Intraarterial Therapy with a New Potent Inhibitor of Tumor Metabolism (3-bromopyruvate): Identification of Therapeutic Dose and Method of Injection in an Animal Model of Liver Cancer

Mustafa Vali, Eleni Liapi, Jeanne Kowalski, Kelvin Hong, Afsheen Khwaja, Michael Torbenson, Christos Georgiades, Jean Francois H. Geschwind

Research output: Contribution to journalArticle

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Abstract

Purpose: A potent new adenosine triphosphate inhibitor-3-bromopyruvate (3-BrPA)-has been shown to have antitumor effects when injected intraarterially in the hepatic artery of rabbits with VX-2 tumors. The authors performed a stepwise study in rabbits to determine the therapeutic dose and method of delivery of 3-BrPA. Materials and methods: White New Zealand rabbits with VX-2 tumors were used for this study. Eight animals were examined to establish the maximum tolerated dose (2.5 or 5.0 mmol/L of 25-mL 3-BrPA) as a single bolus injection. The 2.5 mmol/L dose was then used to compare three methods of delivery: injection of one bolus, two 12.5-mL serial bolus injections administered 1 hour apart, and continuous infusion of 25 mL for 1 hour. Finally, dose-response analysis was performed by using 10 groups of three animals each, with 1-hour intraarterial infusions of 3-BrPA (25 mL) at incremental doses of 0.25 mmol/L (range, 0.5-2.5 mmol/L) with phosphate buffered saline used for control animals. All animals were sacrificed at 48 hours, and histopathologic analysis was performed. χ2 statistics were used to analyze the data. Results: The maximum tolerated dose of 3-BrPA was 2.5 mmol/L; however, it caused substantial peripheral liver necrosis. These effects were minimized when 3-BrPA was infused over 1 hour. Complete tumor necrosis was identified in all samples with at least 2.0 mmol/L of 3-BrPA. The 1.75 mmol/L concentration was identified as therapeutic because it caused complete tumor apoptosis and minimal toxicity (P < .001). Conclusions: The results identified both the therapeutic dose (1.75 mmol/L) and the method of infusion (1 hour intraarterial infusion) of 3-BrPA. This potent new treatment may prove to be an effective way of treating liver cancer and may become part of a new class of anticancer drugs based on the inhibition of tumor metabolism.

Original languageEnglish (US)
Pages (from-to)95-101
Number of pages7
JournalJournal of Vascular and Interventional Radiology
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

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Liver Neoplasms
Animal Models
Injections
Neoplasms
Intra Arterial Infusions
Maximum Tolerated Dose
Therapeutics
Rabbits
Necrosis
bromopyruvate
Hepatic Artery
Adenosine Triphosphate
Phosphates
Apoptosis
Liver
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Radiology Nuclear Medicine and imaging
  • Cardiology and Cardiovascular Medicine

Cite this

Intraarterial Therapy with a New Potent Inhibitor of Tumor Metabolism (3-bromopyruvate) : Identification of Therapeutic Dose and Method of Injection in an Animal Model of Liver Cancer. / Vali, Mustafa; Liapi, Eleni; Kowalski, Jeanne; Hong, Kelvin; Khwaja, Afsheen; Torbenson, Michael; Georgiades, Christos; Geschwind, Jean Francois H.

In: Journal of Vascular and Interventional Radiology, Vol. 18, No. 1, 01.01.2007, p. 95-101.

