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A Dual-radiolabel Marker Quantifies Decrease in HT29 Xenograft Hypoxia Induced by Mild Temperature Hyperthermia

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DOI: 10.4236/ijmpcero.2012.12005    2,822 Downloads   5,784 Views  


Purpose: In this project, we developed novel methods to quantify changes in tumor hypoxia following a mild tempera-ture hyperthermia (MTH) treatment in rat HT29 human colon adenocarcinoma xenograft. Materials and Methods: An exogenous hypoxia marker (IAZGP) was labeled with two radioisotopes of iodine (131I and 123I, respectively) to form two distinct tracers. The two tracers were injected into HT29-bearing nude rats 4-hour before and immediately following 41.5℃, 45-minute mild hyperthermia treatment. The distributions of the two hypoxia tracers were obtained by performing digital autoradiography on tumor sections, and image processing resulted in quantitative information at 50 μm pixel size. Results: Following the hyperthermia treatment, there was a remarkable decrease in hypoxia tracer binding. The average whole tumor hypoxia tracer targeted fraction in five animals changed from 30.3% ± 9.7% to 13.0% ± 5.3% after the hyperthermia treatment (P = 0.001). Detailed pixelby-pixel analysis of the image data revealed a decline in hypoxia tracer uptake after hyperthermia in most regions. However, there was concomitant emergence of some new regions of hypoxia identified by increased tracer uptake. In the control group, the overall hypoxia tracer targeted fraction remained almost constant, with some hypoxic tracer redistribution (putative acute hypoxia) observed. Conclusion: Reoxygenation occurred in the rat HT29 xenograft following MTH treatment. This was evident with preponderance of decreased hypoxia specific tracer uptake on tumor sections. Our methodology might be a useful tool in hypoxia study.

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The authors declare no conflicts of interest.

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M. Zhang, X. Li, M. Suehiro, Z. Zhao, D. Gagne, J. Pizzonia, Z. Zhang, G. Li, C. Ling and J. Humm, "A Dual-radiolabel Marker Quantifies Decrease in HT29 Xenograft Hypoxia Induced by Mild Temperature Hyperthermia," International Journal of Medical Physics, Clinical Engineering and Radiation Oncology, Vol. 1 No. 2, 2012, pp. 32-39. doi: 10.4236/ijmpcero.2012.12005.


