• Journal of Pharmaceutical Investigation
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• 제26권4호
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• pp.281-289
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• 1996

In our previous work, we have studied the effect of lactose and sodium alginate (SA) on the rate of release of 5-fluorouracil (5-FU) from ethylene-vinyl acetate (EVA) matrix. These hydrophilic additives promoted the rate of 5-FU release and the increase in rate was larger when SA was used. Both additives showed better ability to increase the rate than 5-FU itself. In this paper, we extended our study to another hydrophilic additive, Carbopol 940 (CP). Compared to SA or lactose, CP increased the rate of 5-FU release markedly. Release rate increased as the loading amount and the pH of the release medium increased. After release experiment, matrix volume increased up to 15 times of that before release experiment, depending on the amount of CP dispersed in the matrix and the pH of the release medium. On the other hand, the volume of the matrix containing lactose or SA decreased. The weight changes of the dry matrix before and after release experiment imply that CP is not released out of the matrix, to the contrary of lactose and SA. Scanning electron microscope study clearly showed that large cavities and pores are generated on the surface and the inside of the matrix. These results indicate that the mechanism by which CP increases the release rate is quite different from that of monomeric additives such as lactose or SA.

• Biomolecules & Therapeutics
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• 제25권3호
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• pp.315-320
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• 2017

We investigated the role of autophagy in SNUC5/5-FUR, 5-fluorouracil (5-FU) resistant SNUC5 colon cancer cells. SNUC5/5-FUR cells exhibited low level of autophagy, as determined by light microscopy, confocal microscopy, and flow cytometry following acridine orange staining, and the decreased level of GFP-LC3 puncta. In addition, expression of critical autophagic proteins such as Atg5, Beclin-1 and LC3-II and autophagic flux was diminished in SNUC5/5-FUR cells. Whereas production of reactive oxygen species (ROS) was significantly elevated in SNUC5/5-FUR cells, treatment with the ROS inhibitor N-acetyl cysteine further reduced the level of autophagy. Taken together, these results indicate that decreased autophagy is linked to 5-FU resistance in SNUC5 colon cancer cells.

• Asian Pacific Journal of Cancer Prevention
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• 제15권16호
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• pp.6737-6743
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• 2014

It is reported that sinomenine (SIN) and 5-fluorouracil (5-FU) both are effective for colon cancer, but their cooperative suppressive effects and toxicity remain to be clarified in detail. This study aimed to determine suppressive effects and toxicity of sinomenine (SIN) plus 5-fluorouracil (5-FU) on LoVo colon carcinoma cells in vitro and in vivo. CCK-8, Hoechst 33258 staining and an annexin V-FITC/PI apoptosis kit were used to detect suppressive effects. Western blotting was applied to investigate the essential mechanism underlying SIN and 5-FU-induced apoptosis. SIN or 5-FU or both were injected into nude mice, and then suppressive effects and side effects were observed. SIN plus 5-FU apparently inhibited the proliferation of LoVo cells and induced apoptosis. Moreover the united effects were stronger than individually (p<0.05). The results of annexin V-FITC/PI staining and Hoechst 33258 staining showed that the percentage of apoptotic cells induced by SIN and 5-FU combined or alone was significantly higher than the control group (p<0.05). Expression of Bax and Bcl-2 was up-regulated and down-regulated respectively. SIN or 5-FU significantly inhibited effects on the volume of tumour xenografts and their combined suppressive effects were stronger (p<0.05). No obvious side effects were observed. It was apparent that the united effects of SIN and 5-FU on the growth of colorectal carcinoma LoVo cells in vitro and in vivo were superior to those using them individually, and it did not markedly increase the side effects of chemotherapy.

