• Archives of Pharmacal Research
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• v.25 no.5
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• pp.718-723
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• 2002

CKD-602 (7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin) is a recently-developed synthetic camptothecin analogue and currently under clinical development by Chong Kun Dang Pharm (Seoul, Korea). CKD-602 showed potent topoisomerase inhibitory activity in vitro and broad antitumor activity against various human tumor cells in vitro and in vivo in animal models. This study describes the pharmacodynamics of the immediate and delayed cytotoxicity induced by CKD-602 in a human colorectal adenocarcinoma cell line, HT-29, and its intracellular drug accumulation by HPLC. The present study was designed to address whether the higher activity of CKD-602 with prolonged exposure is due to delayed exhibition of cytotoxicity and/or an accumulation of anti proliferative effect on continuous drug exposure. The drug uptake study was performed to determine whether the delayed cytotoxicity is due to a slow drug accumulation in cells. CKD-602 produced a cytotoxicity that was exhibited immediately after treatment (immediate effect) and after treatment had been terminated (delayed effect). Both the immediate and delayed effects of CKD-602 showed a time dependent decrease in 4IC_{50}$ values. Drug uptake was biphasic and the second equilibrium level was obtained as early as at 24hr, indicating that the cumulative and delayed antitumor effects of CKD-602 were not due to slow drug uptake. On the other hand, CKD-602 treatment was sufficient to induce delayed cytotoxicity after 4hr, however, longer treatment (＞24hr) enhanced its cytotoxicity due to the intracellular accumulation of the drug, which requires 24hr to reach maximum equilibrium concentration. In addition, $C^n$$\times$T=h analysis (n=0.481) indicated that increased exposure times may contribute more to the overall antitumor activity of CKD-602 than drug concentration. Additional studies to determine the details of the intracellular uptake kinetics (e.g., concentration dependency and retention studies) are needed in order to identify the optimal treatment schedules for the successful clinical development of CKD-602.

• Proceedings of the Plant Resources Society of Korea Conference
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• 2018.04a
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• pp.14-14
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• 2018

This Camptotheca acuminata Decne. (CA), belonging to Nyssaceae, is a deciduous tree. and has been used as Traditional Chinese medicine since ancient times. The CA produces camptothecin a natural indole alkaloid, and reported to have anti-cancer effects. But the studies on biological activities of CA leaves are insufficient. Therefore, this study confirmed various biological activities such as antioxidant, antidiabetic, anticancer, antiinflammatory and metabolism analysis by HPLC-MS/MS of CA leaves. The $RC_{50}$ values of DPPH radical scavenging activity of ethyl acetate fraction, n-Butanol fraction, methanol extraction, water fraction and n-Hexane fraction were $12.23{\pm}0.01$, $15.93{\pm}0.42$, $55.12{\pm}0.45$, $56.29{\pm}4.15$ and $427.29{\pm}6.13ug/mL$, respectively. The $IC_{50}$ values of ${\alpha}$-glucosidase inhibitory activity of ethyl acetate fraction, n-Butanol fraction, methanol extraction, n-Hexane fraction and water fraction were $24.29{\pm}0.14$, $47.86{\pm}0.45$, $54.23{\pm}1.21$ $466.76{\pm}2.21$ and $623.91{\pm}9.67ug/mL$, respectively. The nitric oxide release activity of n-Hexane fraction, methanol extraction, ethyl acetate fraction, water fraction and n-Butanol fraction were $31.49{\pm}5.74$, $29.79{\pm}0.71$, $26.89{\pm}0.71$, $8.24{\pm}5.83$ and $7.75{\pm}4.08%$ at 25 ug/mL, respectively. The anti-cancer activity of n-Hexane fraction, methanol extraction, ethyl acetate fraction, water fraction and n-Butanol fraction were $31.49{\pm}5.74$, $29.79{\pm}0.71$, $26.89{\pm}0.71$, $8.24{\pm}5.83$ and $7.75{\pm}4.08%$ at 25 ug/mL, respectively. The ethyl acetate fraction activities showed higher biological activities than other fractions. Thus, Additional studies were conducted using ethyl acetate fraction. Metabolite analysis was performed using a LCMS-8040 triple quadrupole mass spectrometer. As a result, Five compounds (1-5) were identified in the ethyl acetate fraction of the CA leave. The identification of these compounds was generated by the analysis of fragmentation methods of the negative and positive ion modes. Five compounds were identified as gallic acid (1), chlorogenic acid (2), isoquercetin (3), astragalin (4) and camptothecin (5). These results suggest that the CA leave can be used for functional materials.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.11
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• pp.4853-4856
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• 2016