[1] R. Cairns, I. Papandreou and N. Denko, “Overcoming Physiologic Barriers to Cancer Treatment by Molecularly Targeting the Tumor Microenvironment,” Molecular Cancer Research, Vol. 4, No. 2, 2006, pp. 61–70. doi: 10.1158/1541-7786.MCR-06-0002
[2] K. L. Bennewith and S. Dedhar, “Targeting hypoxic tumour cells to overcome metastasis,” BMC Cancer, Vol. 11, 2011. doi: 10.1186/1471-2407-11-504
[3] M. Urano, M. Kuroda and Y. Nishimura, “For the clinical application of thermochemotherapy given at mild temperatures,” International Journal of Hyperthermia, Vol. 15, No. 2, 1999, pp. 79–107. doi: 10.1080/026567399285765
[4] E. L. Jones, L. R. Prosnitz, M. W. Dewhirst, P. K. Marcom, P. H. Hardenbergh, L. B. Marks, D. M. Brizel and Z. Vujaskovic, “Thermochemoradiotherapy improves oxygenation in locally advanced breast cancer,” Clinical Cancer Research, Vol. 10, No. 13, 2004, pp. 4287–4293. doi: 10.1158/1078-0432.CCR-04-0133
[5] Z. Vujaskovic, J. M. Poulson, A. A. Gaskin, D. E. Thrall, R. L. Page, H. C. Charles, J. R. MacFall, D. M. Brizel, R. E. Meyer, D. M. Prescott, T. V. Samulski and M. W. Dewhirst, “Temperature-dependent changes in physiologic parameters of spontaneous canine soft tissue sarcomas after combined radiotherapy and hyperthermia treatment,” International Journal of Radiation Oncology, Biology, Physics, Vol. 46, No. 1, 2000, pp. 179–185. doi: 10.1016/S0360-3016(99)00362-4
[6] C. W. Song, H. Park and R. J. Griffin, “Improvement of tumor oxygenation by mild hyperthermia,” Radiation Research, Vol. 155, No. 4, 2001, pp. 515–528. doi: 10.1667/0033-7587(2001)155[0515:IOTOBM]2.0.CO;2
[7] K. Okajima, R. J. Griffin, K. Iwata, A. Shakil and C. W. Song, “Tumor oxygenation after mildtemperature hyperthermia in combination with carbogen breathing: dependence on heat dose and tumor type,” Radiation Research, Vol. 149, No. 3, 1998, pp. 294–299. doi: 10.2307/3579963
[8] A. Shakil, J. L. Osborn and C. W. Song, “Changes in oxygenation status and blood flow in a rat tumor model by mild temperature hyperthermia,” International Journal of Radiation Oncology, Biology, Physics, Vol. 43, No. 4, 1999, pp. 859–865. doi: 10.1016/S0360-3016(98)00516-1
[9] Z. Vujaskovic and C. W. Song, “Physiological mechanisms underlying heatinduced radiosensitization,” International Journal of Hyperthermia, Vol. 20, No. 2, 2004, pp. 163–174. doi: 10.1080/02656730310001619514
[10] A. S. Ljungkvist, J. Bussink, J. H. Kaanders and A. J.van der Kogel, “Dynamics of tumor hypoxia measured with bioreductive hypoxic cell markers,” Radiation Research, Vol. 167, No. 2, 2007, pp. 127-145. doi: 10.1667/RR0719.1
[11] X. Sun, X. F. Li, J. Russell, L. Xing, M. Urano, G. C. Li, J. L. Humm and C. C. Ling, “Changes in tumor hypoxia induced by mild temperature hyperthermia as assessed by dualtracer immunohistochemistry,” Radiotherapy and Oncology, Vol. 88, No. 2, 2008, pp. 269–276. doi: 10.1016/j.radonc.2008.05.015
[12] R. F. Schneider, E. L. Engelhardt, C. C. Stobbe, M. C. Fenning and J. D. Chapman, “The synthesis and radiolabeling of novel markers of tissue hypoxia of the iodi-nated azomycin nucleoside class,” Journal of Labelled Compounds and Radiopharmaceuticals, Vol. 39, No. 7, 1997, pp. 541–557. doi: 10.1002/(SICI)1099-1344(199707)39:7<541::AID-JLCR5>3.0.CO;2-B
[13] R. V. Iyer, P. T. Haynes, R. F. Schneider, B. Movsas and J. D. Chapman, “Marking hypoxia in rat prostate carcinomas with β-D-[125I]Azomycin Galactopyranoside and [99mTc]HL-91: correlation with microelectrode measurements,” Journal of Nuclear Medicine, Vol. 42, No. 2, 2001, pp. 337–344.
[14] J. Saitoh, H. Sakurai, Y. Suzuki, H. Muramatsu, H. Ishi-kawa, Y. Kitamoto, T. Akimoto, M. Hasegawa, N. Mitsuhashi and T. Nakano, “Correlations between in vivo tumor weight, oxygen pressure, 31P NMR spectroscopy, hypoxic microenvironment marking by beta-D-iodinated azomycin galactopyranoside (beta-D-IAZGP), and radiation sensitivity,” International Journal of Radiation On-cology, Biology, Physics, Vol. 54, No. 3, 2002, pp. 903–909. doi: 10.1016/S0360-3016(02)03013-4
[15] P. Zanzonico, J. O'Donoghue, J. D. Chapman, R. Schneider, S. Cai, S. Larson, B. Wen, Y. Chen, R. Finn, S. Ruan, L. Gerweck, J. Humm and C. Ling, “Iodine-124-labeled iodo-azomycin-galactoside imaging of tumor hypoxia in mice with serial microPET scanning,” European Journal of Nuclear Medicine and Molecular Imaging, Vol. 31, No. 1, 2004, pp. 117–128. doi: 10.1007/s00259-003-1322-y
[16] N. Mori, T. Oikawa, T. Katoh, J. Miyahara and Y. Harada, “Application of the ‘imaging plate’ to TEM image re-cording,” Ultramicroscopy, Vol. 25, No. 3, 1988, pp. 195–201. doi: 10.1016/0304-3991(88)90014-9
[17] J. M. Zuo, “Electron detection characteristics of a slow-scan CCD camera, imaging plates and film, and electron image restoration,” Microscopy Research and Technique, Vol. 49, No. 3, 2000, pp. 245–268. doi: 10.1002/(SICI)1097-0029(20000501)49:3<245::AID-JEMT4>3.0.CO;2-O
[18] W. H. Richardson, “Bayesian-Based Iterative Method of Image Restoration,” Journal of the Optical Society of America, Vol. 62, No. 1, 1972, pp. 55–59.
[19] L. B. Lucy, “An iterative technique for the rectification of observed distributions,” Astronomical Journal, Vol. 79, No. 6, 1974, pp. 745–754.
[20] M. Zhang, Q. Chen, X. F. Li, J. O'Donoghue, S. Ruan, P. Zanzonico, C. C. Ling and J. L. Humm, “Image deconvolution in digital autoradiography: a preliminary study,” Medical Physics, Vol. 35, No. 2, 2008, pp. 522–530. doi: 10.1118/1.2828198
[21] P. A. Netti, L. T. Baxter, Y. Boucher, R. Skalak and R. K. Jain, “Time-dependent behavior of interstitial fluid pressure in solid tumors: implications for drug delivery,” Cancer Research, Vol. 55, No. 22, 1995, pp. 5451–5458.
[22] M. W. Dewhirst, R. D. Braun, J. L. Lanzen, “Temporal changes in pO2 of R3230AC tumors in Fischer-344 rats,” International Journal of Radiation Oncology, Biology, Physics, Vol. 42, No. 4, 1998, pp. 723–726. doi: 10.1016/S0360-3016(98)00304-6
[23] D. Fukumura and R. K. Jain, “Tumor microenvironment abnormalities: causes, consequences, and strategies to normalize,” Journal of Cell Biochemistry, Vol. 101, No. 4, 2007, pp. 937–949. doi: 10.1002/jcb.21187
[24] C. W. Song, H. J. Park, C. K. Lee and R. Griffin, “Implications of increased tumor blood flow and oxygenation caused by mild temperature hyperthermia in tumor treatment,” International Journal of Hyperthermia, Vol. 21, No. 8, 2005, pp. 761–767. doi: 10.1080/02656730500204487

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