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

ArticleinJournal of Nuclear Medicine 52(2):225-30 · February 2011with7 Reads
DOI: 10.2967/jnumed.110.083162 · Source: PubMed
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.
    • "However, the experimental models were usually inappropriately selected in many studies using VX2 tumor models. They are enrolled approximately 2 weeks after tumor transplantation [7–10] rather than being considered the stages of their clinical counterparts. Nowadays, the increased measurement precision in preclinical research has somewhat raised expectations regarding human outcome prediction of animal data [11]. "
    [Show abstract] [Hide abstract] ABSTRACT: Based on practice guideline of "management of hepatocellular carcinoma (HCC): update" published by American Association for the Study of Liver Diseases (AASLD) and "Barcelona Clinic Liver Cancer staging system (BCLC)," this study investigated how to enroll the optimal VX2 liver tumor model for HCC researches by dynamically observing the biological progression of the tumor. Thirty-two healthy New Zealand white rabbits were implanted VX2 liver tumor by cell suspension method (n=24) and tissue fragment method (n=8). All the rabbits underwent CT scans on day 7, 14, 21 and 28 after implantation to observe the size of the tumors, the time when metastases and ascites occurred and the survival time. Appropriate intervention times were estimated corresponding to different clinical HCC stages by using tumor diameter-time curve. The VX2 liver tumors grew rapidly within 28 days after implantation. And the tumors in the cell suspension group grew faster than those of the tissue fragment group. The appropriate intervention time corresponding to very early stage, early stage and intermediate stage were <11 days, 11-16.9 days and >16.9 days, respectively in the cell suspension group, and <19.9 days, 19.9-25.5 days and >25.5 days, respectively in the tissue fragment group. Preclinical animal research needs to improve on different levels to yield best predictions for human patients. Researchers should seek for an individualized proposal to select optimal VX2 liver tumor models for their experiments. This approach may lead to a more accurate determination of therapeutic outcomes.
    Full-text · Article · Aug 2013
    • "The model has been used in several studies, e.g., to assess 3-BP effects on glucose uptake, and thus in effect on glycolysis, using FDG-PET (Liapi et al. 2011). This study showed a rapid inhibitory effect on uptake (within hours) of intraarterially administered 3-BP (1.75 mM; 25 mL) and substantial tumor necrosis after 1 week; there was, however, no reduction in tumor volume over the same period (Liapi et al. 2011). Longer times may be required, since with the same tumor model and 3-BP dosage, treated animals showed considerably better survival than controls over 2 months; death was most commonly due to lung metastasesFig. 1 3-BP prevents tumor cell regrowth in combination with lowdose Cisplatin. "
    [Show abstract] [Hide abstract] 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.
    Full-text · Article · Feb 2012
  • [Show abstract] [Hide abstract] 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.
    Full-text · Article · Nov 2011
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