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Inhibitory Effect of Natural Killer Cells on Liver Tumor Growth in Mouse Xenograft Model
Sukgil Song, Ji-sung Park, Hyeran Sung, Il-Hoi Kim, Chong-Kil Lee, Jin Tae Hong 충북대학교 동물의학연구소 2012 Journal of Biomedical and Translational Research Vol.13 No.2
Human natural killer (NK) cells are major players in innate immune response. The functions of these cells as a scavenger of cancer cells are enhanced by cytokines such as interleukin-2 (IL-2), which play an important role in immune response in both tumors and virally infected cells. Liver cancer has a high incidence rate and is a major cause of death in Korea. We provide evidence that human NK cells inhibit tumor growth of the hepatocellular carcinoma cell line SNU-354. NK cells were cultured with human IL-2 for 14 days, yielding an enriched NK cell population containing 35% CD8+cells, 6% CD4+cells, and 51% CD16+/CD56+ cells. Intravenous injection of NK cells at doses from 2.5 to 10 million cells/mouse was administered once per week in a nude mouse model that retains human liver tumor induced by implantation of SNU-354 cells. The results showed that human NK cells were recruited within tumor tissue and inhibited SNU-354 tumor growth by 32%, 58%, and 65%. The current data suggest the potential for use of NK cellbased immunotherapy for treatment of human liver cancer.
음이온계 약물의 간수송과정에 있어서 대향수송의 약물동력학적 모델링 및 시뮬레이션
송석길(Sukgil Song),이준섭(Jun Seup Lee),정연복(Youn Bok Chung) 대한약학회 2005 약학회지 Vol.49 No.4
The purpose of the present study was to kinetically investigate the carrier-mediated uptake in the hepatic transport of organic anions, and to simulate the "in vivo counter-transport" phenomena, using kinetic model which was developed in this study. The condition that the mobility of carrier-ligand complex is greater than that of free carrier is not essential for the occurrence of "counter-transport" phenomenon. To examine the inhibitory effects on the initial uptake of organic anions by the liver, it is necessary to judge whether the true counter-transport mechanism (trans-stimulation) is working or not. Effects of bromophenol blue (BPB) or bromosulfophthalein (BSP) on the plasma disappearance curves of a 1-anilino-8-naphthalene sulfonate (ANS) were then kinetically analyzed based on a flow model, in which the ligand is eliminated only from the peripheral compartment (liver compartment). Moreover "in vivo counter-transport" phenomena were simulated based on the perfusion model which incorporated the carrier-mediated transport and the saturable intracellular binding. The "in vivo counter-transport" phenomena in the hepatic transport of a organic anions were well demonstrated by incorporating the carrier-mediated process. However, the "in vivo counter-transport" phenomena may be also explained by the enhancement of back diffusion due to the displacement of intracellular binding. In conclusion, one should be more cautious in interpreting data obtained from so-called "in vivo counter-transport" experiments.
신규 항암성 화합물 아크리플라빈과 구아노신 복합체를 흰쥐에 근육주사시 아크리플라빈의 체내분포
송석길(Sukgil Song),정연복(Youn Bok Chung) 대한약학회 2006 약학회지 Vol.50 No.1
A 1:1 mixture of acriflavine (ACF; CAS 8063-24-9) and guanosine is currently being evaluated as a possible antitumor agent in preclinical studies. Guanosine is known to potentiate the anticancer activity of some compounds. However, the distributions of trypaflavine (TRF) or proflavine (PRF) have not been investigated in mammals. We, therefore, investigated the distribution of TRF and PRF after i.m. administration of the combination mixture (ACF and guanosine) at a does of 30 ㎎/㎏ ACF in rats. To analyze TRF and PRF levels in biological samples, we used an HPLC-based method. The calibration curves for TRF and PRF in the sample were linear over the concenration range of 0.05~200 ㎍/㎖. The intra- and inter-day assay accuracies of this method were within ±15% of norminal values and the precision did not exceed 15% of relative standard diviation. The lower limits of quantitation were 50 ng/㎖ for both TRF and PRF. The distribution of TRF or PRF was determined by 48h after i.m. administraion of the combination mixture at a dose of 30㎎/㎏ ACF. TRF and PRF were distributed as the followeing order; kidney>lung>liver>small intestine>muscle. Of the various tissues, TRF and PRF were mainly distributed to the kidney and lung. The concentrations of TRF or PRF in the tissues 24 h after i.m. administration decreased to undetectable levels. The concentrations of TRF or PRF in the blood cells were comparable to those for the plasma. However, the concentrations of TRF or PRF in the both plasma and blood cells 12h after i.m. administration were not detected. The number of the platelets in the 1㎖ of the blood was calculated to be 0.183×108/㎖ of blood. The PRF concentration in platelets was higher than that of TRF at initial times after i.m. administration of the combination mixture. However, both the TRF and PRF concentrations in the plateles 24h after i.m. administraion of the combination mixture were below the quantifiable limit. In conclusion, the concentrations of TRF or PRF in the various tissues, plasma, blood cells, and plateles decreased to undetectable levels 24h after i.m. administration of the combination mixture at a dose of 30 ㎎/㎏ ACF.
