• Title/Summary/Keyword: Anticancer activity

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Effects of Ibandronate on the Expression of Matrix Metalloproteinases in Human U2OS Osteosarcoma Cells (사람 U2OS 골육종 세포에서 Matrix Metalloproteinase의 발현에 Ibandronate가 미치는 영향)

  • Jung, Sung-Taek;Seo, Hyoung-Yeon;Xin, Zeng-Feng;Kim, Yang-Kyung;Kim, Hyung-Won
    • The Journal of the Korean bone and joint tumor society
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    • v.15 no.2
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    • pp.111-121
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    • 2009
  • Background: Osteosarcoma is one of the most common primary malignant tumors of bone occurring mainly in children and adolescents. Although surgery combined with chemotherapy has markedly improved patient survival during the last years, the use of anticancer drugs is still associated with serious problem, such as the frequent acquisition of drug-resistant phenotypes and occurrence of "secondary malignancies". Several solid tumors display enhanced expression of matrix metalloproteinases (MMPs), and recently clinical trials have been initiated on MMP-inhibitors. On the other hand, bisphosphonates (BPs) are inhibitors of bone resorption, and widely used to treat osteoclast-mediated bone diseases. Also they appear to possess direct antitumor activity. Methods: One osteosarcoma cell line (U2OS) was treated with ibandronate (0, 0.1, 1, $10{\mu}M$) for 48 hours. Cell viabilities were determined using MTT assay, the mRNA levels of MMP-2 and MT1-MMP were detected by reverse-transcription polymerase chain reaction, the amount of MMP-2 and MT1-MMP protein were measured by Westernblot, the activities of MMP-2 were observed by Gelatin zymography, and Matrigel invasion assays were used to investigate the invasive potential of osteosarcoma cell lines before and after ibandronate treatment. Results: The invasiveness of U2OS cell line was reduced dose-dependently following 48 hour treatment of up to $10{\mu}M$ of the ibandronate at which concentration no cytotoxicity occurred. Furthermore, the gelatinolytic activities and protein and mRNA levels of MMP-2 and MT1-MMP were also suppressed by increasing ibandronate concentrations. Conclusion: Given that MMP-2 is instrumental in tumor cell invasion, it is very likely that the reduction in osteosarcoma cell invasion by ibandronate is a consequence, at least in part, of suppressed expression of both MMP-2 and MT1-MMP. Isolation of a molecule (s) responsible for the bisphosphonate inhibition of tumor cell invasion would pave the way for the development of a new generation of metastasis inhibitors.

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Phytic Acid Protects the Formation of Colonic Aberrant Crypt Foci Induced by Azoxymethane in Male F344 Rats (랫드에서 azoxymethane으로 유도된 대장 전암병변에 대한 피티산의 방어 효과)

  • Hue, Jin-Joo;Lee, Yea-Eun;Lee, Ki-Nam;Nam, Sang-Yoon;Ahn, Byeong-Woo;Yun, Young-Won;Lee, Beom-Jun
    • Journal of Food Hygiene and Safety
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    • v.23 no.3
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    • pp.264-270
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    • 2008
  • Phytic acid(PA) (Inositol hexaphosphate, $IP_6$) is a naturally occurring polyphosphorylated carbohydrate that is present in substantial amounts in almost all plants and mammalian cells. Recently PA has received much attention for its role in anticancer activity. In the present study, the preventive effects of PA on colon carcinogenesis were investigated. Six-week old Fisher 344 male rats were fed a AIN-93G purified diet and PA(0.5% or 2% PA in water) for 8 weeks. The animals received two ($1^{st}\;and\;2^{nd}$ week) injections of azoxymethane(AOM, 15 mg/kg b.w.) to induce colonic aberrant crypt foci(ACF). After sacrifice, the total numbers of aberrant crypts(AC) and ACF in colonic mucosa were examined after staining with methylene blue. Blood and serum were analyzed with a blood cell differential counter and an automatic serum analyzer. AOM induced the total numbers of $142.3{\pm}22.3$ ACF/colon and $336.6{\pm}55.1$ AC/colon. PA at the doses of 0.5 and 2% decreased the numbers of ACF and AC/colon in a dose-dependent manner. The numbers of ACF/colon and AC/colon by PA at the dose of 0.5% were $124.4{\pm}28.5\;and\;302.7{\pm}67.3$, respectively. PA at the dose of 2% significantly decreased the ACF and AC numbers to $109{\pm}18.1\;and\;254.8{\pm}50.6$, respectively(p<0.01). Especially, 2% PA significantly reduced the number of large ACF(${\geq}4$ AC/ACF) from $26.8{\pm}6.2$ ACF/colon to $15{\pm}6.7$ ACF/colon(p<0.01). Although some parameters in blood counts and serum chemistry were changed compared with the control, no specific toxicity was found. These findings suggest that phytic acid can be a chemopreventive agent for colon carcinogenesis resulting from inhibition of the development of ACF in the F344 rat.

