• Radiation Oncology Journal
• /
• v.13 no.2
• /
• pp.121-128
• /
• 1995

Purpose: The enhanced cytotoxic effect of combined treatment of hyper-thermia and chemotherapy by increasing intracellular acidity with HMA was investigated. Materials and Methods: FSall tumor cells were injected on the hindlegs of female $C_3H$ mice. When the tumor volume reached about 200mm3, experiments were performed on the groups classified as follows: Group I :Control, Group II : Melphalan alone (2.5mg/kg, 5mg/kg, 10mg/kg, 15mg/kg), Group III : Heat alone $(42.5^{\cdot}C$ for 1 hour) Group IV : Melphalan + Heat $(42.5^{\cdot}C$ for 1 hour), Group V : HMA(10mg/kg) + Melphalan(5.0mg/kg) + Heat$(42.5^{\cdot}C$ for 1hour). Each group included 8-12 mice on each experiment HMA (3-amino-6-chloro-5-(1-homopiperidyl )-N-(diaminomethylene) -c-pyrazinecarboxamide), an analog of amiloride which increases intracellular pH(pHi) was dissolved in dimethyl sulfoxide (DMS) and injected into the tumor-bearing mice through the tail vein. 10mg/kg of HMA and each dose of melphalan were injected into peritoneum of the tumor-bearing mice 30 minutes before heating. Tumor growth delay was calculated when the tumor volme reached at $1500mm^3$ Excision assay was performed on each group and repeated 2-4 times. Results : Tumor growth delay of each experimental groups at $1500mm^3$ were 9, 10, 13 and 19 days respectively. In vivo-in vitro excision assay using FSall tumor cells, the cytotoxicity of each experimental groups was $1.2{\times}10^7,\;1{\times}10^7,\;6{\times}10^6,\;1.7{\times}10^6\;and\;1{\times}10^5$ clonogenic cells/gm respectively When HMA was added to the combined treatment of heat and .chemotherapy, the tumor growth was delayed more than combined treatment without HMA i.e., 6 days tumor growth delay at $1500mm^3$ of tumor volume. Conclusion: The combined effect of cytotoxicity by heat and chemotherapy can be much more enhanced by HMA.

• Radiation Oncology Journal
• /
• v.12 no.3
• /
• pp.301-305
• /
• 1994

Purpose :. To investigate the effect of aqueous extract of Ganoderma lucidum(G.I.) on the surival of tumor cells in vitro and on the growth of tumors in vivo. Materials and Methods : Dried G.I. was made into powder, extracted with distilled water, filtered and diluted from a maximum concentration of 100 mg/ml in sequence. The cytotoxicity of G.I, in vitro was evaluated from its ability to reduce the clonogenicity of SCK tumor cells. For the tumor growth delay study, about $2{\times}10^5$$ of SCK tumor cells were subcutaneously inoculated in the legs of A/J mice. The first experimental group of mice were injected i.p. with 0.2ml of 250 mg/kg of G.I. from the first day after tomor inoculation for 10 days. The second experimental group of mice were injected i.p. with 0.2ml of 250 mg/kg of G.I. either once a day for 10 days or twice a day for 5 days beginining from the 7th day after tumor inoculation Results : 1. Cytotoxicity in vitro;survival fraction, as judged from the curve, at G.I. concentration of 0.5, 1,5, 10, 25, 50 and 100 mg/ml were 1.0, $0.74{\pm}0.03$, $0.18{\pm}0.03$, $0.15{\pm}0.02$, $0.006{\pm}0.002$, 0.015 and 0.0015, respectively. 2. Tumor growth delay in vivo; a) the time required for the mean tumor volume to grow to $1,000mm^3$ was 11 days in the control group and 14 days in the experimental group. b) the time required for tumor volume to increase 4 times was 11 days in the control group while it was 10.5 and 12 days in the groups injected with G.I. once a day and twice a day from the 7th day after tumor inoculation respectively. Conclusion : Aqueous extracts of G.I. showed a marked cytotoxicity on the SCK mammary cells in vitro. Tumor growth delay was statistically signiricant when G.I. in-jection was started soon after tumor inoculation, but it was not significant when injection was started after the tumors were firmly established.

• East Asian mathematical journal
• /
• v.36 no.1
• /
• pp.81-90
• /
• 2020

Many compartment models assume a kinetically homogeneous amount of materials that have well-stirred compartments. However, based on observations from such processes, they have been heuristically fitted by exponential or gamma distributions even though biological media are inhomogeneous in real environments. Fractional differential equations using a specific kernel in Pharmacokinetic/Pharmacodynamic (PKPD) model are recently introduced to account for abnormal drug disposition. We discuss a tumor growth inhibition (TGI) model using fractional-order derivative from it. This represents a tumor growth delay by cytotoxic agents and additionally show variations in the equilibrium points by the change of fractional order. The result indicates that the equilibrium depends on the tumor size as well as a change of the fractional order. We find that the smaller the fractional order, the smaller the equilibrium value. However, a difference of them is the number of concavities and this indicates that TGI over time profile for fitting or prediction should be determined properly either fractional order or tumor sizes according to the number of concavities shown in experimental data.

