Hypoxia Imaging of Rodent Xenografts with 18F-Fluoromisonidazole: Comparison of Dynamic and Static PET Imaging

DOI: 10.4236/ijmpcero.2012.13013   PDF   HTML   XML   3,450 Downloads   6,737 Views   Citations


Purpose: To generate parametric images of tumor hypoxia in a tumor-bearing rat model using voxel-based compartmental analysis of dynamic fluorine-18 labeled misonidazole (18F-FMISO) microPET? images, and to compare the parametric images thus derived with static “late” 18F-FMISO microPET? images for the detection of tumor hypoxia. Materials and Methods: Nude rats bearing HT-29 colorectal carcinoma xenografts (≈1.5 - 2 cm in diameter) in the right hind limb were positioned in a custom-fabricated, animal-specific foam mold. Animals were injected via the tail vein with ≈55.5 MBq 18F-FMISO and continuously imaged for either 60 or 120 minutes, with additional late static images up to 3 hour post-injection. The raw list-mode data was reconstructed into 37 - 64 frames with earlier frames of shorter time durations (12 - 15 seconds) and later frames of longer durations (up to 300 seconds). Time activity curves (TACs) were generated over regions encompassing the tumor as well as an artery, the latter for use as an input function. A beta version of a compartmental modeling package (BioGuide?, Philips Healthcare) was used to generate parametric images of k3 and Ki, rate constants of entrapment and flux of 18F-FMISO, respectively. Results: Data for 7 HT-29 tumor xenografts were presented, 6 of which yielded clear areas of tumor hypoxia as defined by Ki/k3 maps. Importantly, intratumoral foci with high 18F-FMISO uptakes on the late images did not always exhibit high Ki/k3 values and may there- fore represent false-positives for radiobiologically significant hypoxia. Conclusions: This study attempts to quantify tumor hypoxia using compartmental analysis of dynamic 18F-FMISO PET images in rodent xenograft tumor models. The results demonstrate feasibility of the approach in small-animal imaging studies, and provide evidence for the possible unreliability of late-time static imaging of 18F-FMISO PET in identifying tumor hypoxia.

Share and Cite:

K. Wang, J. Georgi, P. Zanzonico, M. Narayanan, T. Paulus, M. Bal, W. Wang, S. Cai, J. O’Donoghue, C. Ling and J. Humm, "Hypoxia Imaging of Rodent Xenografts with 18F-Fluoromisonidazole: Comparison of Dynamic and Static PET Imaging," International Journal of Medical Physics, Clinical Engineering and Radiation Oncology, Vol. 1 No. 3, 2012, pp. 95-104. doi: 10.4236/ijmpcero.2012.13013.

Conflicts of Interest

The authors declare no conflicts of interest.