Antihepatotoxic and Antigenotoxic Effects of Herb Tea Composed of Chrysanthemum morifolium Ramat. (국화차를 포함하는 허브차의 CCl4로 유도된 간세포손상 보호 및 항유전독성 효과)

  • Lee, Hyun-Jung;Hwang, Young-Il;Park, Eun-Ju;Choi, Sun-Uk
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.40 no.1
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    • pp.78-83
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    • 2011
  • The flower of Chrysanthemum morifolium Ramat. with antioxidant, anticancer, and anti-inflammatory functions has been a widely used traditional herb as a healthy beverage and medicine. The aim of the present study was to investigate a herb tea consisting of C. morifolium Ramat., Corni fructus and Schizandra chinensis Baillon for its hepatoprotective activity against $CCl_4$-induced toxicity in freshly isolated rat hepatocytes and antigenotoxic effect against oxidative stress induced DNA damage in human leukocytes. Three different compositions of the herb tea (Mix I, II, and III) were prepared by extracting with water at $90^{\circ}C$. Freshly isolated rat hepatocytes were exposed to $CCl_4$ along with/without various concentrations of each tea. Protection of rat primary cells against $CCl_4$-induced damage was determined by the MTT assay. The significant antihepatotoxic effect of the tea was shown in Mix I and II. The increased transaminase (AST and/or ALT) release in media of $CCl_4$ treated hepatocytes was significantly lowered by all the teas tested. The effect of the tea on DNA damage in human leukocytes was evaluated by Comet assay. All teas showed a protective effect against $H_2O_2$-induced DNA damage. From these results, it is assumed that herb tea based on C. morifolium Ramat., Corni fructus and Schizandra chinensis Baillon exerted antihepatotoxic and antigenotoxic effects.

Ototoxic Evaluation of Cis-platinum (Cis-Platinum의 이중독증에 관한 임상적 고찰)