Objective: Gimatecan is a new camptothecin (CPT) analogue that inhibits tumor growth by targeting DNA topoisomerase I (TOP I) and introducing strong and persistent DNA cleavage. Anti-tumor activity has been demonstrated with a wide range of solid tumors in previous preclinical and clinical studies. Here, we investigated for the first time the effects of gimatecan on the proliferation of hepatocellular carcinoma (HCC) cells both in vitro and in vivo. Methods: Anticancer efficacy of gimatecan were evaluated in a panel of HCC cell lines and corresponding mouse xenograft models. Inhibition of cell proliferation was measured by CellTiter-Glo cell viability assay. In vivo, gimatecan and control preparations were orally administered every four days, for a total of four times. Tumor volume and body weights of the mice were measured twice weekly. Results: In vitro cytotoxicity evaluation showed that gimatecan inhibited the proliferation of a large panel of HCC cell lines in a dose dependent manner, with IC50 values ranging between 12.1~1085.0 nM. In vivo evaluation in mouse xenograft models showed significant antitumor effects of gimatecan at 0.8mg/kg and 0.4mg/kg as compared to the control group. Conclusion: This study suggested that gimatecan may have the potential to be used as a chemotherapeutic agent for the treatment of HCC.

• Bulletin of the Korean Chemical Society
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• v.29 no.10
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• pp.1988-1992
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• 2008

A series of new derivatives on the ring A of luotonin A were prepared by Friedländer condensation of 6,7,8,10- tetrahydropyrrolo[2,1-b]quinazoline-6,10-dione and suitably substituted 2-aminobenzaldehydes and 2- aminoacetophenones. Their inhibitory activities on topoisomerases and cytotoxicities against selected human cancer cell lines were evaluated. Among the compounds tested, 8-fluoroluotonin A showed similar inhibitory activity on topoisomerase I comparable to camptothecin while luotonin A and 9-hydroxyluotonin A showed 1.37 and 0.94 times stronger inhibitory activity, respectively, on topoisomerase II compared to etoposide. Some derivatives of luotonin A showed moderate cytotoxicity. The possible relationship between the inhibitory activity on Topo II and the cytotoxicity of luotonin A and its analogues, thus, cannot be ruled out.

• YAKHAK HOEJI
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• v.49 no.5
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• pp.428-436
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• 2005

DNA topoisomerase I(TOP1) helps the control of DNA replication, transcription and recombination by assist­ing breaking and rejoining of DNA double strand. Camptothecin (CPT) and its derivative, topotecan, are known to inhibit TOP1 by intercalating into TOP1-DNA complex. Recently various non-CPT intercalators are synthesized for a new class of TOP1 inhibitors. In this study, six compounds isolated from Poria cocos were investigated for their interaction with TOP1­DNA complex using the flexible docking program, FlexiDock. The binding modes were analyzed and compared with the TOP1 inhibition activities. The compounds that showed potent activity were intercalated between the + 1/-1 base pairs of DNA, located near the active site phosphotyrosine723 and formed hydrogen bonds with active site residues. On the other hand, compounds with no activity were not docked at all. The binding modes were well correlated with the inhibition activity, suggesting the possibility that potent inhibitors can be designed from the information presented by the docking study.

