies vs bound radioactivity. Br J Cancer. 1995;72:869-874.
Hodgkiss RJ, Jones G, Long A, et al. Flow cytometric evaluation of hypoxic cells in solid experimental tumours using fluorescence immunodetection. Br J Cancer. 1991;63: 119-125.
Raleigh JA, Miller GG, Franko AJ, Koch CJ, Fuciarelli AF, Kelley DA. Fluorescence immunohistochemical detection of hypoxic cells in spheroids and tumours. Br J Cancer. 1987;56:395-400.
Rasey JS, Grunbaum Z, Magee S, et al. Characterization of radiolabeled fluoromisonidazole as a probe for hypoxic cells. Radiat Res. 1987;111:292-304.
Varghese AJ, Gulyas S, Mohindra JK. Hypoxia-dependent reduction of 1-(2-nitro-1-imidazolyl)-3-methoxy-2-propanol by Chinese hamster ovary cells and KHT tumor cells in vitro and in vivo. Cancer Res. 1976;36:3761-3765.
Evans SM, Joiner B, Jenkins WT, Laughlin KM, Lord EM, Koch CJ. Identification of hypoxia in cells and tissues of epigastric 9L rat glioma using EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl) acetamide]. Br J Cancer. 1995;72:875-882.
Chapman JD, Engelhardt EL, Stobbe CC, Schneider RF, Hanks GE. Measuring hypoxia and predicting tumor radioresistance with nuclear medicine assays. Radiother Oncol. 1998;46:229-237.
Linder K, Chan Y, Cyr J, Malley M, Nowotnik D, Nunn A. TcO(PnA-O-1-(2-nitroimidaxzole)) [BMS-181321] a new technetium-containing nitroimidazole complex for imaging hypoxia: synthesis, characterization, and xanthine oxidase catalyzed reduction. J Med Chem. 1994;37:9-17.
Lord EM, Harwell L, Koch CJ. Detection of hypoxic cells by monoclonal antibody-recognizing 2-nitroimidazole adducts. Cancer Res. 1993;53:5271-5276.
Brown JM, Giaccia AJ. The unique physiology of solid tumors: opportunities (and problems) for cancer therapy. Cancer Res. 1998;58:1408-1416.
Kachur A, Evans SM, Shive C-Y, et al. Synthesis of new hypoxia markers EF1 and (18F]-EF1. Appl Radiat Isot. 1999;51:643-650.
Karp JS, Freifelder R, Geagan MJ, et al. Three-dimensional imaging characteristics of the HEAD PENN-PET scanner. J Nucl Med. 1997;38:636-643.
Cline JM, Thrall DE, Page RL, Franko AJ, Raleigh JA. Immunohistochemical detection of a hypoxia marker in spontaneous canine tumours. Br J Cancer. 1990;62:925-931.
Raleigh JA, Calkins-Adams DP, Rinker LH, et al. Hypoxia and VEGF expression in human squamous cell carcinomas using pimonidazole as a hypoxia marker. Cancer Res. 1998;58:3765-3768.
Bialik S, Greenen DL, Sasson IE, et al. Myocyte apoptosis during acute myocardial infarction in the mouse localizes to hypoxic regions but occurs independently of p53. J Clin Invest. 1997;100:1363-1372.
Parliament MB, Chapman JD, Urtasun RC, et al. Non-invasive assessment of human tumour hypoxia with 123I-iodoazomycin arabinoside: preliminary report of a clinical study. Br J Cancer. 1992;65:90-95.
Cook GJ, Houston S, Barrington SF, Fogelman I. Technetium-99m-labeled HL91 to identify tumor hypoxia: correlation with fluorine-18-FDG. J Nucl Med. 1998;39:99-103.
Valk PE, Mathis CA, Prados MD, Gilbert JC, Budinger TF. Hypoxia in human gliomas: demonstration by PET with fluorine-18-fluoromisonidazole. J Nucl Med. 1992;33:2133-2137.
