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 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.Vali M, 2008, J PHARMACOL EXP THER, V327, P32, DOI 10.1124/jpet.108.141093Park HS, 2007, KOREAN J RADIOL, V8, P216Vali M, 2007, J VASC INTERV RADIOL, V18, P95, DOI 10.1016/j.jvir.2006.10.019Shin SW, 2006, ACTA RADIOL, V47, P1036, DOI 10.1080/02841850600977752Gwak GY, 2005, J HEPATOL, V42, P358, DOI 10.1016/j.jhep.2004.11.020Ko YH, 2004, BIOCHEM BIOPH RES CO, V324, P269, DOI 10.1016/j.bbrc.2004.09.047Llovet JM, 2003, LANCET, V362, P1907Yoon CJ, 2003, RADIOLOGY, V229, P126, DOI 10.1148/radio.2291021029Pedersen PL, 2002, BBA-BIOENERGETICS, V1555, P14Geschwind JFH, 2002, CANCER RES, V62, P3909Ko YH, 2001, CANCER LETT, V173, P83Smith TAD, 2000, BRIT J BIOMED SCI, V57, P170Pedersen PL, 1999, J BIOENERG BIOMEMBR, V31, P291Dang CV, 1999, TRENDS BIOCHEM SCI, V24, P68Bosch FX, 1999, SEMIN LIVER DIS, V19, P271Bruix J, 1997, HEPATOLOGY, V25, P259Rempel A, 1996, CANCER RES, V56, P2468Stuart KE, 1996, CANCER, V77, P2217MATHUPALA SP, 1995, J BIOL CHEM, V270, P16918OKADA M, 1995, BRIT J CANCER, V71, P518WATANABE D, 1995, ONCOLOGY, V52, P76REMPEL A, 1994, BBA-GENE STRUCT EXPR, V1219, P660BRUIX J, 1992, J HEPATOL, V15, P350OKUDA K, 1992, HEPATOLOGY, V15, P948SHINOHARA Y, 1991, FEBS LETT, V291, P55KO YH, 1990, ARCH BIOCHEM BIOPHYS, V278, P373BISMUTH H, 1986, WORLD J SURG, V10, P311JOHANSSON T, 1985, BIOCHEM BIOPH RES CO, V133, P608VIITANEN PV, 1984, J BIOL CHEM, V259, P9679BUSTAMANTE E, 1981, J BIOL CHEM, V256, P8699PEDERSEN PL, 1978, PROGR EXPT TUMOR RES, V22, P190WEINHOUS.S, 1972, CANCER RES, V32, P2007

The Temperature-Composition Phase Diagram and Mesophase Structure Characterization of the Monoolein/Water System

The temperature-composition phase diagram of monoolein in water was constructed using X-ray diffraction in the range of $0~^\circ{\rm C}$ to $104~^\circ{\rm C}$ and 0% (w/w) to 47% (w/w) water in the heating direction. The phases identified in this system include the lamellar crystalline (L$_{\rm c}$) phase, the lamellar liquid crystalline (L$_{\alpha}$) phase, the fluid isotropic (FI) phase, two inverted cubic phases (Q$^{230}$, Ia3d; Q$^{224}$, Pn3m), and the inverted hexagonal (H$_{\rm II}$) phase. The overall features of the monoolein/water phase diagram reported herein match those of existing phase diagrams for this system. There are some important differences, however. Accordingly, every effort has been taken to ensure that the current phase diagram represents equilibrium behavior and that the assorted phase boundaries have been determined accurately. The interpreted phase diagram is based on close to 400 discrete measurements in temperature-composition space recorded as a function of temperature in $5~^\circ{\rm C}$ increments ($3~^\circ{\rm C}$ in the H$_{\rm II}$ phase) and of composition in 2% (w/w) water increments on average. The various mesophases have been characterized structurally as a function of temperature and hydration, and the corresponding thermal and composition expansion coefficients are reported. These and related data show that the average radius of water channels in the fully hydrated bicontinuous cubic Pn3m phase is remarkably sensitive to temperature and to monoacylglycerol chain identity

Intraarterial gene delivery in rabbit hepatic tumors: transfection with nonviral vector by using iodized oil emulsion

PURPOSE: To evaluate the feasibility of an iodized oil emulsion that is used for the chemoembolization of hepatocellular carcinoma as a modifier of a nonviral gene transfer system for intraarterial gene delivery in experimentally induced hepatic tumors. MATERIALS AND METHODS: Experiments were performed in accordance with National Institutes of Health guidelines for the care and use of laboratory animals and were approved by the animal research committee at Seoul National University Hospital. VX2 carcinoma was implanted into the liver of 26 rabbits. Four nonviral gene transfer systems were prepared by using pCMV-luc+ as a reporter gene. The first system consisted of a DNA and polyethylenimine (PEI) complex (n = 7); the second, of a DNA and PEI complex mixed with iopamidol and iodized oil (n = 7); the third, of a DNA and PEI complex mixed with iopamidol (n = 7); and the fourth, of a DNA and PEI complex mixed with iodized oil (n = 5). For the DNA and PEI complex that was mixed with iopamidol and iodized oil, iopamidol was used to stabilize the emulsion. Twenty days after tumor implantation, intraarterial gene delivery was performed by selective catheterization of the hepatic artery. Rabbits were euthanized 24 hours after gene delivery. Luciferase activity was assayed in the tumor, left hepatic lobe, right hepatic lobe, and other organs and was statistically analyzed for comparison between complexes by using the Kruskal-Wallis test. RESULTS: Luciferase activity in the tumor was significantly higher for the group that received DNA, PEI, iopamidol, and iodized oil than for any other group (Kruskal-Wallis test, P < .05). Luciferase activity in the left hepatic lobe, right hepatic lobe, and other organs was not significantly different between complexes. Selective gene expression in tumor cells was confirmed by means of immunohistochemical analysis for luciferase. CONCLUSION: It is feasible to use an iodized oil emulsion system for the intratumoral transfection of nonviral vectors in experimentally induced hypervascular hepatic tumors

Cross-Protective Immunity of Mice Induced by Oral Immunization with Pneumococcal Surface Adhesin A Encapsulated in Microspheres

The global use of a capsular polysaccharide-based pneumococcal vaccine has been limited because of serotype-specific protection and poor effectiveness in individuals with low immunocompetency. The mucosal immune system develops earlier in infants and lasts longer in the elderly than does the systemic immune system. Furthermore, mucosal immunization is beneficial for AIDS patients, because human immunodeficiency virus-infected subjects can develop normal mucosal antibody responses even in late clinical phases. For these reasons, we evaluated recombinant pneumococcal surface adhesin A (rPsaA) of Streptococcus pneumoniae in terms of cross-protective immune responses after oral delivery. Encapsulated rPsaA provided higher immunogenicity than naked rPsaA. Coencapsulation or codelivery of the cholera toxin (CT) B subunit (CTB) and CT also increased the immunogenicity of rPsaA. Cross-protective immunities against five strains of S. pneumoniae (types 4, 6B, 14, 19F, and 23F) were induced after oral immunization with microencapsulated rPsaA. Lung colonization and septicemia caused by the five serotypes were significantly inhibited by oral immunization with microencapsulated rPsaA. These results suggest that rPsaA coencapsulated with CTB can be used as an oral vaccine to induce cross-protective immunity for the prevention of pneumococcal infection