• Asian Pacific Journal of Cancer Prevention
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• 제16권4호
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• pp.1545-1551
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• 2015

Purpose: Rectal cancers with high microsatellite-instable have clinical and pathological features that differentiate them from microsatellite-stable or low-frequency carcinomas, which was studied rarely in stage II rectal cancer, promoting the present investigation of the usefulness of microsatellite-instability status as a predictor of the benefit of adjuvant chemotherapy with fluorouracil in stage II rectal cancer. Patients and Methods: Data of 460 patients who underwent primary anterior resection with a double stapling technique for rectal carcinoma at a single institution from 2008 to 2012 were retrospectively collected. All patients experienced a total mesorectal excision (TME) operation. Survival analysis were analyzed using the Cox regression method. Results: Five-year rate of disease-free survival (DFS) was noted in 390 (84.8%) of 460 patients with stage II rectal cancer. Of 460 tissue specimens, 97 (21.1%) exhibited high-frequency microsatellite instability. Median age of the patients was 65 (50-71) and 185 (40.2%) were male. After univariate and multivariate analysis, microsatellite instability (p= 0.001), female sex (p<0.05) and fluorouracil-based adjuvant chemotherapy (p<0.001), the 3 factors were attributed to a favorable survival status independently. Among 201 patients who did not receive adjuvant chemotherapy, those cancers displaying high-frequency microsatellite instability had a better 5-year rate of DFS than tumors exhibiting microsatellite stability or low-frequency instability (HR, 13.61 [95% CI, 1.88 to 99.28]; p= 0.010), while in 259 patients who received adjuvant chemotherapy, there was no DFS difference between the two groups (p= 0.145). Furthermore, patients exhibiting microsatellite stability or low-frequency instability who received adjuvant chemotherapy had a better 5-year rate of DFS than patients did not (HR, 5.16 [95% CI, 2.90 to 9.18]; p<0.001), while patients exhibiting high-frequency microsatellite instability were not connected with increased DFS (p= 0.696). It was implied that female patients had better survival than male. Conclusion: Survival status after anterior resection of rectal carcinoma is related to the microsatellite instability status, adjuvant chemotherapy and gender. Fluorouracil-based adjuvant chemotherapy benefits patients of stage II rectal cancer with microsatellite-stable or low microsatellite-instable, but not those with high microsatellite-instable. Additionally, free of adjuvant chemotherapy, carcinomas with high microsatellite-instable have a better 5-year rate of DFS than those with microsatellite-stable or low microsatellite-instable, and female patients have a better survival as well.

• Asian Pacific Journal of Cancer Prevention
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• 제16권3호
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• pp.985-989
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• 2015

Background: Docetaxel, cisplatin, 5-fluorouracil (DCF) given every three weeks is an effective, but palliative regimen and significantly toxic especially in patients who have a low performance score. Here, we aimed to evaluate the efficacy and tolerability of a weekly formulation of DCF in locally advanced and metastatic gastric cancer patients. Materials and Methods: 64 gastric cancer patients (13 locally advanced and 51 metastatic) whose ECOG (Eastern Cooperative Oncology Group) performance status (PS) was 1-2 and who were treated with at least two cycles of weekly DCF protocol as first-line treatment were included retrospectively. The weekly DCF protocol included $25mg/m^2$ docetaxel, $25mg/m^2$ cisplatin, and 24 hours infusion of $750mg/m^2$ 5-fluorouracil, repeated every week. Disease and patient characteristics, prognostic factors, treatment response, grade 3-4 toxicity related to treatment, progression free survival (PFS) and overall survival (OS) were evaluated. Results: Of the patients, 41 were male and 23 were female; the median age was 63 (29-82) years. Forty-one patients were ECOG-1 and 23 were ECOG-2. Of the total, 81.2% received at least three cycles of chemotherapy. Partial response was observed in 28.1% and stabilization in 29.7%. Overall, the disease was controlled in 57.8% whereas progression was noted in 42.2%. The median time to progression was 4 months (95%CI, 2.8-5.2 months) and median overall survival was 12 months (95%CI, 9.2-14.8 months). The evaluation of patients for grade 3-4 toxicity revealed that 10.9% had anemia, 7.8% had thrombocytopenia and 10.9% had neutropenia. Non-hematologic toxicity included renal toxicity (7.8%) and thrombosis (1.6%). Conclusions: In patients with locally advanced or metastatic gastric cancer who were not candidates for DCF administered every-3-weeks, a weekly formulation of DCF demonstrated modest activity with minimal hematologic toxicity, suggesting that weekly DCF is a reasonable treatment option for such patients.

