• Archives of Pharmacal Research
• /
• v.27 no.8
• /
• pp.840-844
• /
• 2004

A triterpene was isolated as a cytotoxic principle from the dichloromethane extract of Korean mistletoe (KM； Viscum album colora turn) by repeated silica gel chromatography and recrystalli-zation. In in vitro analysis of cytotoxic activity using various human and murine tumor cell lines, the dichloromethane extract of KM was highly cytotoxic against these cells. We isolated the most active compound, referred to VD-3, from the dichloromethane extract of KM. The VD-3 was shown to be less cytotoxic to normal cells (murine splenocytes). From the identification of the chemical structure of VD-3 by spectral data and chemical synthesis, the compound was proven to be epi-oleanolic acid. Tumor cells treated with VD-3 showed a typical pattern of apo-ptotic cell death, such as apparent morphological changes and DNA fragmentation. These results indicate that epi-oleanolic acid is an important compound responsible for antitumor activity of KM.

• Archives of Pharmacal Research
• /
• v.27 no.11
• /
• pp.1147-1153
• /
• 2004

Bladder cancer is a common cancer with high risk of recurrence and mortality. Intravesicle chemotherapy after trans-urethral resection is required to prevent tumor recurrence and progression. It has been known that antioxidants enhance the antitumor effect of bacillus Calmette-Guerin (BCG), the most effective intravesical bladder cancer treatment. Capsaicin, the major pungent ingredient in genus Capsicum, has recently been tried as an intravesical drug for overactive bladder and it has also been shown to induce apoptotic cell death in many cancer cells. In this study, we investigated the apoptosis-inducing effect and alterations in the cellular redox state of capsaicin in MBT-2 murine bladder tumor cells. Capsaicin induced apoptotic MBT-2 cell death in a time- and dose-dependent manner. The capsaicin-induced apoptosis was blocked by the pretreatment with Z-VAD-fmk, a broad-range caspase inhibitor, or Ac-DEVD-CHO, a caspase-3 inhibitor. In addition to the caspase-3 activation, capsaicin also induced cytochrome c release and decrease in Bcl-2 protein expression with no changes in the level of Bax. Furthermore, capsaicin at the concentration of inducing apoptosis also markedly reduced the level of reactive oxygen species and lipid peroxidation, implying that capsaicin may enhance the antitumor effect of BCG in bladder cancer treatment. These results further suggest that capsaicin may be a valuable intravesical chemotherapeutic agent for bladder cancers.

• The Journal of Korean Medicine
• /
• v.25 no.2
• /
• pp.9-21
• /
• 2004

Objectives : To evaluate the anti-tumor and synergic effect of Bojungikkeehapdaechilki-tang (BJDC) with doxorubicin. Methods : The inhibitory concentration (IC), $IC_{50}{\;}and{\;}IC_{90}$ of single use of doxorubicin and BIDC with their concomitant treatment against Colon-26 (murine rectum carcinoma) cell line were observed using MTT (microculture tetrazolium test) assay. In addition, their anti-tumor effects were also observed in xenograft nude mice models against Colon-26 cell line. Results : BJDC had only minimal direct anti-tumor effect against Colon-26 cell line but it reduced general depressed signs induced by implantation of the tumor cell lines and increased the total WBC and lymphocyte numbers. Conclusions : It is considered or expected that BJDC extract is reducing the critical toxicity of doxorubicin and has favorable synergic anti-tumor effect when administered conconitently with doxorubicin.

• Clinical and Experimental Pediatrics
• /
• v.45 no.3
• /
• pp.354-361
• /
• 2002

Purpose : Selective introduction of genes conferring chemosensitivity into proliferating tumor cells may be used to treat cancer. We first investigated the bystander effect of retrovirus-mediated gene transfer of herpes simplex virus thymidine kinase(HSV-TK) gene to murine neuroblstoma cell line(neuro-2a) in vitro and in vivo. Second, we examined the mechanism and its enhancement of the bystander effect in murine neuroblastoma. Methods : To investigate the bystander effect, we studied tumor growth and survival time after HSV-TK/ganciclovir(GCV) treatment in a syngenic A/J mouse neuroblastoma model by mixing various ratios of HSV-TK-expressing neuro-2a cells with wild type neuro-2a cells followed by GCV treatment. To investigate the mechanism of the bystander effect in murine neuroblastoma, immunohistochemistry using connexin 43, CD4 and CD8-specific monoclonal antibodies was analyzed. We studied whether IL-2-secreting neuro-2a cells(neuro-2a/IL-2) would potentiate the bystander effect. Results : A strong bystander effect was observed in vitro and in vivo. The bystander effect in murine neuroblastoma was dependent on the immune response rather than connexin-mediated gap junction. Neuro-2a/IL-2 treatment enhanced the bystander effect in the HSV-TK/GCV system in murine neuroblastoma model. Conclusion : We conclude that the bystander effect in murine neuroblastoma depends on immune response and is enhanced by neuro-2a/IL-2.