[1] M. H?ckel, C. Knoop, K. Schlenger, B. Vorndran, E. Baussmann, M. Mitze, P. G. Knapstein and P. Vaupel, “Intratumoral PO2 Predicts Survival in Advanced Cancer of the Uterine Cervix,” Radiotherapy & Oncology, Vol. 26, No. 1, 1993, pp. 45-50. doi:10.1016/0167-8140(93)90025-4
[2] M. H?ckel and P. Vaupel, “Biological Consequences of Tumor Hypoxia,” Seminars in Oncology, Vol. 28, No. 2, 2001, pp. 36-41. doi:10.1016/S0093-7754(01)90211-8
[3] B. Movsas, J. D. Chapman, A. L. Hanlon, E. M. Horwitz, R. E. Greenberg, C. Stobbe, G. E. Hanks and A. Pollack, “Hypoxic Prostate/Muscle PO2 Ratio Predicts for Bio- chemical Failure in Patients with Prostate Cancer: Preliminary Findings,” Urology, Vol. 60, No. 4, 2002, pp. 634-639. doi:10.1016/S0090-4295(02)01858-7
[4] W. Choi, S. W. Lee, S. H. Park, J. S. Ryu, S. J. Oh, K. C. Im, E. K. Choi, J. H. Kim, S. H. Jung, S. Kim and S. D. Ahn, “Planning Study for Available Dose of Hypoxic Tumor Volume Using Fluorine-18-Labeled Fluoromi-sonidazole Positron Emission Tomography for Treatment of the Head and Neck Cancer,” Radiotherapy & Oncology, Vol. 97, No. 2, 2010, pp. 176-182. doi:10.1016/j.radonc.2010.04.012
[5] I. Toma-Dasu, J. Uhrdin, L. Antonovic, A. Dasu, S. Nuyts, P. Dirix, K. Haustermans and A. Brahme, “Dose Prescription and Treatment Planning Based on FMISO- PET Hypoxia,” Acta Oncologica, Vol. 51, No. 2, 2012, pp. 222-230. doi:10.3109/0284186X.2011.599815
[6] K. Hendrickson, M. Phillips, W. Smith, L. Peterson, K. Krohn and J. Rajendran, “Hypoxia Imaging with [F-18] FMISO-PET in Head and Neck Cancer: Potential for Guiding Intensity Modulated Radiation Therapy in Overcoming Hypoxia-Induced Treatment Resistance,” Radiotherapy & Oncology, Vol. 101, No. 3, 2011, pp. 369-375. doi:10.1016/j.radonc.2011.07.029
[7] V. Askoxylakis, J. Dinkel, M. Eichinger, B. Stieltjes, G. Sommer, L. G. Strauss, A. Dimitrakopoulou-Strauss, A. Kopp-Schneider, U. Haberkorn, P. E. Huber, M. Bischof, J. Debus and C. Thieke, “Multimodal Hypoxia Imaging and Intensity Modulated Radiation Therapy for Unre- sectable Non-Small-Cell Lung Cancer: The HIL Trial,” Radiotherapy & Oncology, Vol. 7, No. 1, 2012, pp. 157. doi:10.1186/1748-717X-7-157
[8] B. Wen, M. Urano, J. A. O’Donoghue and C. C. Ling, “Measurements of Partial Oxygen Pressure PO2 Using the OxyLite System in R3327-AT Tumors under Isoflurane Anesthesia,” Radiation Research, Vol. 166, 2006, pp. 512-518. doi:10.1667/RR3602.1
[9] B. Wen, M. Urano, J. L. Humm, V. E. Seshan, G. C. Li and C. C. Ling, “Comparison of Helzel and OxyLite Sys- tems in the Measurements of Tumor Partial Oxygen Pressure (PO2),” Radiation Research, Vol. 169, No. 1, 2008, pp. 67-75. doi:10.1667/RR0888.1
[10] J. Bussink, J. H. Kaanders and A. J. van der Kogel, “Tu- mor Hypoxia at the Micro-Regional Level: Clinical Relevance and Predictive Value of Exogenous and En- dogenous Hypoxia Cell Markers,” Radiotherapy & Oncology, Vol. 67, No. 1, 2003, pp. 3-15. doi:10.1016/S0167-8140(03)00011-2
[11] C. J. Mathias, M. J. Welch, M. R. Kilbourn, P. A. Jerabek, T. B. Patrick, M. E. Raichle, K. A. Krohn, J. S. Rasey and D. W. Shaw, “Radiolabeled Hypoxia Cell Sensitizers: Tracers for Assessment of Ischemia,” Life Sciences, Vol. 41, No. 2, 1987, pp. 199-206. doi:10.1016/0024-3205(87)90494-2
