The Antitumor Effect and Hepatotoxicity of a Hexokinase II Inhibitor 3-Bromopyruvate: In Vivo Investigation of Intraarterial Administration in a Rabbit VX2 Hepatoma Model

OBJECTIVE: The purpose of this study was to compare the antitumor effect and hepatotoxicity of an intraarterial delivery of low-dose and high-dose 3-bromopyruvate (3-BrPA) and those of a conventional Lipiodol-doxorubicin emulsion in a rabbit VX2 hepatoma model. MATERIALS AND METHODS: This experiment was approved by the animal care committee at our institution. VX2 carcinoma was implanted in the livers of 36 rabbits. Transcatheter intraarterial administration was performed using low dose 3-BrPA (25 mL in a 1 mM concentration, n = 10), high dose 3-BrPA (25 mL in a 5 mM concentration, n = 10) and Lipiodol-doxorubicin emulsion (1.6 mg doxorubicin/ 0.4 mL Lipiodol, n = 10), and six rabbits were treated with normal saline alone as a control group. One week later, the proportion of tumor necrosis was calculated based on histopathologic examination. The hepatotoxicity was evaluated by biochemical analysis. The differences between these groups were statistically assessed with using Mann-Whitney U tests and Kruskal-Wallis tests. RESULTS: The tumor necrosis rate was significantly higher in the high dose group (93% +/- 7.6 [mean +/- SD]) than that in the control group (48% +/- 21.7) (p = 0.0002), but the tumor necrosis rate was not significantly higher in the low dose group (62% +/- 20.0) (p = 0.2780). However, the tumor necrosis rate of the high dose group was significantly lower than that of the Lipiodol-doxorubicin treatment group (99% +/- 2.7) (p = 0.0015). The hepatotoxicity observed in the 3-BrPA groups was comparable to that of the Lipiodol-doxorubicin group. CONCLUSION: Even though intraarterial delivery of 3-BrPA shows a dose-related antitumor effect, single session treatment seems to have limited efficacy when compared with the conventional method.

FDG-PET for Evaluating the Antitumor Effect of Intraarterial 3-Bromopyruvate Administration in a Rabbit VX2 Liver Tumor Model

OBJECTIVE: We wanted to investigate the feasibility of using FDG-PET for evaluating the antitumor effect of intraarterial administration of a hexokinase II inhibitor, 3-bromopyruvate (3-BrPA), in a rabbit VX2 liver tumor model. MATERIALS AND METHODS: VX2 carcinoma was grown in the livers of ten rabbits. Two weeks later, liver CT was performed to confirm appropriate tumor growth for the experiment. After tumor volume-matched grouping of the rabbits, transcatheter intraarterial administration of 3-BrPA was performed (1 mM and 5 mM in five animals each, respectively). FDG-PET scan was performed the day before, immediately after and a week after 3-BrPA administration. FDG uptake was semiquantified by measuring the standardized uptake value (SUV). A week after treatment, the experimental animals were sacrificed and the necrosis rates of the tumors were calculated based on the histopathology. RESULTS: The SUV of the VX2 tumors before treatment (3.87+/-1.51[mean+/-SD]) was significantly higher than that of nontumorous liver parenchyma (1.72+/-0.34) (p < 0.0001, Mann-Whitney U test). The SUV was significantly decreased immediately after 3-BrPA administration (2.05+/-1.21) (p = 0.002, Wilcoxon signed rank test). On the one-week follow up PET scan, the FDG uptake remained significantly lower (SUV 1.41+/-0.73) than that before treatment (p = 0.002), although three out of ten animals showed a slightly increasing tendency for the FDG uptake. The tumor necrosis rate ranged from 50.00% to 99.90% (85.48%+/-15.87). There was no significant correlation between the SUV or the SUV decrease rate and the tumor necrosis rate in that range. CONCLUSION: Even though FDG-PET cannot exactly reflect the tumor necrosis rate, FDG-PET is a useful modality for the early assessment of the antitumor effect of intraarterial administration of 3-BrPA in VX2 liver tumor.

The Anticancer Efficacy and Toxicity of Oral Paclitaxel- Loaded Lipid Nanoparticle in a C3H2 Bladder Cancer Mice / 대한비뇨기과학회지

Purpose: Paclitaxel is an anticancer drug that blocks cell division by stabilizing microtubules. Even though paclitaxel has been shown to be effective in killing bladder cancer cell lines in vitro, the in vivo absorption was extremely low. A paclitaxel formulation was prepared in solution only, which was bioadhesive, and its effects evaluated in the MBT-2 cell line and in C3H2 bladder cancer mice. In addition, the toxicity of the paclitaxel formulation was also evaluated. Materials and Methods: A muco-adhesive oily paclitaxel formulation was made by the combining of monoolein, tricaprylin, Tween 80 and paclitaxel. MBT-2 cells were cultivated in different concentration of taxol, and the tumoricidal activity measured by the indirect methylthiazol-2-yl-2, 5-diphenyl tetrazolium bromide (MTT) assay. In an in vivo study, the treatment regimen for the s.c. C3H2 mice was five consecutive once daily administrations, beginning on day 4 post tumor implant. The length and width of the tumors were measured twice a week, and the tumor volume calculated. On day 21, the tumor volume change and toxicity were evaluated. Results: The average particle size of paclitaxel-loaded lipid nanoparticle was about 600nm, with a polydispersity of 1,000. Only 2.6% of the MBT-2 cells were viable after 24 hour of treatment with the formulation at a paclitaxel concentration of 10mug/ml, while showing minimal toxicity of the formulation without paclitaxel. Paclitaxel-loaded lipid nanoparticles, administered orally, allowed significant antitumor activity in C3H2 mice (p<0.05). Conclusions: Paclitaxel-loaded lipid nanoparticles have a remarkable cytotoxic effect against MBT-2 cells, in a dose dependent manner, and the oral paclitaxel-loaded lipid nanoparticle therapy had an inhibitory effect on bladder tumors in a MBT-2 model, but without systemic toxicity. Therefore, oral paclitaxel-loaded lipid nanoparticles may be used for advanced bladder cancer patients.

Gene Therapy and Molecular Imaging

No abstract available.

Gene Delivery to the Rat Liver Using Cationic Lipid Emulsion/DNA Complex: Comparison between Intra-arterial, Intraportal and Intravenous Administration

OBJECTIVE: To compare the efficiency of intra-arterial, intraportal, and intravenous administration of cationic lipid emulsion/DNA complex, as used for gene transfer to rat liver. MATERIALS AND METHODS: DNA-carrier complex for the in-vivo experiment was prepared by mixing DNA and a cationic lipid emulsion. According to the administration route used (intra-arterial, intraportal, or intravenous), the animals were assigned to one of three groups. The heart, lung, liver, spleen and kidneys were removed and assayed for total protein and luciferase concentration. RESULTS: The cationic lipid emulsion/DNA complex used successfully transfected the various organs via the different administration routes employed. Luciferase activity in each organ of untreated animals was negligible. Liver luciferase values were significantly higher in the groups in which intra-arterial or intraportal administration was used. CONCLUSION: The intra-arterial or intraportal administration of cationic lipid emulsion/DNA complex is superior to intravenous administration and allows selective gene transfer to the liver.