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.
OBJECTIVE
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.


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. chi2 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.
Vali
Mustafa
M
Division of Vascular and Interventional Radiology, Johns Hopkins Hospital, Baltimore, MD 21287, USA.
Liapi
Eleni
E
Kowalski
Jeanne
J
Hong
Kelvin
K
Khwaja
Afsheen
A
Torbenson
Michael S
MS
Georgiades
Christos
C
Geschwind
Jean-Francois H
JF
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage* / Q000009:adverse effects; D002404:Catheterization; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage* / Q000009:adverse effects; D006499:Hepatic Artery; D007261:Infusions, Intra-Arterial; D007269:Injections, Intra-Arterial; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism; D020714:Maximum Tolerated Dose; D011768:Pyruvate Dehydrogenase Complex / Q000037:antagonists & inhibitors*; D011773:Pyruvates / Q000008:administration & dosage* / Q000009:adverse effects; D011817:Rabbits
D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D011768:Pyruvate Dehydrogenase Complex; D011773:Pyruvates; C017092:bromopyruvate