  • 홍원표;정명현;오혜경;이경재
    • Proceedings of the KOR-BRONCHOESO Conference
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    • 1982.05a
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    • pp.17.1-17
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    • 1982
  • In 1965, Rosenberg reported that platinum compounds not only inhibit growth and cell division of E. coli but also has anti-tumor activity. Since then, through animal and clinical experiments by Welsch(1971), Speer(1972), Rossof(1972), Hill(1974), and Wittes(1975), it was proved that Cis-platinum has excellent supressive effects on malignant tumor, especially on head and neck cancer. Accordingly, Cis-platinum is now widely used, sometimes without any other durg, or sometimes with Bleomycin and Methotrexate etc. Inspite of the strong anticancer effect, the use of Cis-platinum is quite often discouraged because of the reports that Cis-platinum causes auditory impairment at high frequencies above the speech range due to inner ear damage and irreversible change in the renal tubules. Since Kohonen et al(1965), Standnicki et al(1974) reported that Cisplatinum has toxic effects at the basal turn of the cochlea using guinea pig, many studies on ototoxicity after infusion of Cis-platinum have been carried out using animals. But the studies on ototoxicity in human beings can hardly be found except in reports by Piel et al(1974) and Hong et al (1979). So the authors did a study which tried to clarify the ototoxic effect by comparing the hearing level after infusion of Cis-plastinum with the hearing level before infusion of Cis-plastinum in 30 patients who was treated with Cis-platinum and admitted to the dept. of otolaryngology of Yonsei University Hospital during 2 years and a half from July. 1979 to March. 1982 and the following results were obtained. 1) The results of auditory evaluation, using the pure tone average, hearing loss of 4kHz and 8kHz, Speech Reception Threshold, PB score, SISI showed that the difference of dosage does not change the hearing level after infusion of Cis-platinum and before infusion of Cis-platinum. 2) Cis-platinum had no effect on the hearing level of patients with conductive hearing loss, or with sensorineural hearing loss, as well as with normal hearing level. 3) The infusion of Cis-platinum did not cause any change in creatinine clearance, creatinine, uric acid, but only one case showed that Cis-platinum caused severe nephrotoxicity. 4) The infusion of Cis-plastinum did not cause any change in hemoglobin, leukocyte count, platelet count and there was no correlation with the amount of infusion. 5) To see the side effect of hydration practiced with the infusion of Cis-platinum, the electrolytes, particularly the K level in the serum was measured. But the results did not show any change. 6) Judging from the results of this study mentioned above, ototoxicity caused by infusion of Cis-platinum can be prevented by sufficient hydration. Also the results might say that the appropriate method of infusion of Cis-platinum might be effective in the patients with head and neck cancer who had sensorineural hearing loss for whom the infusion of Cis-platinum has been absolutely cotraindicated.

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Effects of Onion Flesh and Peel on Chemical Components, Antioxidant and Anticancer Activities (양파 육질 및 껍질의 화학성분과 항산화 및 항암 활성 비교)

  • Jang, Joo-Ri;Lim, Sun-Young
    • Journal of Life Science
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    • v.19 no.11
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    • pp.1598-1604
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    • 2009
  • In order to determine chemical components of onion flesh and peel, general nutrients, vitamin C, and total flavonoids were measured. Onion peel showed less moisture (14.3%) and no vitamin C compared to onion flesh. Onion peel contained more amounts of total flavonoids compared to onion flesh. In addition, the inhibitory effects of solvent extracts from onion flesh and peel on $H_2O_$-induced oxidative stress and growth of cancer cell lines (AGS human gastric adenocarcinoma and HT-29 human colon cancer cells) were investigated. Acetone with methylene chloride (A+M) and methanol (MeOH) extracts from onion flesh and peel appeared to significantly reduce the levels of intracellular reactive oxygen species (ROS) (p<0.05) and a greater antioxidant effect was observed in onion peel. Among fractions, 85% aq. methanol showed a higher protective activity against oxidative stress in both flesh and peel and there was no effect in the water and hexane fractions. The growth of cancer cells exposed to medium containing extracts and fractions from onion flesh and peel was inhibited dose-dependently. The growth of AGS was inhibited more in both flesh and peel compared to HT-29, and onion peel was more effective than onion flesh. Among fractions, 85% aq. methanol showed the greatest effect on growth inhibition in both flesh and peel. $IC_{50}$ values of 85% aq. methanol fraction from onion flesh and peel on AGS were 0.04 and 0.03 mg/ml, respectively, while those on HT-29 were 0.23 and 0.04 mg/ml. From our results, 85% aq. methanol fraction had an inhibitory effect against oxidative stress and growth of cancer cells, suggesting that it may contain biological active compounds.

