Assessment of Tumoricidal Efficacy and Response to Treatment with F-18-FDG PET/CT After Intraarterial Infusion with the Antiglycolytic Agent 3-Bromopyruvate in the VX2 Model of Liver Tumor
ABSTRACT The purpose of this study was to determine the effects of 3-bromopyruvate (3-BrPA) on tumor glucose metabolism as imaged with (18)F-FDG PET/CT at multiple time points after treatment and compare them with those after intraarterial control injections of saline.
Twenty-three New Zealand White rabbits implanted intrahepatically with VX2 tumors were assigned to 1 of 2 groups: 14 rabbits were assigned to the treatment group (TG) and 9 to the saline control group (SG). All animals were infused with 25 mL of either 1.75 mM 3-BrPA or saline over 1 h via a 2-French catheter, which was secured in the hepatic artery. For PET/CT, the animals were injected with 37 MBq of (18)F-FDG at 1 d before treatment and 2 h, 24 h, and 1 wk after treatment. Tumor size, tumor and liver maximal standardized uptake value (SUV(max)), and tumor-to-background ratios were calculated for all studies. Seven TG and 5 SG animals were sacrificed at 1 wk after treatment for histopathologic analysis.
Intense (18)F-FDG uptake was seen in untreated tumors. A significant reduction in tumor SUV(max) was noted in TG animals, when compared with SG animals, at 1 wk after treatment (P = 0.006). The tumor-to-liver background ratio in the TG animals, compared with the SG animals, was significantly reduced as early as 24 h after treatment (P = 0.01) and remained reduced at 1 wk (P = 0.003). Tumor SUV(max) increased from the baseline levels at 7 d in controls (P = 0.05). The histopathologic analysis of explanted livers revealed increased tumor necrosis in all TG samples. There was a significant inverse correlation (r(2) = 0.538, P = 0.005) between the percentage of tumor necrosis on histopathology and tumor SUV(max) on (18)F-FDG PET at 7 d after treatment with 3-BrPA.
Intraarterial injection of 3-BrPA resulted in markedly decreased (18)F-FDG uptake as imaged by PET/CT and increased tumor necrosis on histopathology at 1 wk after treatment in the VX2 rabbit liver tumor. PET/CT appears to be a useful means to follow antiglycolytic therapy with 3-BrPA.
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ABSTRACT: The pyruvate mimetic 3-bromopyruvate (3-BP) is generally presented as an inhibitor of glycolysis and has shown remarkable efficacy in not only preventing tumor growth, but even eradicating existant tumors in animal studies. We here review reported molecular targets of 3-BP and suggest that the very range of possible targets, which pertain to the altered energy metabolism of tumor cells, contributes both to the efficacy and the tumor specificity of the drug. Its in vivo efficacy is suggested to be due to a combination of glycolytic and mitochondrial targets, as well as to secondary effects affecting the tumor microenvironment. The cytotoxicity of 3-BP is less due to pyruvate mimicry than to alkylation of, e.g., key thiols. Alkylation of DNA/RNA has not been reported. More research is warranted to better understand the pharmacokinetics of 3-BP, and its potential toxic effects to normal cells, in particular those that are highly ATP-/mitochondrion-dependent.Journal of Bioenergetics 02/2012; 44(1):7-15. DOI:10.1007/s10863-012-9419-2 · 2.71 Impact Factor
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ABSTRACT: To investigate the optimal PET protocol and analytical method to characterize the glucose metabolism in nasopharyngeal carcinoma (NPC). Newly diagnosed NPC patients were recruited and a dynamic PET-CT scan was performed. The optimized threshold to derive the arterial input function (AIF) was studied. Two-tissue compartmental kinetic modeling using three, four, and five parameters, Patlak graphical analysis, and time sensitivity (S-factor) analysis were performed. The best compartmental model was determined in terms of goodness of fit, and correlated with Ki from Patlak graphical analysis and the S-factor. The methods with R>0.9 and P<0.05 were considered acceptable. The protocols using two static scans with its retention index (RI=(SUV(2)/SUV(1)-1)×100%, where SUV is the standardized uptake value) were also studied and compared with S-factor analysis. The best threshold of 0.6 was determined and used to derive AIF. The kinetic model with five parameters yields the best statistical results, but the model with k4=0 was used as the gold standard. All Ki values and some S-factors from data between various intervals (10-30, 10-45, 15-30, 15-45, 20-30, and 20-45 min) fulfilled the criteria. The RIs calculated from the S-factor were highly correlated to RI derived from simple two-point static scans at 10 and 30 min (R=0.9, P<0.0001). The Patlak graphical analyses and even a 20-min-interval S-factor analysis or simple two-point static scans were shown to be sufficient to characterize NPC metabolism, confirming the clinical feasibility of applying a short dynamic with image-derived AIF or simple two-point static PET scans for studying NPC.Nuclear Medicine Communications 11/2011; 33(2):191-7. DOI:10.1097/MNM.0b013e32834dfa0c · 1.37 Impact Factor
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ABSTRACT: The Warburg hypothesis states that aggressive cancers obtain much of their adenosine triphosphate (ATP) by metabolizing glucose directly to lactic acid. As a result of its high tumor selectivity, 3-bromopyruvic acid (3-BrPA), a well-known inhibitor of energy metabolism, has been proposed as a specific anticancer agent. We investigated the effect of 3-BrPA in a mouse model of aggressive metastatic lymphoma. Epstein-Barr-virus-infected human Raji lymphoma cells with lentivirally transfected green fluorescent protein and luciferase were incubated with RPMI/fetal bovine serum, and various concentrations of 3-BrPA were used to determine the LD50 in vitro. In total, 18 severely combined immunodeficient mice were injected with 1 million human Raji lymphoma cells via the tail vein. Using bioluminescent imaging, tumor growth was measured daily for 12 days to determine the tumor burden. At day 0 (start of treatment), the mice were randomized. Six mice received 10 mg/kg 3-BrPA i.p. daily for 7 days, 6 mice received 1 treatment at day 0, and 6 mice received the control buffer. Tumor growth was assessed daily from day 0 until day 7 using bioluminescent imaging. All data were normalized to acquisition time (luminescence/second; L/s). Body weight was measured daily to determine the toxicity of 3-BrPA. The LD50 for Raji lymphoma cells exposed to 3-BrPA in vitro was 11 μM with an extremely steep dose response curve. At day 0, tumor activity medians in the group with daily treatment was 2131 L/s (244-12,725), with a 1-day dose of 3095 L/s (523-9650) and in the nontreated control group, 2997 L/s (1521-6911). In mice treated with a daily dose of 10 mg/kg 3-BrPa for 7 days, a significant reduction in tumor activity was found during the whole treatment period compared with the control mice (P = 0.0043 at day 7). In mice with a single treatment at day 0, growth delay was only evident at day 2 (P = 0.0152 at day 2) but not for the rest of the observation period. The only manifestation of toxicity of the daily administration of 10 mg/kg 3-BrPA was a reduction in body weight. Body weight at day 0 was 17.22 g ± 0.84 g in the treatment group and 17.58 g ± 0.86 g in the control group. Body weight at day +6 was 15.02 g ± 2.04 g in the treated group and 19.4 g ± 0.63 g in the control group. 3-BrPA demonstrated a significant positive tumor response both in vitro and in vivo. This, to our knowledge, is the first report of the use of 3-BrPA in a systemic tumor model. Based on these data, 3-BrPA holds promise for treatment of systemic metastatic cancers.01/2012; 159(1):51-7. DOI:10.1016/j.trsl.2011.08.008