TY - JOUR
T1 - Preclinical evaluation and validation of [F-18]HX4, a promising hypoxia marker for PET imaging
AU - Dubois, Ludwig J.
AU - Lieuwes, Natasja G.
AU - Janssen, Marco H. M.
AU - Peeters, Wenny J. M.
AU - Windhorst, Albert D.
AU - Walsh, Joseph C.
AU - Kolb, Hartmuth C.
AU - Ollers, Michel C.
AU - Bussink, Johan
AU - van Dongen, Guus A. M. S.
AU - van der Kogel, Albert J.
AU - Lambin, Philippe
PY - 2011/8/30
Y1 - 2011/8/30
N2 - Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [F-18] HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [F-18] HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P <0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 +/- 0.926 and optimal imaging properties 4 h after injection. [F-18] HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [F-18] HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [F-18] HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P <0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P <0.001) in [F-18] HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P <0.05). [F-18] HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.
AB - Hypoxia has been shown to be an important microenvironmental parameter influencing tumor progression and treatment efficacy. Patient guidance for hypoxia-targeted therapy requires evaluation of tumor oxygenation, preferably in a noninvasive manner. The aim of this study was to evaluate and validate the uptake of [F-18] HX4, a novel developed hypoxia marker for PET imaging. A heterogeneous accumulation of [F-18] HX4 was found within rat rhabdomyosarcoma tumors that was significantly (P <0.0001) higher compared with the surrounding tissues, with temporal increasing tumor-to-blood ratios reaching a plateau of 7.638 +/- 0.926 and optimal imaging properties 4 h after injection. [F-18] HX4 retention in normal tissues was found to be short-lived, homogeneous and characterized by a fast progressive temporal clearance. Heterogeneity in [F-18] HX4 tumor uptake was analyzed based on 16 regions within the tumor according to the different orthogonal planes at the largest diameter. Validation of heterogeneous [F-18] HX4 tumor uptake was shown by a strong and significant relationship (r = 0.722; P <0.0001) with the hypoxic fraction as calculated by the percentage pimonidazole-positive pixels. Furthermore, a causal relationship with tumor oxygenation was established, because combination treatment of nicotinamide and carbogen resulted in a 40% reduction (P <0.001) in [F-18] HX4 tumor accumulation whereas treatment with 7% oxygen breathing resulted in a 30% increased uptake (P <0.05). [F-18] HX4 is therefore a promising candidate for noninvasive detection and evaluation of tumor hypoxia at a macroscopic level.
KW - cancer
KW - nuclear medicine
KW - experimental research
U2 - 10.1073/pnas.1102526108
DO - 10.1073/pnas.1102526108
M3 - Article
SN - 0027-8424
VL - 108
SP - 14620
EP - 14625
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 35
ER -