Induction of Apoptosis by Piceatannol in YD-15 Human Oral Cancer Cells (피세아타놀에 의한 YD-15 구강암세포의 세포자가사멸 유도 효과)

  • Lee, Hae-Nim;Jang, Hye-Yeon;Kim, Hyeong-Jin;Shin, Seong-Ah;Choo, Gang-Sik;Park, Byung-Kwon;Kim, Byeong-Soo;Jung, Ji-Youn
    • Journal of the Korean Society of Food Science and Nutrition
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    • v.44 no.7
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    • pp.975-982
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    • 2015
  • Piceatannol (trans-3,4,3',5'-trihydroxystilbene), a natural stilbene, is an analogue of resveratrol. In the present study, possible mechanisms by which piceatannol exerts its pro-apoptotic action in cultured human oral cancer YD-15 cells were investigated. To investigate whether or not piceatannol has effects on cancer cell viability, human oral YD-15 cells were treated with piceatannol (0, 50, and $100{\mu}M$). Piceatannol treatment ($100{\mu}M$) showed the strongest inhibition of cell proliferation and reduced cell viability in a dose-dependent manner. Chromatin condensation detected by DAPI staining significantly increased in a concentration-dependent manner, indicating apoptosis. Piceatannol treatment activated initiator Bax (pro-apoptotic) and cPARP in a concentration-dependent manner. Further, piceatannol induced down-regulation of Bcl-2 (anti-apoptotic). We also evaluated the activity of piceatannol against oral cavity cancer tumors in mice. Piceatannol-treated nude mice bearing YD-15 xenograft tumors exhibited significantly reduced tumor volume and weight due to the potent effect of piceatannol on tumor cell apoptosis, as determined by terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling assay. Immunohistochemistry staining showed elevated expression of cleaved-caspase-3 as well as reduced expression of Ki-67 in the piceatannol-treated group. Therefore, piceatannol can be developed as a cancer preventive medicine due to its growth inhibitory effects and induction of apoptosis in human oral cancer cells.

APOPTOTIC EFFECT IN COMBINATION OF CYCLOSPORIN A AND TAXOL ON ORAL SQUAMOUS CELL CARCINOMA CELL LINE THROUGH THE PI-3 KINASE/AKT1 PATHWAY (구강 편평세포암종 세포주에서 Cyclosporin A와 Taxol 투여시 PI-3 kinase/Akt1 Pathway에 의한 세포사멸 병용효과)

  • Kim, Kyu-Young;Lee, Jae-Hoon
    • Journal of the Korean Association of Oral and Maxillofacial Surgeons
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    • v.33 no.5
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    • pp.426-436
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    • 2007
  • Oral cancer take up 2-6% of all carcinomas and squamous cell carcinoma, which is the most common type in oral cancer, has a poor prognosis due to its high metastasis and recurrence rates. In treating oral cancer, chemotherapy to the primary, metastasized and recurrent lesion is a very important and useful treatment, even though its widespread usage is limited due to high general toxicity and local toxicity to other organs. Taxol, a microtubule stabilizing agent, is an anticancer drug that induces cell apoptosis by inhibiting depolymerization of microtubules in between the metaphase and anaphase of the cell mitosis. Recently, its effectiveness and mechanism on various tumor has been reported. However, not much research has been done on the application of Taxol to oral squamous cell carcinoma. Cyclosporin A, which is an immunosuppressant, is being used on cancers and when co-administered with Taxol, effectiveness of Taxol is enhanced by inhibition of Taxol induced multidrug resistance. In this study, Cyclosporin A with different concentration of Taxol was co-administered to HN22, the oral squamous cell carcinomacell line. To observe the cell apoptosis and the mechanisms that take part in this process, mortality evaluation of tumor cell using wortmannin, c-DNA microarray, RT-PCR analysis, cytometry analysis and western blotting were used, and based upon the observation on the effect and mechanism of the agent, the following results were obtained: 1. The HN22 cell line viability was lowest when $100{\mu}M$ of Wortmannin and $5{\mu}g/ml$ of Taxol were co-administered, showing that Taxol participates in P13K-AKT1 pathway. 2. In c-DNA microarray, where $1{\mu}g/ml$ of cyclosporine A and 3mg/ml of Taxol were co-administered, no up regulation of AKT1, PTEN and BAD c-DNA that participate in cell apoptosis was observed. 3. When $1{\mu}g/ml$ of Cyclosporin A was applied alone to HN22 cell line, no difference was found in AKT1, PTEN and BAD mRNA expression. 4. Increased AKT1, mRNA expression was observed when $3{\mu}g/ml$ of Taxol was applied alone to HN22 cell line. 5. When $1{\mu}g/ml$ of Cyclosporin A and Taxol($3{\mu}g/ml\;and\;5{\mu}g/ml$) were co-administered to HN22 cell line, PTEN mRNA expression increased, whereas AKT1 and BAD mRNA decreased. 6. As a result of cytometry analysis, in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration, increased Annxin V was observed, which shows that apoptosis occurred by deformation of plasma membrane. However, no significant difference was observed with vary ing concentration. 7. In western blot analysis, no caspase 3 was observed in the group of Cyclosporin A($1{\mu}g/ml$) and Taxol($3{\mu}g/ml$) co-administration. From the results of this study, it can be concluded that synergistic effect can be observed in combination therapy of Taxol and Cyclosporin A on oral squamous cell carcinoma cell line, where decreased activity of the cell line was observed. This resulted in decreased AKT1 and BAD mRNA and increased PTEN mRNA expression and when wortmannin and Taxol were co-administered, the viability decreased which confirms that Taxol decreases the viability of tumor cell line. Hence, when Taxol and cyclosporine A are co-administered, it can be assumed that cell apoptosis occurs through AKt1 pathway.

