• YAKHAK HOEJI
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• v.40 no.5
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• pp.532-538
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• 1996

In cancer chemotherapy, it is necessary to control the phamacokinetic behavior of an antitumor drug for effective treatment. Therefore, two 5-fluorouracil derivatives synthesize d with N-a-cyloxycarbonyl derivatives {1-(N-t-butyloxycarbonyl)leucyloxymethyl-5-FU(BLFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU)}. prodrugs of 5-fluorouracil, antitumor agent, were loaded into liposome of different lipid compositions. After liposomal drugs were injected intramuscularly, their pharmacokinetics and tissue distribution were assessed. The $AUC_{0{\to}{\infty}$ values were 1.29, 72.50, 85.57, 66.40 and 103.60${\mu}$g.hr/ml for 5-FU, BLFU, CLFU, BLFU- and CLFU-loaded liposome, respectively. 5-FU was distributed to spleen and liver with a maximal concentration after 1 hr and eliminated after 24 hr. But both prodrugs and dimyristoylphosphatidylcholine liposome entrapped prodrugs were distributed to spleen and liver at a lower concentration but maintained for a long time with a relatively high concentration in lung. Especially, liposome-entrapped CLFU was distributed to lung with a maximal concentration after 1 hr and redistributed to spleen increasingly, while the concentration of liposome-entrapped BLFU in lung reached a maximal level after 12 hr.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.9
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• pp.3907-3912
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• 2015

Purpose: To investigate the antitumor activity and mechanism of chloroquine (CQ) in combination with cisplatin (DDP) in nude mice xenografted with gastric cancer SGC7901 cells. Materials and Methods: 35 cases of gastric cancer patients with malignant ascites were enrolled and intraperitoneal cisplatin injection was performed. Ascites were collected before and 5 days after perfusion for assessment of autophagy levels in cancer cells. In addition, 24 tumor-bearing mice were randomly divided into control, DDP, CQ and CQ + DDP groups. Results: In 54.3% (19/35) of patients the treatment was therapeutically effective (OR), 5 days after peritoneal chemotherapy, 13 patients had the decreased ascites Beclin-1 mRNA levels. In 16 patients who had NR, only 2 cases had decreased Beclin-1 (P=0.001). Compared with the control group, the xenograft growth in nude mice in the DDP group was low, and the inhibition rate was 47.6%. In combination with chloroquine, the inhibition rate increased to 84.7% (P<0.01). The LC3-II/I ratio, and Beclin1 and MDR1/P-gp expression were decreased, while caspase 3 protein levels increased (P<0.05). Conclusions: Antitumor ability of cisplatin was associated with autophagy activity and chloroquine can enhance chemosensitivity to cisplatin in gastric cancer xenografts nude mice.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.5
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• pp.2015-2020
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• 2012

Oleanolic acid (OA) is a naturally occurring triterpenoid in food materials and is a component of the leaves and roots of Olea europaea, Viscum album L., Aralia chinensis L. and more than 120 other plant species. There are several reports validating its antitumor activity against different cancer cells apart from its hepatoprotective activity. However, antitumor activity against skin cancer has not beed studied well thus far. Hence the present study of effects of OA against HaCaT (immortalized keratinocyte) cells - a cell-based epithelial model system for toxicity/ethnopharmacology-based studies - was conducted. Radical scavenging activity ($DPPH{\cdot}$) and FRAP were determined spectrophotometrically. Proliferation was assessed by XTT assay at 24, 48 and 72 hrs with exposure to various concentrations (12.5-200 ${\mu}M$) of OA. Apoptotic induction potential of OA was demonstrated using a cellular DNA fragmentation ELISA method. Morphological studies were also carried out to elucidate its antitumor potential. The results revealed that OA induces apoptosis by altering cellular morphology as well as DNA integrity in HaCaT cells in a dose-dependent manner, with comparatively low cytotoxicity. The moderate toxicity observed in HaCaT cells, with induction of apoptosis, possibly suggests greater involvement of programmed-cell death-mediated mechanisms. We conclude that OA has relatively low toxicity and has the potential to induce apoptosis in HaCaT cells and hence provides a substantial and sound scientific basis for further validation studies.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.5
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• pp.3191-3196
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• 2013

Leaf extracts of Cassia alata L (akapulko), traditionally used for treatment of a variety of diseases, were evaluated for their potential antitumor properties in vitro. MTT assays were used to examine the cytotoxic effects of crude extracts on five human cancer cell lines, namely MCF-7, derived from a breast carcinoma, SK-BR-3, another breast carcinoma, T24 a bladder carcinoma, Col 2, a colorectal carcinoma, and A549, a nonsmall cell lung adenocarcinoma. Hexane extracts showed remarkable cytotoxicity against MCF-7, T24, and Col 2 in a dose-dependent manner. This observation was confirmed by morphological investigation using light microscopy. Further bioassay-directed fractionation of the cytotoxic extract led to the isolation of a TLC-pure isolate labeled as f6l. Isolate f6l was further evaluated using MTT assay and morphological and biochemical investigations, which likewise showed selectivity to MCF-7, T24, and Col 2 cells with $IC_{50}$ values of 16, 17, and 17 ${\mu}g/ml$, respectively. Isolate f6l, however, showed no cytotoxicity towards the non-cancer Chinese hamster ovarian cell line (CHO-AA8). Cytochemical investigation using DAPI staining and biochemical investigation using terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL)-a method used to detect DNA fragmentation-together with caspase assay, demonstrated apoptotic cell death. Spectral characterization of isolate f6l revealed that it contained polyunsaturated fatty acid esters. Considering the cytotoxicity profile and its mode of action, f6l might represent a new promising compound with potential for development as an anticancer drug with low or no toxicity to non-cancer cells used in this study.