• Journal of Pharmacopuncture
• /
• v.19 no.2
• /
• pp.114-121
• /
• 2016

Objectives: Lung cancer remains a deadly disease with unsatisfactory overall survival. Cisplatin, a standard platinum (Pt)-based chemotherapeutic agent, has the potential to inhibit the growth of lung cancer. Its use, however, is occasionally limited by severe organ toxicity. However, until now, no systematic study has been conducted to verify its efficacy with proper experimental support in vivo. Therefore, we examined whether biosynthesized Pt nanoparticles (NPs) inhibited human lung cancer in vitro and in vivo to validate their use in alternative and complementary medicine. Methods: We evaluated the in vitro and the in vivo anticancer efficiencies of biosynthesized Pt NPs in a subcutaneous xenograft model with A549 cells. Severe combined immune deficient mice (SCID) were divided into four groups: group 1 being the vehicle control group and groups 2, 3 and 4 being the experimental groups. Once the tumor volume had reached $70-75mm^3$, the progression profile of the tumor growth kinetics and the body weights of the mice were measured every week for 6 weeks after oral administration of Pt NPs. Doses of Pt NPs of 500, 1,000 and 2,000 mg/kg of body weight were administered to the experimental groups and a dose of honey was administered to the vehicle control group. The efficacy was quantified by using the delay in tumor growth following the administration of Pt NPs of A549 human-lung-cancer xenografts growing in SCID mice. Results: The in vitro cytotoxicity evaluation indicated that Pt NPs, in a dose-dependent manner, inhibited the growth of A549 cells, and the in vivo evaluation showed that Pt NPs at the mid and high doses effectively inhibited and delayed the growth of lung cancer in SCID mice. Conclusion: These findings confirm the antitumor properties of biosynthesized Pt NPs and suggest that they may be a cost-effective alternative for the treatment of patients with lung cancer.

• Journal of Microbiology and Biotechnology
• /
• v.25 no.7
• /
• pp.1036-1046
• /
• 2015

Extracts from Asian medicinal herbs are known to be successful therapeutic agents against cancer. In this study, the effects of three types of herbal extracts on anti-tumor growth were examined. Among the three types of herbal extracts, H9 showed stronger anti-tumor growth effects than H5 and H11 in vivo. To find the molecular mechanism by which H9 inhibited the proliferation of breast cancer cell lines, the levels of apoptotic markers were examined. Proapoptotic markers, including cleaved PARP and cleaved caspases 3 and 9, were increased, whereas the anti-apoptotic marker Bcl-2 was decreased by H9 treatment. Next, the combined effect of H9 with the chemotherapeutic drugs doxorubicin/cyclophosphamide (AC) on tumor growth was examined using 4T1-tumor-bearing mice. The combined treatment of H9 with AC did not show additive or synergetic anti-tumor growth effects. However, when tumor-bearing mice were co-treated with H9 and the targeted anti-tumor drug trastuzumab, a delay in tumor growth was observed. The combined treatment of H9 and trastuzumab caused an increase of natural killer (NK) cells and a decrease of myeloid-derived suppressor cells (MDSC). Taken together, H9 induces the apoptotic death of tumor cells while increasing anti-tumor immune activity through the enhancement of NK activity and diminishment of MDSC.