• Journal of Society of Preventive Korean Medicine
• /
• v.6 no.2
• /
• pp.147-155
• /
• 2002

The musk has been reported to have significant anti-inflammatory activities in clinical use and several animal models and we examined the effects of water soluble fraction(WSF) of the musk on murine peritoneal macrophages. WSF decreased the production of nitric oxide from the lipopolysaccharide(LPS)-treated murine peritoneal macrophages and also reduced the phagocytic activity of macrophages on the opsonized sheep red blood cells(SRBC). Transcriptional expression level of the inducible nitric oxide synthase(iNOS) was also decreased and the viability of the treated macrophages was not affected by WSF, suggesting that the effects could be partly explained by transcriptional regulation. Contrary to down-regulating iNOS expression, WSF slightly increased the release of tumor necrosis factor-alpha$(TNF-{\alpha})$, which implied its selective action on cellular pathways activated by LPS. Our results showed that anti-inflammatory activities of the musk could be partly explained by the inhibitory effects of the water soluble fraction on the macrophageal activation.

• Current Optics and Photonics
• /
• v.3 no.1
• /
• pp.54-65
• /
• 2019

To develop a biomarker predicting tumor treatment efficacy is helpful to reduce time, medical expenditure, and efforts in oncology therapy. In clinics, microvessel density using immunohistochemistry has been proposed as an indicator that correlates with both tumor size and metastasis of cancer. In the preclinical study, we hypothesized that vascular morphometrics using optical coherence tomography angiography (OCTA) could be potential indicators to estimate the treatment efficacy of breast cancer. To verify this hypothesis, a 13762-MAT-B-III rat breast tumor was grown in a dorsal skinfold window chamber which was applied to a nude mouse, and the change in vascular morphology was longitudinally monitored during tumor growth and metronomic cyclophosphamide treatment. Based on the daily OCTA maximum intensity projection map, multiple vessel parameters (vessel skeleton density, vessel diameter index, fractal dimension, and lacunarity) were compared with the tumor size in no tumor, treated tumor, and untreated tumor cases. Although each case has only one animal, we found that the vessel skeleton density (VSD), vessel diameter index and fractal dimension (FD) tended to be positively correlated with tumor size while lacunarity showed a partially negative correlation. Moreover, we observed that the changes in the VSD and FD are prior to the morphological change of the tumor. This feasibility study would be helpful in evaluating the tumor vascular response to treatment in preclinical settings.

• IMMUNE NETWORK
• /
• v.9 no.6
• /
• pp.236-242
• /
• 2009

Background: Melanoma is the most fatal form of skin cancer due to its rapid metastasis. Recently, several studies reported that selenium can induce apoptosis in melanoma cells. However, the precise mechanism remains to be elucidated. In this study, we investigated the effect of selenium on cell proliferation in murine melanoma and on tumor growth and metastasis in C57BL/6 mice. Methods: Cell proliferation was measured by MTT assay in selenium-treated melanoma cells. Cell cycle distribution was analysized by staining DNA with propidum iodide (PI). mRNA and protein expression related to cell cycle arrest was measured by reverse transcription PCR and western blot. Tumor growth and metastasis was measured by in vivo model. Results: Selenium was suppressed the proliferation of melanoma cells in a dose dependent manner. The growth inhibition of melanoma by selenium was associated with an arrest of cell cycle distribution at G0/G1 stage. The mRNA and protein level of CDK2/CDK4 was suppressed by treatment with selenium in a time-dependent manner. In vivo, tumor growth was not suppressed by selenium; however tumor metastasis was suppressed by selenium in mouse model. Conclusion: These results suggest that selenium might be a potent agent to inhibit proliferative activity of melanoma cells.

