• Journal of Physiology & Pathology in Korean Medicine
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• v.16 no.1
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• pp.146-149
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• 2002

To evaluate the protective effect of Ziziphi Jujubae Semen(ZJS) on 5-Fluorouracil(5-Fu) in cultured vestibular neurons(VN), neurotoxicity was assessed by XTT assay after VN was exposed to 3-24ug/ml 5-Fu for 48 hours. and also, the neuroprotective effect of ZJS was measured by XTT assay in these cultrures. Cell viability was remarkably decreased dose-dependently, after the treatment with 12ug/ml 5-Fu to cultured VN for 48 hours. In the neuroprotective effect of ZJS on the toxicity induced by 5-Fu, ZJS prevented the neurotoxicity induced by 5-Fu in these cultures. From above the results, it suggests that 5-Fu is toxic in cultured VN and herb extract, ZJS has protective effect over the neurotoxicity induced by 5-Fu.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.9
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• pp.4807-4814
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• 2012

Purpose: The chemoresistance of human hepatocellular carcinoma (HCC) to cytotoxic drugs, especially intrinsic or acquired multidrug resistance (MDR), still remains a major challenge in the management of HCC. In the present study, possible mechanisms involved in MDR of HCC were identified using a 5-fluorouracil (5-FU)-resistant human HCC cell line. Methods: BEL-7402/5-FU cells were established through continuous culturing parental BEL-7402 cells, imitating the pattern of chemotherapy clinically. Growth curves and chemosensitivity to cytotoxic drugs were determined by MTT assay. Doubling times, colony formation and adherence rates were calculated after cell counting. Morphological alteration, karyotype morphology, and untrastructure were assessed under optical and electron microscopes. The distribution in the cell cycle and drug efflux pump activity were measured by flow cytometry. Furthermore, expression of potential genes involved in MDR of BEL-7402/5-FU cells were detected by immunocytochemistry. Results: Compared to its parental cells, BEL-7402/5-FU cells had a prolonged doubling time, a lower mitotic index, colony efficiency and adhesive ability, and a decreased drug efflux pump activity. The resistant cells tended to grow in clusters and apparent changes of ultrastructures occurred. BEL-7402/5-FU cells presented with an increased proportion in S and G2/M phases with a concomitant decrease in G0/G1 phase. The MDR phenotype of BEL-7402/5-FU might be partly attributed to increased drug efflux pump activity via multidrug resistance protein 1 (MRP1), overexpression of thymidylate synthase (TS), resistance to apoptosis by augmentation of the Bcl-xl/Bax ratio, and intracellular adhesion medicated by E-cadherin (E-cad). P-glycoprotein (P-gp) might play a limited role in the MDR of BEL-7402/5-FU. Conclusion: Increased activity or expression of MRP1, Bcl-xl, TS, and E-cad appear to be involved in the MDR mechanism of BEL-7402/5-FU.

• Korean Journal of Head & Neck Oncology
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• v.31 no.2
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• pp.21-28
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• 2015

서론: 국소 진행성 두경부암 환자에서 선행 항암요법 후 동시 항암화학방사선요법은 원격 전이를 줄이고, 국소병변을 줄여 방사선 치료의 효과를 높이거나, 기관의 기능을 보존할 목적으로 시도된다. 선행 항암요법의 약제로 는 docetaxel, cisplatin, fluorouracil (DPF) 삼제요법이 가장 효과적인 것으로 알려져 있다. 선행 항암요법 후 동시 항암화학방사선요법과 표준치료인 동시화학방사선요법을 비교한 3상 연구들이 모두 선행 항암요법이 더 낫다는 결과를 보여 주지 못하였지만, 이 연구들은 충분한 환자를 모집하지 못하고 조기 종료된 불완전한 연구라는 한계가 있었다. 이에 저자들은 DPF 선행 항암요법 후 동시 화학방사선요법과 표준치료인 동시 화학방사선요법을 비교하는 메타분석을 시행하였다. 대상 및 방법: 체계적 문헌고찰을 통해 국소진행성 두경부암 환자를 대상으로 시행된 DPF 선행 항암요법 후 동시화학방사선요법과 현재 표준치료인 동시화학방사선요법을 비교한 5개의 3상 연구 결과를 분석하였다. 대상환자는 862 명이었고, 분석 결과 DPF 선행 항암요법 후 동시화학방사선요법은 표준치료와 비교하였을 때 반응률, 2년 및 3년 생존율, 2년 및 3년 무진행 생존율, 점막염 및 빈혈 발생 빈도에서 통계적으로 유의한 차이가 없었다. 하지만, 완전관해율과 3~4도의 백혈구감소증 및 혈소판 감소증의 빈도는 선행 항암요법 시행군에서 더 높았다. 결론: 국소진행성 두경부암의 치료에서 DPF 선행 항암요법 후 동시 항암화학방사선요법을 시행하는 것은 표준치료인 항암화학방사선요법에 비해 생존율 개선을 보이지 못하였다. 선행항암치료를 추가하는 것이 특정 환자군에서 효과가 있을지에 대해서는 추가적인 연구가 필요하다.