Effects of BCG on the DNA Synthesis and Ultrastructure of Mouse Gastric Mucosal Epithelial Cells Inoculated with Ehrlich Carcinoma Cells (BCG가 Ehrlich 암세포를 이식한 생쥐의 위점막 상피세포의 DNA합성 및 미세구조에 미치는 영향)

  • Ko, Jeong-Sik;Ryoo, In-Sang;Park, Kyung-Ho;Park, Dae-Kyoon
    • Applied Microscopy
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    • v.39 no.3
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    • pp.205-218
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    • 2009
  • This experiment was performed to evaluate the morphological responses of the gastric epithelial cells of the mouse, inoculated with Ehrlich carcinoma cells in the inguinal area, following administration of BCG. Healthy adult ICR mice weighing 25 gm each were divided into normal and experimental groups (tumor control group and BCG-treated group). In the experimental groups, each mouse was inoculated with $1{\times}10^7$ Ehrlich carcinoma cells subcutaneously in the inguinal area. From next day after inoculations, 0.2 mL of saline or BCG (0.5 mL/25 g B.W.: $0.03{\times}10^8{\sim}0.32{\times}10^8$ CFU) were injected subcutaneously to the animals every other day, respectively. The day following the 7th injection of saline or BCG, each mouse was injected with a single dose of 0.7 ${\mu}Ci/g$ of methyl-$^3H$-thymidine (25 Ci/mmol, Amersham Lab., England) through tail vein. Seventy minutes after the thymidine injection, animals were sacrificed, and gastric tissues were taken and fixed in 10% neutral formalin. Deparaffinized sections were coated with autoradiographic emulsion EM-1 (Amersham Lab., England) in a dark room. The number of labeled epithelial cells in the gastric mucosae (mean number of labeled epithelial cells per 3.5 mm length of mucosa) were observed and calculated. And for electron microscopic observation, gastric tissues were prefixed with 2.5% glutaraldehyde-1.5% paraformaldehyde solution, followed by post-fixation with 1% osmium tetroxide solution. On the light microscopic study, gastric mucosae had no morphological changes following the injection of BCG. On the electron microscopic study, in the BCG-treated mice, myelin figures and multivesicular bodies within the gastric epithelial cells were observed more frequently than in those of the normal control ones. On the autoradiographic study, number of the labeled cells of normal control, tumor control and BCG-treated mice were 380.2 (${\pm}31.35$), 426.1 (${\pm}28.43$) and 301.8 (${\pm}34.63$), respectively. In the BCG-treated mice, poorly-labeled cells containing only a few silver grains of 3H-thymidine were observed more frequently as compared in those of the normal control and tumor control ones. From the above results, BCG may suppress the DNA synthesis of the gastric epithelial cells, but does not results severe fine structural defect on the gastric epithelial cells. These results suggest that BCG is expected as one of the effective supplemental anticancer drugs.

