Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma.
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.
Department of Surgery, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania, USA.
Robert J
RJ
Canter
Rong
R
Zhou
Susan B
SB
Kesmodel
Yawei
Y
Zhang
Daniel F
DF
Heitjan
Jerry D
JD
Glickson
Dennis B
DB
Leeper
Douglas L
DL
Fraker
D019797:3-Iodobenzylguanidine / Q000008:administration & dosage* / Q000494:pharmacology*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000494:pharmacology*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000494:pharmacology*; D010478:Chemotherapy, Cancer, Regional Perfusion / Q000379:methods*; D004195:Disease Models, Animal; D004347:Drug Interactions; D005260:Female; D005947:Glucose / Q000627:therapeutic use*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D006943:Hyperglycemia; D007424:Intracellular Fluid / Q000737:chemistry; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology* / Q000662:veterinary; D008558:Melphalan / Q000008:administration & dosage / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology* / Q000662:veterinary
D000970:Antineoplastic Agents; D018906:Antineoplastic Agents, Alkylating; D019797:3-Iodobenzylguanidine; D005947:Glucose; D008558:Melphalan