This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services 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 Canter, R. J. Articles by Fraker, D. L. Search for Related Content PubMed PubMed Citation Articles by Canter, R. J. Articles by Fraker, D. L. Related Collections Other Melanoma

Metaiodobenzylguanidine and Hyperglycemia Augment Tumor Response to Isolated Limb Perfusion in a Rodent Model of Human Melanoma

From the Departments of Surgery (RJC, SBK, DLF), Radiology (RZ, JDG), and Biostatistics & Epidemiology (YZ, DFH), University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania; and Department of Radiation Oncology (DBL), Thomas Jefferson University School of Medicine, Philadelphia, Pennsylvania.

Correspondence: Address correspondence and reprint requests to: Douglas L. Fraker, MD, Division of Surgical Oncology, Department of Surgery, University of Pennsylvania Medical Center, 3400 Spruce Street, 4 Silverstein, Philadelphia, PA 19104; Fax: 215-662-3629; E-mail: frakerd{at}uphs.upenn.edu

Background: Perfusate acidification with dilute hydrochloric acid augments tumor response rates in a rodent model of isolated limb perfusion (ILP). This study investigates the combination of metaiodobenzylguanidine (MIBG), a mitochondrial inhibitor, and systemic hyperglycemia as a strategy to selectively acidify tumors and thereby sensitize them to ILP.

Methods: Human melanoma xenografts were implanted into the hind limbs of athymic rats. When tumors reached 12 to 15 mm in diameter, animals were randomized to ILP with or without melphalan, with or without systemic MIBG, and hyperglycemia of 485 ± 35 mg/dL. Intratumoral pH was measured during MIBG and glucose treatment by using magnetic resonance spectroscopy.

Results: MIBG at 30 mg/kg plus hyperglycemia decreased intracellular pH by .6 units and extracellular pH by .8 units. MIBG at 22.5 mg/kg plus hyperglycemia decreased intracellular and extracellular pH by .4 and .5 units, respectively. Tumor growth was unaffected by systemic MIBG and hyperglycemia alone. When MIBG at 30 mg/kg and hyperglycemia were combined with ILP, tumor growth was delayed for 33 days after control ILP and for 44 days after melphalan ILP. However, this dose of MIBG was complicated by a 40% mortality rate after ILP. MIBG at 22.5 mg/kg, in combination with MIBG in the perfusate, did not cause mortality and delayed tumor growth by 51 days after melphalan ILP.

Conclusions: MIBG and hyperglycemia improve tumor response rates after ILP in a rodent model of human melanoma. Selective tumor acidification with MIBG and hyperglycemia may offer added benefit to current regional perfusion strategies.

Key Words: Isolated limb perfusion • Acidification • MIBG • Human melanoma xenografts

This article has been cited by other articles:

				F. Turturro, G. Von Burton, and E. Friday Hyperglycemia-Induced Thioredoxin-Interacting Protein Expression Differs in Breast Cancer-Derived Cells and Regulates Paclitaxel IC50 Clin. Cancer Res., June 15, 2007; 13(12): 3724 - 3730. [Abstract] [Full Text] [PDF]

				R. J. Canter, S. B. Kesmodel, D. F. Heitjan, N. K. Veeramachaneni, N. A. Mokadam, J. A. Drebin, and D. L. Fraker Suppression of {beta}-Catenin by Antisense Oligomers Augments Tumor Response to Isolated Limb Perfusion in a Rodent Model of Adenomatous Polyposis Coli-Mutant Colon Cancer Ann. Surg. Oncol., September 1, 2005; 12(9): 733 - 742. [Abstract] [Full Text] [PDF]