• The Journal of Korean Medicine
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• v.33 no.2
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• pp.47-55
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• 2012

Objectives: This study aimed to investigate the preventive effect of red ginseng (RG) on 5-fluorouracil (5-FU)-induced side effects focusing on myelosuppression. Methods: Rats (n = 50) were divided into five groups, nave, control (ip, 5-FU injection of 150 mg/kg), and RG pre-treatment (po, 25, 50 and 100 mg/kg for 5 days before 5-FU injection). On the $7^{th}$ day after 5-FU injection, we evaluated the effects using peripheral hematological parameters, colony-forming assay, cytokine levels and histopathological finding. Results: The peripheral white blood cell and the differential count were dramatically suppressed by 5-FU, while RG (50 and 100 mg/kg) treatment significantly improved total white blood cell, neutrophil, lymphocyte and platelet counts. Also, RG (100 mg/kg) pre-treatment significantly increased the number of CFU-GM colony compared with the control group. RG pre-treatment also ameliorated the histopathological damage in bone marrow, spleen, stomach and small intestine tissue. Conclusions: These results demonstrate that Korean RG has preventive effects against 5-FU-induced myelotoxicity and gastrointestinal damage.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.16
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• pp.6727-6732
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• 2014

Objectives: Advanced gastric cancer (AGC) patients have a poor prognosis. The best benefit of chemotherapy is usually achieved by first line setting. Very few studies have compared combination regimens. This study was designed to compare two combination regimens. Methods: Patients with advanced gastric cancer receiving first line chemotherapy were retrospectively collected, and divided into two groups, receiving DCF (docetaxel, cisplatin and fluorouracil) or ECF (epirubicin, cisplatin and fluorouracil) regimens. Data were collected for the retrospective analysis in a single center. Results: Eighty-six patients were eligible for analysis. Median overall survival (OS) was 10.0 months in the ECF group and 11.0 months in the DCF group (p=0.31). Median progression free survival (PFS) for ECF and DCF was equal at 6.0 months. Second line chemotherapy were administered in more than one third of patients. Both regimens had similar toxicity. Conclusions: This is the first study investigating the outcomes of gastric cancer chemotherapy in this region. ECF and DCF regimens have similar efficacy and a similar tolerability profile for first line treatment of advanced gastric cancer. The decision of the first line chemotherapy in advanced gastric cancer could be improved with patient selection according to clinical parameters and molecular markers.

• Journal of Gastric Cancer
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• v.16 no.3
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• pp.177-181
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• 2016

Purpose: The International Organization for Standardization-5fluorouracil (FU) 10 trial found that bolus 5-FU and l-leucovorin was not inferior to S-1 in the treatment of gastric cancer (GC). Continuous 5-FU and the rapid injection of 5-FU have different anti-cancer effects. Thus, bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. Materials and Methods: We retrospectively analyzed the medical records of all patients with S-1 or capecitabine-resistant, unresectable, or recurrent GC treated with bolus 5-FU and l-leucovorin between January 2010 and December 2015 at Hokkaido University Hospital. The bolus 5-FU and l-leucovorin regimen consisted of intravenous l-leucovorin ($250mg/m^2/2h$) and bolus 5-FU ($600mg/m^2$) administered once weekly followed by a 2-week rest period; each cycle was repeated every 8 weeks. Results: A total of 14 patients were identified. The disease control rate was 35.7%. The median progression-free survival was 1.6 months (95% confidence interval [CI], 1.3~2.0 months), and the median overall survival was 6.3 months (95% CI, 4.7~7.9 months). No patient died from treatment-related causes. The most common severe adverse event associated with bolus 5-FU and l-leucovorin was neutropenia, which occurred in 21.4% of patients. Conclusions: Bolus 5-FU and l-leucovorin treatment might be useful for oral FU-resistant GC. We are planning a multi-center prospective phase II trial to evaluate the efficacy and safety of bolus 5-FU and l-leucovorin treatment for pre-treated unresectable or recurrent GC to confirm the results of this limited, retrospective study.