Effect of Korean Mistletoe Extract M11C (Non-lectin Components) on the $TNF-\alpha$ Expression and Secretion from Human Peripheral Blood Monocytes (한국산 겨우살이 추출물 M11C (렉틴 구성물질)가 단구세포의 $TNF-\alpha$ 유전자 발현유도 및 분비에 미치는 효과)

  • Jun, Myung-Ha;Kang, Tae-Bong;Chang, Sung-Ho;Choi, Wahn-Soo;Seong, Nak-Sul;Her, Erk
    • Korean Journal of Medicinal Crop Science
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    • v.15 no.1
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    • pp.30-37
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    • 2007
  • It is well-known that Korean mistletoe (Viscum album) extract has an immune activity and anticancer effect. In this study, Korean mistletoe extract, M11C (non-lectin components), was used to examine whether this extract might activate human peripheral monocyte to produce tumor necrosis $factor-\alpha$ $(TNF-\alpha)$. To examine the effect of M11C on the production of $TNF-\alpha$ from monocyte, the monocyte were stimulated by the M11C, and then collected the supernatant (M11C stimulated monocyte-conditioned media; MCM). MCM was treated to the $TNF-\alpha$ sensitive L929 cells, and then L929 cytotoxicity was measured by means of MTT. MCM had cytotoxic effect on L929. And the cytotoxic effect of MCM on L929 was almost abolished by $anti-TNF-\alpha$ antibody. These data indicated that MCM contained $TNF-\alpha$, suggesting the $TNF-\alpha$ generation from M11C-stimulated monocyte. This suggestion was confirmed from the data that $TNF-\alpha$ was highly detected in MCM by immunoblotting technique. M11C effect on $TNF-\alpha$ production from monocyte was in the dose and stimulating time dependent manners. Also the effect of M11C on the expression of $TNF-\alpha$ mRNA from monocyte was shown in the dose and stimulating time dependent manners. As a result, Korean mistletoe extract, M11C, could be used for an immunostimulator.

Gene Expression of Enzymes Related to Glutathione Metabolism in Anticancer Drug-resistant L1210 Sublines (항암제 내성 L1210세포의 Glutathione 대사 관련효소 유전자의 발현 양상)

  • Kim, Seong-Yong;Kim, Jae-Ryong;Kim, Jung-Hye
    • Journal of Yeungnam Medical Science
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    • v.12 no.1
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    • pp.32-47
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    • 1995
  • Glutathione(GSH) has a very important role in detoxification of cells and is closely related to antitumor drug-resistance of cancer cells. In order to evaluate the importance of glutathione metabolism in the drug-resistant cancer cells, the concentration of celluar GSH and activities of ${\gamma}$-glutamylcysteine synthetase(GCS), ${\gamma}$-glutamyl transpeptidase (GGT) and glutathione S-transferases(GST) in the adriamycin, vincristine, or cisplatin resistant L1210 (L1210AdR, L1210VcR, or L1210Cis) sublines were measured. Expression and amplification of GCS, GGT, and GST-${\pi}$ genes were also observed in the parent Ll210 and the drug-resistant Ll210 sublines. The concentration of GSH was increased 5.34 fold in L1210Cis, 2.83 fold in L1210VcR, and 1.78 fold in L1210AdR, compared to L1210. The activities of GCS and GGT were increased in drug-resistant L1210 sublines. The GST activity was increased in L1210VcR and L1210Cis but decreased in L1210AdR compared to Ll210. Expression of GCS, GGT, and GST-${\pi}$ genes were increased in the resistant L1210 sublines compare to the parent L1210 in northern blot analyses. Overexpression of GCS, GGT, and GST-${\pi}$ were observed in the resistant sublines, and the increases of the concentration of glutathione and the activities of GCS and GGT in the resistant sublines may be involved in a part of the drug-resistance in the resistant sublines.

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