[12] D. Stypinski, L. I. Wiebe, A. J. McEwan, R. P. Schmidt, Y. K. Tam and J. R. Mercer, “Clinical Pharmacokinetics of 123I-IAZA in Healthy Volunteers,” Nuclear Medicine Communications, Vol. 20, No. 6, 1999, pp. 559-567. doi:10.1097/00006231-199906000-00011
[13] P. E. Volk, C. A. Mathis, M. D. Prados, J. C. Gilbert and T. F. Budinger, “Hypoxia in Human Gliomas: Demon-stration by PET with Fluorine-18-Fluoromisonidazole,” Journal of Nuclear Medicine, Vol. 33, No. 12, 1992, pp. 2133-2137.
[14] J. S. Rasey, W. J. Koh, M. L. Evans, L. M. Peterson, T. K. Lewellen, M. M. Graham and K. A. Krohn, “Quanfifying Regional Hypoxia in Human Tumors with Positron Emission Tomography of [18F]Fluoromisonidazole: A Pre- therapy Study of 37 Patients,” International Journal of Radiation Oncology * Biology * Physics, Vol. 36, No. 2, 1996, pp. 417-428. doi:10.1016/S0360-3016(96)00325-2
[15] J. G. Rajendran, D. C. Wilson, E. U. Conrad, L. M. Peterson, J. D. Bruckner, J. S. Rasey, L. K. Chin, P. D. Hof-strand, J. R. Grierson, J. F. Eary and K. A. Krohn, “[(18)F]FMISO and [(18)F]FDG PET Imaging in Soft Tissue Sarcomas: Correlation of Hypoxia, Metabolism and VEGF Expression,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 30, No. 5, 2003, pp. 695-704. doi:10.1007/s00259-002-1096-7
[16] F. Dehdashti, P. W. Grigsby, M. A. Mintun, J. S. Lewis, B. A. Siegel and M. J. Welch, “Assessing Tumor Hypoxia in Cervical Cancer by Positron Emission Tomo- graphy with 60Cu-ATSM: Relationship to Therapeutic Response—A Preliminary Report,” International Journal of Radiation Oncology * Biology * Physics, Vol. 55, No. 5, 2003, pp. 1233-1238. doi:10.1016/S0360-3016(02)04477-2
[17] K. Lehti?, V. Oikonen, S. Nyman, T. Gr?nroos, A. Roivainen, O. Eskola and H. Minn, “Quantifying Tumor Hypoxia with Fluorine-18 Fluoroerythronitroimidazole ([18F]FETNIM) and PET Using the Tumor to Plasma Ratio,” European Journal of Nuclear Medicine and Mo- lecular Imaging, Vol. 30, No. 1, 2003, pp. 101-108. doi:10.1007/s00259-002-1016-x
[18] R. Beck, B. R?per, J. M. Carlsen, M. C. Huisman, J. A. Lebschi, N. Andratschke, M. Picchio, M. Souvatzoglou, H. J. Machulla and M. Piert, “Pretreatment 18F-FAZA PET Predicts Success of Hypoxia-Directed Radiochemotherapy Using Tirapazamine,” Journal of Nuclear Medicine, Vol. 48, No. 6, 2007, pp. 973-980. doi:10.2967/jnumed.106.038570
[19] L. S. Ziemer, S. M. Evans, A. V. Kachur, A. L. Shuman, C. A. Cardi, W. T. Jenkins, J. S. Karp, A. Alavi, W. R. Jr. Dolbier and C. J. Koch, “Noninvasive Imaging of Tumor Hypoxia in Rats Using the 2-Nitroimidazole 18F-EF5,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 34, No. 10, 2007, pp.1566-1575.
[20] J. G. Rajendran, D. A. Mankoff, F. O’Sullivan, L. M. Peterson, D. L. Schwartz, E. U. Conrad, A. M. Spence, M. Muzi, D. G. Farwell and K. A. Krohn, “Hypoxia and Glucose Metabolism in Malignant Tumors: Evaluation by FMISO and FDG Positron Emission Tomography Imaging,” Clin. Cancer Res, Vol. 10, No. 7, 2004, pp. 2245-2252. doi:10.1158/1078-0432.CCR-0688-3
[21] W. J. Koh, J. S. Rasey, M. L. Evans, J. R. Grierson, T. K. Lewellen, M. M. Graham, K. A. Krohn and T. W. Griffin, “Imaging of Hypoxia in Human Tumors with [F-18]Fluoromisonidazole,” International Journal of Radiation Oncology * Biology * Physics, Vol. 22, No. 1, 1992, pp. 199-212. doi:10.1016/0360-3016(92)91001-4