• Radiation Oncology Journal
• /
• v.20 no.2
• /
• pp.155-164
• /
• 2002

Purpose : A ginkgo biloba extract (GBE) has been known as a hypoxic cell radiosensitizer. Its mechanisms of action are increase of the red blood cell deformability, decrease the blood viscosity, and decrease the hypoxic cell fraction in the tumor. The aims of this study were to estimate the effect of GBE on fractionated radiotherapy and to clarify the mechanism of action of the GBE by estimating the blood flow in tumor and normal muscle. Materials and Methods : Fibrosarcoma (FSall) growing in a C3H mouse leg muscle was used as the tumor model. When the tumor size reached 7 mm in diameter, the GBE was given intraperitoneally at 1 and 25 hours prior to irradiation. The tumor growth delay was measured according to the various doses of radiation (3, 6, 9, 12 Gy and 15 Gy) and to the fractionation (single and fractionated irradiation) with and without the GBE injection. The radiation dose to the tumor the response relationships and the enhancement ratio of the GBE were measured. In addition, the blood flow of a normal muscle and a tumor was compared by laser Doppler flowmetry according to the GBE treatment. Results : When the GBE was used with single fraction irradiation with doses ranging from 3 to 12 Gy, GBE increased the tumor growth delay significantly (p<0.05) and the enhancement ratio of the GBE was 1.16. In fractionated irradiation with 3 Gy per day, the relationships between the radiation dose (D) and the tumor growth delay (TGD) were TGD $(days)=0.26{\times}D$ (Gy)+0.13 in the radiation alone group, and the TGD $(days)=0.30{\times}D$ (Gy)+0.13 in the radiation with GBE group. As a result, the enhancement ratio was 1.19 ($95\%$ confidence interval; $1.13\~1.27$). Laser Doppler flowmetry was used to measure the blood flow. The mean blood flow was higher in the muscle (7.78 mL/100 g/min in tumor and the 10.15 mL/100 g/min in muscle, p=0.005) and the low blood flow fraction (less than 2 mL/100 g/min) was higher in the tumor $(0.5\%\;vs.\;5.2\%,\;p=0.005)$. The blood flow was not changed with the GBE in normal muscle, but was increased by $23.5\%$ ( p=0.0004) in the tumor. Conclusion : Based on these results, it can be concluded that the GBE enhanced the radiation effect significantly when used with fractionated radiotherapy as well as with single fraction irradiation. Furthermore, the GBE increased the blood flow of the tumor selectively.

• Radiation Oncology Journal
• /
• v.18 no.2
• /
• pp.133-137
• /
• 2000

Purpose :To investigate whether combined beta-carotene with X-Irradiation has more enhanced radition response than X-irradiation or not, we peformed a experiment about in vitro cytotoxlcity of beta-carotene and/or X-irradiation in the fibrosarcoma cells, tumor growth delay of combined beta-caroten with/or X-irradiation in the mouse fibrosarcoma. Materials and Methods : 2$\%$ emulsion of beta-carotene was serially diluted and used. X-Irradiation was given by 6 MeV linear accelerator. The cytotoxicity of beta-carotene in vitro was evaluated from clonogenic assay. To compare the cytotoxiclty between combined beta-carotene with X-irradiation and X-irradiation group, 2 mg/ml of beta-carotene was contacted to fibrosarcoma (FSall) cells for 1 hour before X-irradiation. For the tumor growth delay, single 20 Gy was given to FSall tumor hearing C3H/N mice whic was classified as beta-crotene with X-irradiation group (n=5) and X-irradiation alone group (n=5). 0.2 ml of 20 mg/kg of beta-carotene were i.p. injected to mice 30 minute before X-irradiation in the beta-crotene with X-irradiation group. The tumor growth delay defined as the time which reach to 1,000 mm$^{3}$ of tumor volume. Results : (1) Cytotoxicity in vitro: 1) survival fraction at beta-carotene concentration of 0.002,0.02,0.2 and 2 mg/ml were 0.69$\pm$0.07, 0.59$\pm$0.08, 0.08$\pm$0.008 and 0.02$\pm$0.006, respectively. 2) each survival fraction at 2, 4, 6 and 8 Gy in the 2 mg/ml of beta-carotene + X-irradiation group were 0.13$\pm$0.05, 0.03$\pm$0.005, 0.01 $\pm$0.002 and 0.009$\pm$0.0008, respectively. But each survival fraction at same irradiation dose in the X-irradiation group were 0.66$\pm$0.05, 0.40$\pm$0.04, 0.11$\pm$0.01 and 0.03$\pm$0.006, respectively(p<0.05). (2) The time which reach to 1,000 mm$^{3}$ of tumor volume of beta-carotene + X-irradiation group and X-irradiation alone group were 18, 19 days, respectively(p>0.05) Conclusion : The contact of beta-caroten to Fsall cells showed mild cytotoxicity which 띤as increased according to concentration. The cytotoxicity of combined beta-carotene with X-irradiation more increased than that of X-irradiation, additionally, And there was significant difference of cytotoxicity between two groups. But there were no significant difference of the growth delay of fibrosarcoma between two groups.