• 대한한방내과학회지
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• 제28권2호
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• pp.304-320
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• 2007

목적 : 황기추출물이 생쥐의 5-FU로 유발된 골수억제와 삶의 질 저하의 개선에 미치는 효과를 연구하고자 한다. 방법 : 골수억제에 미치는 영향이 평가를 위해 Complete Blood Count, Histological Analysis of BM, Cell Colony Forming Assay for Hematopoietic Progenitor를 시행하고, 삶의 질에 미치는 영향을 평가하기 위해 Swimming Test, Survival Rate, Nitric Oxide (NO) Assay, $^{51}Cr$ Release Assay in NK Cell, mRNA Expressions of $IL-1{\beta}$, IL-2, IL-4, IL-6, IL-10, $TNF-{\alpha}$, $IFN-{\gamma}$, $TGF-{\beta}$ and GM-CSF in Spleen Cells를 시행하였다. 결과 : 황기추출물을 골수억제를 호전시켜 말초혈액수치를 회복시키고, 골수파괴를 보호하는 효과를 보이며, 대조군에 비해 혈구생성을 촉진시키며, 대조군에 비해 생존율과 수영시간을 증가시키며, 대식세포와 자연살상세포의 활동성을 증가시키며, 종양면역과 관련된 싸이토카인(IL-2, IL-6, $IFN-{\gamma}$)의 발현을 증가시켰다. 결론 : 5-FU로 유발된 골수억제와 삶의 질 저하의 개선에 미치는 황기추출물의 유용성이 기대되며 향후 이에 대한 지속적인 연구가 필요할 것으로 사료된다.

• 공업화학
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• 제1권2호
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• pp.190-196
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• 1990

생물활성을 가질 것으로 예상되는 1-(methacryloyloxymethyl)-5-fluorouracil(MAOMFU)을 2, 4-bis(trimethylsilyloxy)-5-fluoropyrimidine으로 부터 합성하고, MAOMF와 메틸메타크릴레이트(MMA)를 cyclohexanone 용매로 사용하여 $60^{\circ}C$에서 라디칼 공중합을 하였다. 공중합체 내의 단량체조성은 공중합체의 UV스펙트럼으로 부터 정량분석하여 구하였다. $Kelen-T\ddot{u}d\ddot{o}s$법에 의해 구한 각각의 단량체 반응성비의 값은 $r_1(MAOMFU)=0.72$, $r_2(MMA)=1.24$ 이었다. 얻어진 단량체 반응성비의 값들로부터 MAOMFU와 MMA의 공중합에서 MAOMFU의 입체장애 효과가 영향을 미치는 것을 알 수 있다. MAOMFU와 poly(MAOMFU)의 가용매분해속도상수는 각각 $6.42{\times}10^{-5}sec^{-1}$와 $7.40{\times}10^{-6}sec^{-1}$ 이었다. 얻어진 가용매분해속도상수로부터 poly(MAOMFU)에서 5-fluorouracil의 가용매분해속도는 MAOMFU 보다 약 5배 느리다는 것을 알 수 있었다.

• Journal of Pharmaceutical Investigation
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• 제25권3호
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• pp.249-264
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• 1995