[22] D. Thorwarth, S. M. Eschmann, F. Paulsen and M. Alber, “A Kinetic Model for Dynamic [18F]-Fmiso PET Data to Analyze Tumor Hypoxia,” Physics in Medicine and Biology, Vol. 50, No. 10, 2005, pp. 2209-2224. doi:10.1088/0031-9155/50/10/002
[23] P. Zanzonico, J. Campa, D. Polycarpe-Holman, G. Froster, R. Finn, S. Larson, J. Humm and C. Ling, “Ani- mal-Specific Positioning Molds for Registration of Re- peat Imaging Studies: Comparative microPET Imaging of F18-Labeled Fluoro-Deoxyglucose and Fluoro-Misonidazole in Rodent Tumors,” Nuclear Medicine and Biol- ogy, Vol. 33, No. 1, 2006, pp. 65-70. doi:10.1016/j.nucmedbio.2005.07.011
[24] A. Cherif, D. J. Yang, W. Tansey, E. E. Kim and S. Wallace, “Rapid Synthesis of 3-[18F]Fluoro-1-9-(2’-nitro-1’- imidazolyl)-2-propanol([18F]fluoromisonidazole),” Pharmaceutical Research, Vol. 11, No. 3, 1994, pp. 466-469. doi:10.1023/A:1018937709835
[25] D. J. Yang, S. Wallace, A. Cherif, C. Li, M. B. Gretzer, E. E. Kim and D. A. Podoloff, “Development of F-18-Labled Fluoroerythronitroimidazole as a PET Agent for Imaging Tumor Hypoxia,” Radiology, Vol. 194, No. 3, pp. 795-800.
[26] M. Zhang, M. Huang, C. Le, P. B. Zanzonico, F. Claus, K. S. Kolbert, K. Martin, C. C. Ling, J. A. Koutcher and J. L. Humm, “Accuracy and Reproducibility of Tumor Positioning during Prolonged and Multi-Modality Animal Imaging Studies,” Physics in Medicine and Biology, Vol. 53, No. 20, 2008, pp. 5867-5882. doi:10.1088/0031-9155/53/20/021
[27] W. O. Kermack and A. G. McKendrick, “Contributions to the Mathematical Theory oF Epidemics: IV. Analysis of Experimental Epidemics of the Virus Disease Mouse Ectromelia,” Journal of Hygiene, Vol. 37, No. 2, 1937, pp. 172-187. doi:10.1017/S0022172400034902
[28] R. K. Jain and L. E. Gerlowski, “Extravascular Transport in Normal and Tumor Tissues,” Critical Reviews in On- cology/Hematology, Vol. 5, No. 2, 1986, pp. 115-170. Reviewdoi:10.1016/S1040-8428(86)80023-3
[29] J. J. Casciari, M. M. Graham and J. S. Rasey, “A Modeling Approach for Quantifying Tumor Hypoxia with [F- 18]Fluoromisonidazole PET Time-Activity Data, Medical Physics, Vol. 22, No. 7, 1995, pp. 112-139. doi:10.1118/1.597506
[30] M. Bruehlmeier, U. Roelcke, P. A. Schubiger and S. M. Ametamey, “Assessment of Hypoxia and Perfusion in Human Brain Tumors Using PET with 18F-Fluoromi-sonidazole and 15O-H2O,” Journal of Nuclear Medicine, Vol. 45, No. 11, 2004, pp. 1851-1859.
[31] W. Wang, J. C. Georgi, S. A. Nehmeh, M. Narayanan, T. Paulus, M., Bal, J. A. O’Donoghue, P. B. Zanzonico, C. R. Schmidtlein, N. Y. Lee and J. L. Humm, “Evaluation of a Compartmental Model for Estimating Tumor Hypoxia via FMISO Dynamic PET Imaging,” Physics in Medicine and Biology, Vol. 54, No. 10, 2009, pp. 3083-3099. doi:10.1088/0031-9155/54/10/008
[32] R. M. Bartlett, B. J. Beattie, M. Naryanan, J. C. Georgi, Q. Chen, S. D. Carlin, G. Roble, P. B. Zanzonico, M. Gonen, J. O’Donoghue, A. Fischer, J. L. Humm, “Image-Guided PO2 Probe Measurements Correlated with Parametric Images Derived from 18F-Fluoromisonidazole Small-Ani- mal PET Data in Rats”, Journal of Nuclear Medicine, Vol. 53, No. 10, 2012.

comments powered by Disqus

Copyright © 2020 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.