Research output: Contribution to journalArticle

Vali, Mustafa ; Liapi, Eleni ; Kowalski, Jeanne ; Hong, Kelvin ; Khwaja, Afsheen ; Torbenson, Michael ; Georgiades, Christos ; Geschwind, Jean Francois H. / Intraarterial Therapy with a New Potent Inhibitor of Tumor Metabolism (3-bromopyruvate) : Identification of Therapeutic Dose and Method of Injection in an Animal Model of Liver Cancer. In: Journal of Vascular and Interventional Radiology. 2007 ; Vol. 18, No. 1. pp. 95-101.
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abstract = "Purpose: A potent new adenosine triphosphate inhibitor-3-bromopyruvate (3-BrPA)-has been shown to have antitumor effects when injected intraarterially in the hepatic artery of rabbits with VX-2 tumors. The authors performed a stepwise study in rabbits to determine the therapeutic dose and method of delivery of 3-BrPA. Materials and methods: White New Zealand rabbits with VX-2 tumors were used for this study. Eight animals were examined to establish the maximum tolerated dose (2.5 or 5.0 mmol/L of 25-mL 3-BrPA) as a single bolus injection. The 2.5 mmol/L dose was then used to compare three methods of delivery: injection of one bolus, two 12.5-mL serial bolus injections administered 1 hour apart, and continuous infusion of 25 mL for 1 hour. Finally, dose-response analysis was performed by using 10 groups of three animals each, with 1-hour intraarterial infusions of 3-BrPA (25 mL) at incremental doses of 0.25 mmol/L (range, 0.5-2.5 mmol/L) with phosphate buffered saline used for control animals. All animals were sacrificed at 48 hours, and histopathologic analysis was performed. χ2 statistics were used to analyze the data. Results: The maximum tolerated dose of 3-BrPA was 2.5 mmol/L; however, it caused substantial peripheral liver necrosis. These effects were minimized when 3-BrPA was infused over 1 hour. Complete tumor necrosis was identified in all samples with at least 2.0 mmol/L of 3-BrPA. The 1.75 mmol/L concentration was identified as therapeutic because it caused complete tumor apoptosis and minimal toxicity (P < .001). Conclusions: The results identified both the therapeutic dose (1.75 mmol/L) and the method of infusion (1 hour intraarterial infusion) of 3-BrPA. This potent new treatment may prove to be an effective way of treating liver cancer and may become part of a new class of anticancer drugs based on the inhibition of tumor metabolism.",
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T2 - Identification of Therapeutic Dose and Method of Injection in an Animal Model of Liver Cancer

AU - Vali, Mustafa

AU - Liapi, Eleni

AU - Kowalski, Jeanne

AU - Hong, Kelvin

AU - Khwaja, Afsheen

AU - Torbenson, Michael

AU - Georgiades, Christos

AU - Geschwind, Jean Francois H.

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Purpose: A potent new adenosine triphosphate inhibitor-3-bromopyruvate (3-BrPA)-has been shown to have antitumor effects when injected intraarterially in the hepatic artery of rabbits with VX-2 tumors. The authors performed a stepwise study in rabbits to determine the therapeutic dose and method of delivery of 3-BrPA. Materials and methods: White New Zealand rabbits with VX-2 tumors were used for this study. Eight animals were examined to establish the maximum tolerated dose (2.5 or 5.0 mmol/L of 25-mL 3-BrPA) as a single bolus injection. The 2.5 mmol/L dose was then used to compare three methods of delivery: injection of one bolus, two 12.5-mL serial bolus injections administered 1 hour apart, and continuous infusion of 25 mL for 1 hour. Finally, dose-response analysis was performed by using 10 groups of three animals each, with 1-hour intraarterial infusions of 3-BrPA (25 mL) at incremental doses of 0.25 mmol/L (range, 0.5-2.5 mmol/L) with phosphate buffered saline used for control animals. All animals were sacrificed at 48 hours, and histopathologic analysis was performed. χ2 statistics were used to analyze the data. Results: The maximum tolerated dose of 3-BrPA was 2.5 mmol/L; however, it caused substantial peripheral liver necrosis. These effects were minimized when 3-BrPA was infused over 1 hour. Complete tumor necrosis was identified in all samples with at least 2.0 mmol/L of 3-BrPA. The 1.75 mmol/L concentration was identified as therapeutic because it caused complete tumor apoptosis and minimal toxicity (P < .001). Conclusions: The results identified both the therapeutic dose (1.75 mmol/L) and the method of infusion (1 hour intraarterial infusion) of 3-BrPA. This potent new treatment may prove to be an effective way of treating liver cancer and may become part of a new class of anticancer drugs based on the inhibition of tumor metabolism.

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