Although liposome has many advantages as a pharmaceutical dosage form, its application in the industrial field has been limited because of some problems such as preparation method, reproducibility, scale-up, stability and sterilization etc. Liposomes prepared by microemulsification method had defined size, narrow size distribution, reproducibility and high entrapment efficiency. For enhancing the stability, the dry form of liposome was recommended. These types of liposome are proliposome and freeze-dried liposome. The liposome must have some properties for preparing of freeze-dried liposome; small size $(50{\sim}200\;nm)$, narrow size distribution and cryoprotectant. In this experiment, the liposomes containing 5-Fluorouracil(5-FU) and its prodrug(pentyl-5-FU-1-acetate; PFA, hexyl-5-FU-1-acetate; HFA) were made with soybean phosphatidylcholine, cholesterol, stearylamine(SA) and dicetyl phosphate(DCP) employing hydration method or microemulsification method using $Microfluidizer^{TM}$. Both or liposome types were MLV and MEL. After preparation, freeze drying and rehydration were performed. In the process of freezing, trehalose(Tr) was added as a cryoprotectant. Their evaluation methods were as follows; entrapment efficiency, mean particle size and size distribution, dissolution test, retain of entrapment efficiency and turbidity after freeze-drying. The results are summarized as belows. The entrapment efficiency of 5-FU was dependent on total lipid concentration and cholesterol content but that of PFA and HFA was decreased when cholesterol was added. When DCP and SA were added, entrapment efficiency was decreased. As the partition coefficient of drug was increased, entrapment efficiency was increased. Under the same condition, entrapment efficiency of MEL is similar to that of MLV. The mean particle size and size distribution of MEL were smaller than those of MLV. Dissolution rates of drug from both liposome types were comparatively similar. Dissolution rates of drugs with serum and liver homogenate were faster than without these material. After preparation of liposome, free drug was removed efficiency by Dowex 50W-X4. When liposome was freeze-dried and then rehydrated in the presence of Tr, characteristics of liposome were maintained well in MEL than MLV. Tr Was used successfully as a cryoprotectant in the process of freeze drying and the optimal ratio of Tr:Lipid was 4:1(g/g).

• 생명과학회지
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• 제26권9호
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• pp.1015-1021
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• 2016

Pyrimidine 유도체의 일종인 5-fluorouracil (5-FU)은 광범위하게 사용되는 항암제의 일종으로, thymidylate synthase의 활성을 억제시켜 핵산의 합성 및 대사기능 자애 유발 물질이다. 본 연구에서는 Ewing′s 육종 CHP-100 세포에서 5-FU의 증식억제와 연관된 기전 해석으로 시도하였다. 본 연구의 결과에 의하면, 5-FU 처리 시간의 경과에 따른 CHP-100 세포의 증식억제가 세포주기 G1 arrest 유발에 따른 것임을 알 수 있었다. 5-FU에 의한 CHP-100 세포의 G1 arrest는 retinoblastoma protein (pRB)의 탈인산화에 따른 전사인자 E2F-1 및 E2F-4와의 결합 촉진과 연관성이 있었다. 비록 5-FU 처리가 cyclin-dependent kinases의 발현에는 크게 영향을 주지 않았으나, 정상배지에서 배양된 대조군에 비하여 cyclin A 및 B의 발현이 5-FU 처리 시간 의존적으로 억제되었다. 또한 5-FU에 의한 CHP-100 세포의 G1 arrest는 apoptosis 유도와 연관이 있음을 핵 내 염색질의 응축에 따른 apoptotic body의 형성증가, poly (ADP-ribose) polymerase의 단편화 및 annexin V 염색 등을 통하여 확인하였다. 아울러 5-FU는 pro-apoptotic Bax 단백질의 발현 증가 및 anti-apoptotic Bcl-2의 발현 감소를 통한 mitochondrial membrane potential의 소실을 촉진시켰으며, 이로 인하여 미토콘드리아에서 세포질로의 cytochrome c 유리가 증가시켰음을 알 수 있었다. 따라서 본 연구의 결과는 5-FU에 의한 CHP-100 세포의 증식억제와 연관된 G1 arrest 및 apoptosis 유도에는 pRB의 인산화 억제 및 미토콘드리아 기능의 손상이 최소한 관여하고 있음을 의미하는 것이다.

• 한국생물공학회:학술대회논문집
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• 한국생물공학회 2000년도 추계학술발표대회 및 bio-venture fair
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• pp.759-760
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• 2000

5-fluorouracil loaded chitosan-cellulose microspheres was prepared by W/O/W multiple emulsions solvent evaporation technique which is appropriate to oral drug delivery. The influences of process parameters on the physical characteristics of microspheres and on in vitro drug release were investigated.