• Molecules and Cells
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• v.37 no.7
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• pp.540-546
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• 2014

Several types of genetic and epigenetic regulation have been implicated in the development of drug resistance, one significant challenge for cancer therapy. Although changes in the expression of non-coding RNA are also responsible for drug resistance, the specific identities and roles of them remain to be elucidated. Long non-coding RNAs (lncRNAs) are a type of ncRNA (> 200 nt) that influence the regulation of gene expression in various ways. In this study, we aimed to identify differentially expressed lncRNAs in 5-fluorouracil-resistant colon cancer cells. Using two pairs of 5-FU-resistant cells derived from the human colon cancer cell lines SNU-C4 and SNU-C5, we analyzed the expression of 90 lncRNAs by qPCR-based profiling and found that 19 and 23 lncRNAs were differentially expressed in SNU-C4R and SNU-C5R cells, respectively. We confirmed that snaR and BACE1AS were down-regulated in resistant cells. To further investigate the effects of snaR on cell growth, cell viability and cell cycle were analyzed after transfection of siRNAs targeting snaR. Down-regulation of snaR decreased cell death after 5-FU treatment, which indicates that snaR loss decreases in vitro sensitivity to 5-FU. Our results provide an important insight into the involvement of lncRNAs in 5-FU resistance in colon cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• v.15 no.18
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• pp.7611-7615
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• 2014

Aims: To prepare 5-fluorouracil (5-Fu) nanoparticles with higher encapsulation efficiency and drug loading, and then investigate interaction with the SGC-7901 gastric cancer cell line. Materials and Methods: Prescription was optimized by orthogonal experiments, the encapsulation efficiency and loading capacity were tested by high-performance liquid chromatography, and inhibition of proliferation by 5-Fu nanoparticles and 5-Fu given to cells for 24, 48 and 72 hours was investigated by methyl thiazolyl tetrazolium assay (MTT). In addition, 5-Fu nanoparticles were labeled by fluorescein isothiocyanate (FITC), and absorption into cells was tested by flow cytometry. Results: The optimal conditions for preparation were concentrations of 5-Fu of 5mg/ml, of $CaCl_2$ of 60 mg/ml and of chitosan of 2 mg/ml. With a stirring speed of 1200rpm, encapsulation efficiency of 5-Fu nanoparticles was $55.4{\pm}1.10%$ and loading capacity was $4.22{\pm}0.14%$; gastric cancer cells were significantly inhibited by 5-Fu nanoparticles in a time and concentration dependent manner, and compared to 5-Fu with slower drug release, in a certain concentration range, inhibition with 5-Fu nanoparticles was stronger. 5-Fu nanoparticles were absorbed by the cells in line with the concentration. Conclusions: 5-Fu nanoparticles can inhibit growth of gastric cancer cells in vitro to a greater extent than with 5-Fu with good adsorption characteristics, supporting feasibility as a carrier.

• Applied Microscopy
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• v.27 no.2
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• pp.165-175
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• 1997

This paper aims to prove the effects of Squalene (SQ) on the cellular toxicity of 5-FU to the mouse which pretreated with SQ and then treated with 5-FU. The results of the group A (treated with only 5-FU) are as follows. The nucleus was destroyed at 24 hours and 48 hours group, however, somewhat repaired at 72 hours group. The dilated inner cavity and the irregular lamellae of the rough surfaced endoplasmic reticulum (RER) were observed continually until 72 hours group. The inner cavity of the smooth surfaced endoplasmic reticulum (SER) were dilated in all groups. However, the destroyed and the normal membrane were observed simultaneously at 72 hours group. The inner membrane of the mitochondria were almost repaired at 96 hours group. The results of the group B (treated with 5-FU and squalene) are as follows. The nucleus was a little influenced by the toxicity of 5-FU at 24 hours and 48 hours, RER were observed to keep the typical lamella structure of cisternae from 24 to 72 hours group, but inner cavity kept on dilating. In SER, inner cavity were also observed to flatten from 24 to 72 hours group. Mitochnodria were always shown normal. All cell organelles were simillar to those of normal groups at 96 hours. Accordingly, it can be said that the treatment of 50 prevents the cytotoxicity of 5-FU on cell organelles of liver cell and that is concerned with the formation of membrane system of cell organelles.

• YAKHAK HOEJI
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• v.49 no.6
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• pp.511-517
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• 2005

Low sensitivity to anticancer drugs such as 5-fluorouracil (5-FU) has been associated with decreased expression of genes involved in cell proliferation, apoptosis and metastasis. Recently, it has been shown that the expression levels of some of these genes are reduced by transcription inhibition due to epigenetic silencing on CpG islands. Therefore, epigenetic therapy has been proposed, where epigenetic silencing is repressed with DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors alone or in combination with other chemotherapeutic agents. The aim of our study was to evaluate the combination effect of 5-FU and its association with the status of epigenetic silencing using methylation-specific PCR of $p14^{ARF}$ when given with S-aza-2'-deoxycytidine (5-aza-dC), a DNMT inhibitor and depsipeptide, an HDAC inhibitor in DLD-1 human colorectal cancer cells. The combination of 5-aza-dC with depsipeptide showed a synergism and induced unmethylation of $p14^{ARF}$. However, triplet combination of 5-aza-dc/depsipeptide and 5-FU resulted in antagonistic effects and abrogated unmethylation of $p14^{ARF}$. These results suggest that unfavorable interaction of 5-aza-dC/depsipeptide with 5-FU in DLD-1 cells may be related with the failure in repression of epigenetic silencing, which warrants further investigation.