Yeh SH, Liu RS, Wu LC, et al. Fluorine-18 fluoromisonidazole tumour to muscle retention ratio for the detection of hypoxia in nasopharyngeal carcinoma. Eur J Nucl Med. 1996;23:1378-1383.
Cherif A, Wallace S, Yang DJ, et al. Development of new markers for hypoxic cells: [131I]iodomisonidazole and [131I]iodoerythronitroimidazole. J Drug Target. 1996;4:31-39.
Groshar D, McEwan AJ, Parliament MB, et al. Imaging tumor hypoxia and tumor perfusion. J Nucl Med. 1993;34:885-888.
Okada RD, Johnson G III, Nguyen KN, Edwards B, Archer CM, Kelly JD. 99mTc-HL91. Effects of low flow and hypoxia on a new ischemia-avid myocardial imaging agent. Circulation. 1997;95:1892-1899.
Ballinger JR, Kee JW, Rauth AM. In vitro and in vivo evaluation of a technetium-99m-labeled 2-nitroimidazole (BMS181321) as a marker of tumor hypoxia. J Nucl Med. 1996;37:1023-1031.
Koh WJ, Bergman KS, Rasey JS, et al. Evaluation of oxygenation status during fractionated radiotherapy in human nonsmall cell lung cancers using [F-18]fluoromisonidazole positron emission tomography. Int J Radiat Oncol Biol Phys. 1995;33:391-398.
Minn H, Clavo AC, Wahl RL. Influence of hypoxia on tracer accumulation in squamous-cell carcinoma: in vitro evaluation for PET imaging. Nucl Med Biol. 1996;23:941-946.
Laughlin KM, Evans SM, Jenkins WT, et al. Biodistribution of the nitroimidazole EF5 (2-[2-nitro-1H-imidazol-1-yl]-N-(2,2,3,3,3-pentafluoropropyl) acetamide) in mice bearing subcutaneous EMT6 tumors. J Pharmacol Exp Ther. 1996;277:1049-1057.
Aboagye EO, Lewis AD, Graham MA, et al. The pharmacokinetics, bioavailability and biodistribution in mice of a rationally designed 2-nitroimidazole hypoxia probe SR-4554. Anticancer Drug Des. 1996;11:231-242.
Brown JM, Yu NY, Brown DM, Lee WW. SR-2508: a 2-nitroimidazole amide which should be superior to misonidazole as a radiosensitizer for clinical use. Int J Radiat Oncol Biol Phys. 1981;7:695-703.
Wahl RL, Hutchins GD, Buchsbaum DJ, Liebert M, Grossman HB, Fisher S. 18F-2-deoxy-2-fluoro-D-glucose uptake into human tumor xenografts: feasibility studies for cancer imaging with positron-emission tomography. Cancer. 1991;67: 1544-1550.
Kubota R, Kubota K, Yamada S, Tada M, Ido T, Tamahashi N. Active and passive mechanisms of [fluorine-18] fluorodeoxyglucose uptake by proliferating and prenecrotic cancer cells in vivo: a microautoradiographic study. J Nucl Med. 1994;35:1067-1075.
Slosman DO, Pittet N, Donath A, Polla BS. Fluorodeoxyglucose cell incorporation as an index of cell proliferation: evaluation of accuracy in cell culture. Eur J Nucl Med. 1993;20:1084-1088.
Koch CJ, Giandomenico AR, Iyengar CW. Bioreductive metabolism of AF-2[2-(2-furyl)-3-(5-nitro-2-furyl)acrylamide] combined with 2-nitroimidazoles: implications for use as hypoxic cell markers. Biochem Pharmacol. 1993;46:1029-1036.
Wiebe LI, Stypinski D. Pharmacokinetics of SPECT radiopharmaceuticals for imaging hypoxic tissues. Q J Nucl Med. 1996;40:270-284.