신규 피리미딘 구조를 함유한 항바이러스성 화합물 CPD의 수용약중 가용화
송석길(Sukgil Song),권호석(Ho Seok Kweon),정연복(Youn Bok Chung) 대한약학회 2006 약학회지 Vol.50 No.1
The purpose of the present study was to formulate the aqueous solution of 1-cyclopent-3-enylmethyl-6(3,5-dimethyl-benzoyl)-5-ethyl-1H-pyrimidine-2,4-dione (CPD), a novel antivirus compound containing pirimidine structure. For this purpose, the effects of various solubilization agents such as cosolvents [ethanol, propylene glycol (PG), polyethylene glycol 300 (PEG 300), polyethylene glycol 400 (PEG 400), glycerin], surfactants (Tween 80, Cremophor?? RH40, Cremophor?? EL, Poloxamer 407, Poloxamer 188) and complexation agent [hydroxypropyl-β-cyclodextrin (HPBCD)], on the solubility of CPD in aqueous solution were evaluated. The solubility of CPD in water was under 1 ㎍/㎖ at 20℃. Cosolvents such as ethanol, PG, PEG 300, PEG 400 and glycerin did not enhance the solubility of CPD at the 0~40% concentration range. The solubility of CPD was significantly elevated by the addition of cosolvents over the 80% concentration range. On the other hand, tween 80, Cremophor?? L, Cremophor?? RH40, and HPBCD showed enhanced effects on the solubility of CPD. The enhanced effects of Poloxamer 407 or Poloxamer 188 on the CPD solubility were less pronounced compared with tween 80, Cremophor?? L or Cremophor?? RH40. As a results, tween 80 aqueous solution was selected as an optimum solvent system. The aqueous solutions containing 20% tween 80 were formulated as a dosing solution containing CPD for its intraperitoneal and intrahypodermic administration, respectively. The formular showed physical stability after stored for 7 days at 4℃. Keywords : CPD, solubility, stability, cosolvent, surfactant
Lee, Pung-Sok,Song, Im-Sook,Shin, Tae-Ha,Chung, Suk-Jae,Shim, Chang-Koo,Song, Sukgil,Chung, Youn-Bok The Pharmaceutical Society of Korea 2003 Archives of Pharmacal Research Vol.26 No.4
The purpose of the present study was to investigate the bidirectional transport of 1-anilino-8-naphthalene sulfonate (ANS) using isolated rat hepatocytes. The initial uptake rate of ANS by isolated hepatocytes was determined. The uptake process of ANS was saturable, with a $K_m of 29.1\pm3.2 \mu M and V_{max} of 2.9\pm0.1$ mmol/min/mg protein. Subsequently, the initial efflux rate of ANS from isolated hepatocytes was determined by resuspending preloaded cells to 3.0% (w/v) BSA buffer. The efflux process for total ANS revealed a little saturability. The mean value of the efflux clearance was $2.2\pm0.1 \mu$ L/min/mg protein. The efflux rate of ANS from hepatocytes was markedly decreased at $4^{\circ}C$, indicating that the apparent efflux of ANS might not be attributed to the release of ANS bound to the cell surface, but to the efflux of ANS from intracellular space. The efflux clearance was furthermore corrected for the unbound intracellular ANS concentration on the basis of its binding parameters to cytosol. The relation between efflux rate and unbound ANS concentration was fitted well to the Michaelis-Menten equation with a saturable and a nonsaturable components. The $V_{max} and K_m$ values were 0.54 mmol/min/mg protein, and 10.0 $\mu$ M, respectively. Based on the comparison of the ratios of $V_{max} to K_m (V_{max}/K_m)$ corresponding to the transport clearance, the influx clearance was two times higher than the efflux clearance. Together with our preliminary studies that ATP suppression in hepatocytes substantially inhibited ANS influx rate, we concluded that the hepatic uptake of ANS is actively taken up into hepatocytes via the carrier mediated transport system.