• Journal of Physiology & Pathology in Korean Medicine
• /
• v.18 no.1
• /
• pp.200-205
• /
• 2004

Uterine leiomyoma is the most common tumor in the female genital tract. Although the tumor is benign, it is of paramount importance since it often causes profuse menstrual bleeding, pressure symptoms, and infertility. Nevertheless, the etiology and patholphysiology of this abnormality remain poorly understood. The traditional definitive treatment for uterine leiomyomas is hysterectomy and, even today, symptomatic leiomyomas are the leading cause of hysterectomy in Korea. Clearly, the development of a safe, effective, and nonsurgical method of treatment for leiomyoma would be of great benefit to many women. The present study was designed to investigate the effect of Rhubarb on apoptosis in uterine leiomyoma cells. Results demonstrate that Rhubarb inhibited cell growth in dose-dependent manner. Cell growth significantly decreased to 60% of control in the treatment of Rhubarb (300㎍/㎖). Associated with the decreased response, there was a concomitant and significant delay of subG1 8.32% above baseline in the treatment of Rhubarb (300㎍/㎖). The delay of subG1 showed a dose-dependent manner, as evidenced by the flow cytometry. The reduced cellular viability on exposure to Rhubarb may represent the induction of apoptosis, at least in part, as concomitantly evidenced by enhanced DNA fragmentation, PARP cleavage and caspase 9 and decreased pro-caspase 3. In addition, Rhubarb decreased clAP1 expression levels in dose-dependent manner. Talcen together, there results suggest that Rhubarb can produce a potent inhibition effect of apoptosis and implicate the delay of G1 phase in the cell cycle and pathways of caspase 3 and 9 in the mechanism underlying inhibitory apoptosis effect of Rhubarb.

• Natural Product Sciences
• /
• v.23 no.1
• /
• pp.35-39
• /
• 2017

D-chiro-inositol (DCI) is a secondary messenger in insulin signal transduction. It is produced in vivo from myo-inositol via action of epimerase. In this study, we evaluated antitumor activity of DCI against human breast cancer both in vitro and in vivo. In order to determine the inhibitory effects of DCI on growth of human breast cancer cells (MDA-MB-231), two different assessment methods were implemented: MTT assay and mouse xenograft assay. MTT assay demonstrated downturn in cell proliferation by DCI treatment (1, 5, 10, 20 and 40 mM) groups by 18.3% (p < 0.05), 17.2% (p < 0.05), 17.5% (p < 0.05), 18.4% (p < 0.05), and 24.9% (p < 0.01), respectively. Also, inhibition of tumor growth was investigated in mouse xenograft model. DCI was administered orally at the dose of 500 mg/kg and 1000 mg/kg body weight to treat nude mouse for 45 consecutive days. On the 45th day, tumor growth of DCI (500 mg/kg and 1000 mg/kg) groups was suppressed by 22.1% and 67.6% as mean tumor volumes were $9313.8{\pm}474.1mm^3$ and $3879.1{\pm}1044.1mm^3$, respectively. Furthermore, breast cancer stem cell (CSC) phenotype ($CD44^+/C24^-$) was measured using flow cytometry. On the 46th day, CSC ratios of DCI (500 mg/kg) and co-treatment with doxorubicin (4 mg/kg) and DCI (500 mg/kg) group decreased by 24.7% and 53.9% (p < 0.01), respectively. Finally, from tumor recurrence assay, delay of 5 days in the co-treatment group compared to doxorubicin (4 mg/kg) alone group was observed. Based on these findings, we propose that DCI holds potential as an anti-cancer drug for treatment of breast cancer.

• Radiation Oncology Journal
• /
• v.18 no.2
• /
• pp.120-126
• /
• 2000

Purpose : Tumor hypoxia can be overcome with hypoxic cytotoxin. In mouse tumor, tirapazamine's efficacy of the potentiating radiation effect was tested by the tumor oxygenation status combined with hype facti on ated rad iotherapy .:The control and hypoxic mouse tumors we established by inoculation of RIF-1 tumor cells into the normal or previously irradiated back and thigh of C3H mice. When the tumors reached a proper size, both the control and hypoxic tumors were given hypefractionated treatments (8fractions/4 days) with saline (0.02 ml/g), tirapazamin (0.08 mM/0.02 ml/kg), irradiation (2.5 Gy), irradiation combined with tirapazamine given 30 minutes prior to each irradiation. The response was evaluated by the growth delay assay by measuring tumor size from day 0 (12 hrs prior to the first fractionation) to the day when the volume had 4-fold increase or cross sectional area had 2-fold increase. Results : Overall growth pattern showed that tirapazamine Potentiated radiation effect in back and thigh tumors grew in the normal and preirradiated tumor bed. With growth delay assay using reference point of initial tumor volume or cross sectional area, tirapazamine potentiated radiation effect 1.9 times for the control and 2.4 times for the hypoxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. With reference of 4-fold increase of the initial volume or 2-fold increase of the cross sectional area, tirapazamine potentiated radiation effect 1.48 times for the control and 2.02 times for the hypxic tumors in back, and 1.85 times for the control and 1.6 times for the hypoxic tumors. Conclusions : Present result indicated that radiation response of hypoxic tumors was potentiated by tirapazamine in the back or thigh tumors grew in the control or preirradiated tumor bed, and potentiation of the hypoxic tumors was eDual to or greater than that of the control tumors in the back or thigh.