• Korean Journal of Veterinary Research
• /
• v.45 no.1
• /
• pp.17-23
• /
• 2005

In the present study, we expected the anti-tumor effect by combined treatment of arsenic trioxide and interferon (IFN)-${\alpha}$ on murine Lewis lung carcinoma (LL2) cells through in vivo study. As a experimental model, LL2 cells ($1{\times}10^{6}$/mouse) were injected subcutaneously into the back region of mice. When the tumor volume reached $100mm^3$, mice were treated with 1 mg/kg arsenic trioxide, 50000 IU IFN-${\alpha}$, or arsenic trioxide and IFN-${\alpha}$. The development of tumor cells was significantly inhibited by combined treatment with arsenic trioxide and IFN-${\alpha}$. In arsenic trioxide and IFN-${\alpha}$ treated group, apoptotic index was reached a peak valve at 48 hr after the treatment and it was restored to approximately the control level at 8 days. Also, positive signals of Bax and Bad were increased at 48 to 96 hr and decreased at 8 day. Whereas, positive cells of Bcl-2 were steadily decreased at 12 to 48 hr and restored to the background level at 8 days. Our data showed that immunoreactivity of Bcl-2 was decreased at 12 to 48 hr, while positive signals of Bax and Bad were increased in accordance with apoptotic index at these times. In conclusion, our results suggest that the combined treatment with arsenic trioxide and IFN-${\alpha}$ significantly inhibited the growth of LL2 tumor cells and induced apoptosis through the up and down-regulation of Bcl-2 gene family.

• Journal of Microbiology and Biotechnology
• /
• v.23 no.9
• /
• pp.1339-1346
• /
• 2013

Conventional chemotherapeutic regimens often accompany severe side effects and fail to induce complete regression of chemoresistant or relapsing metastatic cancers. The need for establishing more efficacious anticancer strategies led to the development of a combined modality treatment of chemotherapy in conjunction with immunotherapy or radiotherapy. It has been reported that poly-gamma-glutamate (${\gamma}$-PGA), a natural polymer composed of glutamic acids, increases antitumor activity by activating antigen-presenting cells and natural killer (NK) cells. Here, we investigated the antitumor effect of ${\gamma}$-PGA in combination with cyclophosphamide in a murine melanoma model. Whereas cyclophosphamide alone directly triggered apoptosis of tumor cells in vitro, ${\gamma}$-PGA did not show cytotoxicity in tumor cells. Instead, it activated macrophages, as reflected by the upregulation of surface activation markers and the secretion of proinflammatory factors, such as nitric oxide and tumor necrosis factor ${\alpha}$. When the antitumor effects were examined in a mouse model, combined treatment with cyclophosphamide and ${\gamma}$-PGA markedly suppressed tumor growth and metastasis. Notably, ${\gamma}$-PGA treatment dramatically increased the NK cell population in lung tissues, coinciding with decreased metastasis and increased survival. These data collectively suggest that ${\gamma}$-PGA can act as an immunotherapeutic agent that exhibits a synergistic antitumor effect in combination with conventional chemotherapy.

• Proceedings of the Korean Society of Applied Pharmacology
• /
• 1993.04a
• /
• pp.73-73
• /
• 1993

As part of a research program to develope 3rd generation anti tumor platinum complexes, a series of platinum complexes which have 4, 5-bis-(aminomethyl)- 1, 3-dioxolane derivatives as bidenate amine ligands, represented by the general structual formula was prepared. The R$_1$ and/or R$_2$ substituents in this series of platinum complexes can be hydrogen. alkyl, of jointly formed cyclohexane. Two Xs can be a bidenate leaving ligand such as 1, 1-cyclobutanedicarboxylate, malonate, dimethylmalonate, ethylmalonate, glycolate, L-lactate, or N-methyliminodiacetate. From based on the pharmacological and toxicological studies, we have chosen SKI 2053R, cis-malonato[(4R, 5R)-4, 5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane] platinum(II) complex (NSC D644591) as a candidate for clinical evaluation. The antitumor activity of a new anti tumor platinum complex, cis-malonato [(4R, 5R)-4, 5-bis(aminomethyl)-2-isopropyl-1, 3-dioxolane] platinum(II) (SKI 2053R, NSC D644591), was compared with those of cisplatin and carboplatin using murine tumors. We evaluated three platinum complexes against L1210/CPR, a subline of L1210 leukemia resistant to cisplatin for their abilities to overcome tumor resistance to cisplatin. The in vitro cytotoxicity of SKI 2053R to L1210 cell line was 2.5-fold less potent thann that of cisplatin, and was 10-fold more cytotoxic than that of carboplatin. SKI 2053R retained similar cytotoxic effect and anti tumor activity to L1210/CPR cell line, like the cytotoxicity of SKI 2053R to L1210 cell line, while either cisplatin or carboplatin had not property to overcome the acquired cisplatin-resistance. SKI 2053R exhibited greater or comparable antitumor activity than cisplatin or carboplatin in murine tumor models.