Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma

Robert J. Canter, Rong Zhou, Susan B. Kesmodel, Yawei Zhang, Daniel F. Heitjan, Jerry D. Glickson, Dennis B. Leeper, Douglas L. Fraker

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)265-273
Number of pages9
JournalAnnals of Surgical Oncology
Volume11
Issue number3
DOIs
StatePublished - Dec 1 2004

Fingerprint

Hyperglycemia
Rodentia
Melanoma
Extremities
Perfusion
Neoplasms
Melphalan
Growth
Nude Rats
Mortality
Hydrochloric Acid
Heterografts
Magnetic Resonance Spectroscopy
Glucose

Keywords

  • Acidification
  • Human melanoma xenografts
  • Isolated limb perfusion
  • MIBG

ASJC Scopus subject areas

  • Surgery
  • Oncology

Cite this

Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma. / Canter, Robert J.; Zhou, Rong; Kesmodel, Susan B.; Zhang, Yawei; Heitjan, Daniel F.; Glickson, Jerry D.; Leeper, Dennis B.; Fraker, Douglas L.

In: Annals of Surgical Oncology, Vol. 11, No. 3, 01.12.2004, p. 265-273.

Research output: Contribution to journalArticle

Canter, Robert J. ; Zhou, Rong ; Kesmodel, Susan B. ; Zhang, Yawei ; Heitjan, Daniel F. ; Glickson, Jerry D. ; Leeper, Dennis B. ; Fraker, Douglas L. / Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma. In: Annals of Surgical Oncology. 2004 ; Vol. 11, No. 3. pp. 265-273.
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abstract = "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.",
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T1 - Metaiodobenzylguanidine and hyperglycemia augment tumor response to isolated limb perfusion in a rodent model of human melanoma

AU - Canter, Robert J.

AU - Zhou, Rong

AU - Kesmodel, Susan B.

AU - Zhang, Yawei

AU - Heitjan, Daniel F.

AU - Glickson, Jerry D.

AU - Leeper, Dennis B.

AU - Fraker, Douglas L.

PY - 2004/12/1

Y1 - 2004/12/1

N2 - 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.

AB - 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.

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KW - Human melanoma xenografts

KW - Isolated limb perfusion

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