HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH RSS TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Figures Only Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Lewis, J. S. Articles by Welch, M. J. Search for Related Content PubMed PubMed Citation Articles by Lewis, J. S. Articles by Welch, M. J.

Tumor Uptake of Copper-Diacetyl-Bis(N⁴-Methylthiosemicarbazone): Effect of Changes in Tissue Oxygenation

Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri; and Biomedical Imaging Research Center, Fukui Medical University, Matsuoka, Fukui, Japan

We showed previously that, in vitro, copper-diacetyl-bis(N⁴-methylthiosemicarbazone) (Cu-ATSM) uptake is dependent on the oxygen concentration (pO₂). We also showed that, in vivo, Cu-ATSM uptake is heterogeneous in animal tumors known to contain hypoxic fractions. This study was undertaken to confirm the pO₂ dependence of this selective uptake in vivo by correlating Cu-ATSM uptake with measured tumor pO₂. Methods: Experiments were performed with the 9L gliosarcoma rat model using a needle oxygen electrode to measure tissue pO₂. Using PET and electronic autoradiography, Cu-ATSM uptake was measured in tumor tissue under various pO₂ levels. The oxygen concentration within implanted tumors was manipulated by chemical means or by altering the inhaled oxygen content. Results: A good correlation between low pO₂ and high Cu-ATSM accumulation was observed. Hydralazine administration in animals caused a decrease in the average tumor pO₂ from 28.61 ± 8.74 mm Hg to 20.81 ± 7.54 mm Hg in untreated control animals breathing atmospheric oxygen. It also caused the tumor uptake of Cu-ATSM to increase by 35%. Conversely, in animals breathing 100% oxygen, the average tumor pO₂ increased to 45.88 ±15.9 mm Hg, and the tumor uptake of Cu-ATSM decreased to 48% of that of the control animals. PET of animals treated in a similar fashion yielded time–activity curves showing significantly higher retention of the tracer in hypoxic tissues than in oxygenated tissues. Conclusion: These data confirm that Cu-ATSM uptake in tissues in vivo is dependent on the tissue pO₂, and that significantly greater uptake and retention occur in hypoxic tumor tissue. Therefore, the possible use of Cu-ATSM PET as a prognostic indicator in the management of cancer is further validated.

Key Words: hypoxia • copper-diacetyl-bis(N⁴-methylthiosemicarbazone) • oxygen measurement

This article has been cited by other articles:

				T. G. Lohith, T. Kudo, Y. Demura, Y. Umeda, Y. Kiyono, Y. Fujibayashi, and H. Okazawa Pathophysiologic Correlation Between 62Cu-ATSM and 18F-FDG in Lung Cancer J. Nucl. Med., December 1, 2009; 50(12): 1948 - 1953. [Abstract] [Full Text] [PDF]

				K. A. Krohn, J. M. Link, and R. P. Mason Molecular Imaging of Hypoxia J. Nucl. Med., June 1, 2008; 49(Suppl_2): 129S - 148S. [Abstract] [Full Text] [PDF]

				P. S. Donnelly, A. Caragounis, T. Du, K. M. Laughton, I. Volitakis, R. A. Cherny, R. A. Sharples, A. F. Hill, Q.-X. Li, C. L. Masters, et al. Selective Intracellular Release of Copper and Zinc Ions from Bis(thiosemicarbazonato) Complexes Reduces Levels of Alzheimer Disease Amyloid-{beta} Peptide J. Biol. Chem., February 22, 2008; 283(8): 4568 - 4577. [Abstract] [Full Text] [PDF]

				T. Z. Wong, J. L. Lacy, N. A. Petry, T. C. Hawk, T. A. Sporn, M. W. Dewhirst, and G. Vlahovic PET of Hypoxia and Perfusion with 62Cu-ATSM and 62Cu-PTSM Using a 62Zn/62Cu Generator Am. J. Roentgenol., February 1, 2008; 190(2): 427 - 432. [Abstract] [Full Text] [PDF]

				H.-J. Wester Nuclear Imaging Probes: from Bench to Bedside Clin. Cancer Res., June 15, 2007; 13(12): 3470 - 3481. [Abstract] [Full Text] [PDF]

				L. Wei, J. Easmon, R. K. Nagi, B. D. Muegge, L. A. Meyer, and J. S. Lewis 64Cu-Azabicyclo[3.2.2]Nonane Thiosemicarbazone Complexes: Radiopharmaceuticals for PET of Topoisomerase II Expression in Tumors J. Nucl. Med., December 1, 2006; 47(12): 2034 - 2041. [Abstract] [Full Text] [PDF]

				K. Takakura, S. Yaguchi, Y. Kanansugi, K. Kobayashi, R. Okayasu, and Y. Fujibayashi Enhancement of chromosomal aberrations in tumor cells with a non-labeled Cu-PTSM and irradiation with Cu K-shell monochromatic X rays Radiat Prot Dosimetry, December 1, 2006; 122(1-4): 188 - 194. [Abstract] [Full Text] [PDF]

				H. Yuan, T. Schroeder, J. E. Bowsher, L. W. Hedlund, T. Wong, and M. W. Dewhirst Intertumoral Differences in Hypoxia Selectivity of the PET Imaging Agent 64Cu(II)-Diacetyl-Bis(N4-Methylthiosemicarbazone) J. Nucl. Med., June 1, 2006; 47(6): 989 - 998. [Abstract] [Full Text] [PDF]

				R. L. Aft, J. S. Lewis, F. Zhang, J. Kim, and M. J. Welch Enhancing Targeted Radiotherapy by Copper(II)diacetyl- bis(N4-methylthiosemicarbazone) Using 2-Deoxy-D-Glucose Cancer Res., September 1, 2003; 63(17): 5496 - 5504. [Abstract] [Full Text] [PDF]

				J. S. Lewis, P. Herrero, T. L. Sharp, J. A. Engelbach, Y. Fujibayashi, R. Laforest, A. Kovacs, R. J. Gropler, and M. J. Welch Delineation of Hypoxia in Canine Myocardium Using PET and Copper(II)-Diacetyl-bis(N4-Methylthiosemicarbazone) J. Nucl. Med., November 1, 2002; 43(11): 1557 - 1569. [Abstract] [Full Text] [PDF]

				J. S. Lewis, J. M. Connett, J. R. Garbow, T. L. Buettner, Y. Fujibayashi, J. W. Fleshman, and M. J. Welch Copper-64-pyruvaldehyde-bis(N4-methylthiosemicarbazone) for the Prevention of Tumor Growth at Wound Sites following Laparoscopic Surgery: Monitoring Therapy Response with microPET and Magnetic Resonance Imaging Cancer Res., January 1, 2002; 62(2): 445 - 449. [Abstract] [Full Text] [PDF]