• Journal of Microbiology and Biotechnology
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• v.11 no.3
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• pp.399-405
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• 2001

Urushiol, a natural pro-electrophilic quinone compound, has potential structural characteristics as antitumor chemotherapeutic agents. However, urushiol's use as an antitumor drug has some problems, because it is hardly miscible with an aqueous solution. Purified urushiol is highly viscous and soluble only in strong solvents. for this study, we prepared an urushiol-ethanol micro-emulsion with a unimodal size distribution by high-speed homogenization. This generated effective delivery of urushiol to its action wites, so that we could investigate its cytotoxic activity against cancer cells. Using a colony-forming assay, we were able to show that urushiol selectively inhibited the growth of the ovarian cancer cells PA-1 and 2774 at a concentration of $10^{-6}$, whereas it had only a negligible effect on normal CHO cells at the same concentration. The data suggest that urushiol may have potential as an effective antitumor agent in the treatment of ovarian cancer. In addition, we addressed the question of whether the specific cytotoxic effect of urushiol is linked to apoptosis, by DNA fragmentation and DAPI staining assays. The inhibitory effects of urushiol on the growth of ovarian cancer cells was found to be associated with DNA fragmentation and the fragmented nuclei formation, both of which represent markers for the induction of apoptosis. Therefore, the results suggested that urushiol affected its profound cytotoxicity by triggering apoptosis in ovarian cancer cells.

• The Korean Journal of Pharmacology
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• v.31 no.1 s.57
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• pp.103-114
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• 1995

Platinum coordination complexes are currently one of the most compounds used in the treatment of solid tumors. However, its use is limited by severe side effects such as renal toxicity. Our platinum-based drug discovery program is aimed at developing drugs capable of diminishing toxicity and improving antitumor activity. We synthesized new Pt (Ⅱ) complex analogue containing 1,2-diaminocyclohexane (dach) as carrier ligand and 1,2-bis(diphenylphosphino) ethane (DPPE) as a leaving group. Furthermore, nitrate was added to improve the solubility. A new series of [Pt(trans-ddach)(DPPE).$2NO_3(PC)$ was synthesized and characterized by their elemental analysis and by various spectroscopic techniques [infrared (IR), $^{13}carbon$ nuclear magnetic resonance (NMR)]. PC demonstrated acceptable antitumor activity aganist P388, L-1210 lymphocytic leukemia cells and SK=OV3 human ovarian adenocarcinoma cells, and significant. activity as compared with that. cisplatin. The toxicity of PC was found quite less than thar of cisplatin using MTT, $[^3H]$ thymidine uptake and glucose consumption tests in rabbit proximal tubule cells, human kidney cortical cells and human renal cortical tissues. Based on these results, this novel platinum compound represent a valuable lead in the development of a new anticancer chemotherapeutic agent capable of improving antitumor activity and low toxicity.

• Journal of Veterinary Clinics
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• v.28 no.6
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• pp.549-554
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• 2011

FK506 is a widespread immunosuppressive drug after liver transplantion in patients with advanced-stage hepatocellular carcinoma. Dexamethasone is frequently used as co-treatment in cytotoxic cancer therapy, e.g. to prevent nausea, to protect normal tissue or for other reasons. Our aim was to investigate antitumor effects of FK506 in Hep3B cells, one of differentiated human hepatocellular carcinoma cell lines and inhibitory effects of dexamethsone on FK506- induced antitumor effects. Cell injury was evaluated by biochemical assays as cell viability, lactate dehydrogenase (LDH) and reactive oxygen species (ROS) in Hep3B cells. Intracellular calcium concentration ([$Ca^{2+}$]i) and the level of activation of the c-Jun-N-terminal kinase (JNK) and the Bax protein in cultured Hep3B cells was measured. Exposure of 0.1 ${\mu}M$ FK506 to Hep3B cells led to cell death accompanied by a decrease in cell viability and an increase in LDH, ROS and [$Ca^{2+}$]i. FK506 induced an increase in activity of Bax and JNK protein but inhibited the activity of Bcl-2 protein. Treatment of dexamethsone, per se, had no effects on cell viability, LDH and ROS. However, co-treatment of FK506 and dexamethasone diminished the FK506-induced LDH release, ROS generation and JNK activation. These results demonstrate that FK506 has antitumor effect in Hep3B cells but the combination of FK506 and dexamethasone antagonizes the FK506-induced antitumor effects.

