This Article 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 Zhou, R. Articles by Glickson, J. D. Search for Related Content PubMed PubMed Citation Articles by Zhou, R. Articles by Glickson, J. D.

Intracellular Acidification of Human Melanoma Xenografts by the Respiratory Inhibitor m-Iodobenzylguanidine Plus Hyperglycemia: A ³¹P Magnetic Resonance Spectroscopy Study¹

Department of Radiology, University of Pennsylvania, Philadelphia, Pennsylvania 19104 [R. Z., N. B., J. D. G.], and Department of Radiation Oncology, Thomas Jefferson University, Philadelphia, Pennsylvania 19107 [D. B. L.]

In vivo ³¹P magnetic resonance spectroscopy demonstrates that human melanoma xenografts can be significantly acidified by induction of hyperglycemia combined with administration of m-iodobenzylguanidine (MIBG), an inhibitor of mitochondrial respiration. In melanoma xenografts (8 mm diameter), intracellular pH (pH_i, measured by the chemical shift of the P_i resonance) and extracellular pH (pH_e, measured with 3-aminopropylphosphonate) was reduced by less than 0.2 unit during i.v. infusion of glucose for 40 min. Administration of MIBG (30 mg/kg) under hyperglycemic conditions (26 mM) reduced tumor pH_i and pH_e by 0.4 (P < 0.001) and 0.6 (P < 0.001) unit, respectively; coincidentally, the nucleoside triphosphates:P_i ratio decreased 60% (P < 0.004) relative to the baseline level. Minimal changes in pH_i and pH_e and a small decrease in nucleoside triphosphates:P_i ratio (26%, P = 0.2) were observed in liver in response to MIBG plus hyperglycemia. These results suggest that under normoglycemic and hyperglycemic conditions, small human melanoma xenografts (8 mm) may exhibit a relatively high level of oxidative phosphorylation that may be blocked by MIBG. The acidification may result from increased lactate production as a direct effect of MIBG inhibition of respiration in mitochondria of tumor cells, or through indirect systemic effects, which remain to be identified. The synergetic effects of MIBG and hyperglycemia result in significant acidification of the tumor and a decrease in tumor bioenergetic status, and the effects are largely selective for tumors in comparison with normal tissues.

This article has been cited by other articles:

				Y. Shimoyama, Y. Akihara, D. Kirat, H. Iwano, K. Hirayama, Y. Kagawa, T. Ohmachi, K. Matsuda, M. Okamoto, T. Kadosawa, et al. Expression of Monocarboxylate Transporter 1 in Oral and Ocular Canine Melanocytic Tumors Vet. Pathol., July 1, 2007; 44(4): 449 - 457. [Abstract] [Full Text] [PDF]

				L. E. Gerweck, S. Vijayappa, and S. Kozin Tumor pH controls the in vivo efficacy of weak acid and base chemotherapeutics Mol. Cancer Ther., May 1, 2006; 5(5): 1275 - 1279. [Abstract] [Full Text] [PDF]

				A. Auricchio, R. Zhou, J. M. Wilson, and J. D. Glickson In vivo detection of gene expression in liver by 31P nuclear magnetic resonance spectroscopy employing creatine kinase as a marker gene PNAS, April 5, 2001; (2001) 81508598. [Abstract] [Full Text]

				A. Auricchio, R. Zhou, J. M. Wilson, and J. D. Glickson In vivo detection of gene expression in liver by 31P nuclear magnetic resonance spectroscopy employing creatine kinase as a marker gene PNAS, April 24, 2001; 98(9): 5205 - 5210. [Abstract] [Full Text] [PDF]