• Toxicological Research
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• v.20 no.4
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• pp.375-380
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• 2004

The toxicity of CKD-602 was investigated at doses of 0, 3, 9, and 27 mg/kg in rats, by administering the same total dose over 24-hr continuous infusion or bolus injection. CKD-602 treatment caused gastrointestinal symptoms such as diarrhea, soft stool, and soiled perineal region. It also decreased body weight at doses of 9 and 27 mg/kg in a dose-dependant manner. At 3 mg/ kg, clinical signs and body weight decrease were more severe in the infusion group than in the bolus group. In the bolus group, mortalities were 0/8, 0/8, 1/8, and 3/8 at 0, 3, 9, and 27 mg/kg, respectively, whereas those were 0/8, 1/8, 8/8, and 8/8 in the infusion group. $LD_{50}$ values were 36.25 mg/kg for bolus and 3.50 mg/kg for infusion, respectively. This finding indicates that the toxic potency of CKD-602 by continuous infusion is about 10 times higher than by bolus injection. Our findings suggest that the toxic effects of CKD-602 are dependant upon the duration of intravenous administration.

• Toxicological Research
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• v.20 no.4
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• pp.381-389
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• 2004

The toxicity of CKD-602 was investigated at doses of 3, 9, and 27 mg/kg in rats, when the same total dose of CKD-602 was administered over 24 hr-continuous infusion or bolus injection. At 3 and 9 mg/kg, the 24-hr infusion group showed a more decreased WBC count on day 3, compared with the bolus group. Administration of CKD-602 caused more toxic effects such as the significant decreases of RBC counts, hematocrit, hemoglobin, and platelet count on day 7 post-administarion in the 24-hr infusion group than in the bolus group. Administration of CKD-602 also caused histopathological changes such as extramedullary hemopoiesis of liver and spleen, hyperplasia of femoral bone marrow, and caecal dilation. These toxic effects were more severe in the 24-hr infusion group than in the bolus injection group, indicating that the toxicity of CKD-602 may be dependant upon the duration of administration.

• Molecules and Cells
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• v.39 no.3
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• pp.204-210
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• 2016

DNA damage responses are important for the maintenance of genome stability and the survival of organisms. Such responses are activated in the presence of DNA damage and lead to cell cycle arrest, apoptosis, and DNA repair. In Caenorhabditis elegans, double-strand breaks induced by DNA damaging agents have been detected indirectly by antibodies against DSB recognizing proteins. In this study we used a comet assay to detect DNA strand breaks and to measure the elimination of DNA strand breaks in mitotic germline nuclei of C. elegans. We found that C. elegans brc-1 mutants were more sensitive to ionizing radiation and camptothecin than the N2 wild-type strain and repaired DNA strand breaks less efficiently than N2. This study is the first demonstration of direct measurement of DNA strand breaks in mitotic germline nuclei of C. elegans. This newly developed assay can be applied to detect DNA strand breaks in different C. elegans mutants that are sensitive to DNA damaging agents.

• Archives of Pharmacal Research
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• v.26 no.6
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• pp.466-470
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• 2003

Nine diarylheptanoids (1-9), one triterpene (10), one sesquiterpenoid (11), one naphthoquinone (12), four tetralones (13-16), one naphthalene carboxylic acid glucoside (17) and six naphthalenyl glycosides (18-23) were isolated from the roots of Juglans mandshurica Maximowicz (Juglandaceae), and their structures determined from the chemical and spectral data. Here, we report the inhibitory effects, on the DNA topoisomerases I and II activities, of all these compounds. Compounds 10 and 23 showed more potent inhibitory effects, on the DNA topoisomerases I and II (94.0 and 86.0% inhibitions at the concentration of 5 $\mu$ g/mL, respectively), than the positive control compounds, camptothecin and etoposide.

• Tuberculosis and Respiratory Diseases
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• v.73 no.5
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• pp.288-291
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• 2012

Typhlitis is a necrotizing colitis that usually occurs in neutropenic patients and develops most often in patients with hematologic malignancies such as leukemia and lymphoma. Typhlitis may proceed to bowel perforation, peritonitis and sepsis, which requires immediate treatment. Irinotecan is a semisynthetic analogue of the natural alkaloid camptothecin which prevents DNA from unwinding by inhibition of topoisomerase I. It is mainly used in colon cancer and small cell lung carcinoma (SCLC), of which the most common adverse effects are gastrointestinal toxicities. To the best of our knowledge, no case of typhlitis after chemotherapy with a standard dose of irinotecan in a solid tumor has been reported in the literature. We, herein, report the first case of typhlitis developed after chemotherapy combining irinotecan and cisplatin in a patient with SCLC.