• The Journal of Internal Korean Medicine
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• v.12 no.2
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• pp.96-112
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• 1991

Attempts were made to see the antitumor effects of Sigbunhwan widely used in Oh-jug(五積) employing tumor cells Lines such as K562 derived from erythroleukemia, Raji from lympoma and MO-4 from blastogenic tumor. Different concentrations of Sigbunhwan and combined therapy of Sigbunhwan and Bigihwan were treated to those tumor cells lines and then live cells were counted by Trypan blue assay and $^{3}H-Thymidine$ uptake assay. The results obtained were as follows. 1. $^{3}H-Thymidine$ uptake of various tumor cells lines when treated with high concentrations of Sigbunhwan for 48hours showed that the rate of DNA synthesis decreased 76% to 90% by the treatment of 1% Sigbunhwan but this inhibition was rather decreased when Sigbunhwan concentration was increased to 10, 15 and 20%.(Fig 3) 2. When Sigbunhwan was combined with Bigihwan which was also an antitumor drug, the effectiveness of tumor cells dealth was somewhat inceased showing a generally similar pattern to that of Bigihwan alone used.(Fig 4) This combination therapy also showed that higher concentrations of antitumor agent were no more·effective or rather harmful according to the tumor cells lines having different growth rate.(Fig 5,6) 3. The antitumor effects of combined Sigbunhwan and Bigihwan was decreased if the concentrations of this combination therapy was increased to 10 times showing relatively sluggish decrease in K562 and MO-4 but a sharp inhibitory effect in Raji which grows slowly.(Fig 7). 4. When Sigbunhwan was treated at low concentrations, K562 was more inhibited by 0.75% to 1.0% of Sigbunhwan while Raji was more inhibited by 0.25% to 0.5% of that.(Fig 8) 5. When Sigbunhwan was treated together with Bigihwan at low concentrations, the tumor cells death rate was 75% to 89% in Baji, 31% to 95% in MO-4 and 41 to 89% in K562, showing this combination therapy was more effect to Raji derived from lymphoma.(Fig 9) 6. The number of live tumor cells was correlated with optical density of MTT assay when measured with 2% Sigbunhwan treatment to tumor cells lines for 24 hours.(Fig 10) 7. 7 days treatment of 0.25% Sigbunhwan was compared with one day treatment of 1% suggesting long term treatment more effective.(Fig 11)

• Toxicological Research
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• v.14 no.3
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• pp.365-370
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• 1998

To evaluate the renal toxicity of the antitumor agent, p-{N,N,-Bis(2-chloroethyl)amino}-4-phenyl acetyl-amino-2,6-piperidinedione(CK-15), rats were treated with CK-15 (acute: 50mg/kg. i.p., single and subacute: 5mg/kg, i.p., daily for 7 days). The changes in the body weight, water consumption, kidney weights and urine volume after and during the treatment were observed. The concentrations of urinary creatinine and portein, the activities of N-acetyl-${\beta}$-D-glucosaminidase (NAG), alanine aminopeptidase (AAP), ${\gamma}$-glutamyl transpeptidase (${\gamma}$-GT) and lactate dehydrogenase (LDH) in 24hr urine were also determined. The body weight, water consumption, and urine volume were decreased after the acute and subacute administration. However the weights of kidney were not changed after the treatments. The excretion of creatinine was significantly decreased 1 day after acute administration but, returned to the control value. In subactute administration, the excretion of creatinine was gradually decreased. However, the protein excretion did not changed in both treatment. Those indicate that CK-15 might decrease the metabolic rate of muscle. THe urinary activities of NAG, AAP, ${\gamma}$-GT, and LDH were significantly affected bythe drug treatment. The urinary activities of NAG, AAP and ${\gamma}$-GT were significantly increased 1 day after the acute administration and then returned to the control value. However, the urinary activities of LDH were not changed in acute treatment. In subacute treatment, although the urinary activities of NAG were not changed, those of AAP and ${\gamma}$-GT were significantly increased 2.3 times at 3 days during the subacute administration. Also the urinary activities of LDH were significantly increased at 7 day after the administration. These results indicate that the high and subacute administration might induce a damage in the kidney cells. Furthermore the present results suggest that the toxic effects of CK-15 might be due to the accumulation of the metabolites.

• Polymer(Korea)
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• v.35 no.5
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• pp.483-487
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• 2011

For the preparation of effective non-vascular drug eluting stent (DES), pullulan acetate (PA) was investigated as a coating material for polytetrafluorethylene (PTFE)-covered stent. PA was coated on PTFE-covered stent (PTFE-stent) by dip coating technique, and then its surface morphology, drug release behavior and cellular toxicity were tested. Field emission-scanning electron microscopy (FE-SEM) result indicated that its surface was smoother after PA coating without any cracking. The sustained release behavior of paclitaxel from PA-coated PTFE membrane was observed for 80 days. Also, the biological stability of paclitaxel in the membrane was confirmed by annexin V binding assays. Furthermore, the antitumor activity was demonstrated by an in vivo test against CT-26 murine colorectal tumors. From the results, we concluded that PA was expected as a useful coating material to design an effective non-vascular DES.