The Effect of Combination of Radiation with 5-Fluorouracil on Mouse Jejunal Crypt Cells

허승재(Seung Jae Huh),박찬일(Charn Il Park) 대한방사선종양학회 1985 Radiation Oncology Journal Vol.3 No.2

방사선조사와 5-Fluorouracil(5-FU)과의 병용시 5-FU투여로 인한 마우스 공장 소낭선세포의 방사선 감수성에 미치는 영향과 방사선조사 효과 증강율을 측정하기 위하여 C_3H마우스 110마리를 대상으로 동물실험용 세시움 방사선 조사기를 이용하였다. 방사선조사 단독시행군은 1,000~1,600rad를, 5-FU와 병용군은 800~1,400rad의 방사선조사와 복강내 5-FU투여를 병용하였다. 방사선조사 단독시행 군은 조사 후 90시간 후에, 병용요법군은 120시간 후에 마우스 공장을 횡절단하여 마우스공장 소낭선 측정 법을 이용하여 평군치사선량과, 5-FU주입이 공장 소낭선세포 생존케 미치는 dose effect factor(DEF)를 측정하였으며, 결과는 다음과 같다. 1. 방사선조사 단독시행 군, 방사선조사 분전 5-FU주입군, 방사선조사 6시간 후에 5-FU주입군의 평균치사선량(Do)은 각각 135, 135, 114rad였다. 2. 방사선조사 단독시행 군에 비하여 방사선조사 15분전 5-FU주입군과, 방사선조사 6시간 후에 5-FU주입군의 DEF는 각각 1.13, 1.27이였다. The interaction of radiation and 5-Fluorouracil (5-FU) on mouse jejunal crypt cells was studied using the microcolony survival assay. 150mg/kg of 5-FU was injected intraperitoneally 15 minutes before irradiation and 6 hours after irradiation. Jejunal crypt cells of mouse survived more when 5-FU was given 15 minutes before irradiation than giving it 6 hours after irradiation. The mean lethal doses (Do) of each of irradiation alone group, 5-FU injection group of 15 minutes preceding irradiation, and 5-FU injection group of 6 hours post irradiation were, 135, 135, and 114 rad respectively. The dose effect factor (DEF) of each of 5-FU injection groups of 15 minutes preceding irradiation and of 6 hours post irradiation were 1.13 and 1.27

Carboplatin/5-fluorouracil as an Alternative to Cisplatin/5-Fluorouracil for Metastatic and Recurrent Head and Neck Squamous Cell Carcinoma and Nasopharyngeal Carcinoma

Kua, Voon Fong,Ismail, Fuad,Phua, Vincent Chee Ee,Aslan, Nik Muhd Asian Pacific Journal of Cancer Prevention 2013 Asian Pacific journal of cancer prevention Vol.14 No.2

Background: Palliative chemotherapy with cisplatin/5-fluorouracil (5FU) is the commonest regimen employed for metastatic and recurrent head and neck squamous cell carcinoma (SCCHN) and nasopharyngeal carcinoma (NPC). However, this regimen is cumbersome requiring 5 days of admission to hospital. Carboplatin/5FU may be an alternative regimen without compromising survival and response rates. This study aimed to compare the efficacy and toxicity of carboplatin/5FU regimen with the cisplatin/5FU regimen. Materials and Methods: This retrospective study looked at patients who had palliative chemotherapy with either cisplatin/5FU or carboplatin/5FU for metastatic and recurrent SCCHN and NPC. It included patients who were treated at UKMMC from $1^{st}$ January 2004 to $31^{st}$ December 2009 with either palliative IV cispaltin 75 $mg/m^2$ D1 only plus IV 5FU 750 $mg/m^2$ D1-5 infusion or IV Carboplatin AUC 5 D1 only plus IV 5FU 500 $mg/m^2$ D1-2 infusion plus IV 5FU 500 $mg/m^2$ D1-2 bolus. The specific objectives were to determine the efficacy of palliative chemotherapy in terms of overall response rate (ORR), median progression free survival (PFS) and median overall survival (OS) and to evaluate the toxicities of both regimens. Results: A total of 41 patients were eligible for this study. There were 17 in the cisplatin/5FU arm and 24 in the carboplatin/5FU arm. The ORR was 17.7 % for cisplatin/5FU arm and 37.5 % for carboplatin/5FU arm (p-value=0.304). The median PFS was 7 months for cisplatin/5FU and 9 months for carboplatin/5FU (p-value=1.015). The median OS was 10 months for cisplatin/5FU arm and 12 months for carboplatin/5FU arm (p-value=0.110). There were 6 treatment-related deaths (6/41=14.6%), four in the carboplatin/5FU arm (4/24=16.7%) and 2 in the cisplatin/5FU arm (2/17=11.8%). Grade 3 and 4 hematologic toxicity was also more common with carboplatin/5FU group, this difference being predominantly due to grade 3-4 granulocytopenia (41.6% vs. 0), grade 3-4 anemia (37.5% vs. 0) and grade 3-4 thrombocytopenia (16.6% vs. 0). Conclusions: Carboplatin/5FU is not inferior to cisplatin/5FU with regard to its efficacy. However, there was a high rate of treatment-related deaths with both regimens. A better alternative needs to be considered.

The Effect of Juakium-derivative(左歸飮加味方) on Aplastic Anemia

Lee,Jang-hoon,Woo,Hong-jung,Kim,Sun-min INSTITUTE OF ORIENTAL MEDICINE KYUNG-HEE UNIVERSIT 1997 JOURNAL OF ORIENTAL MEDICINE Vol.2 No.1

Aplastic anemia is a fatal disease characterized by a peripheral pancytopenia and markedly decreased hematopoietic activity in the bone marrow. It may be inherited but more commonly may develop as a reaction to a drug. 5-Fluorouracil(5-FU) is a chemotherapeutic mainly for stomach cancer, but the suppression of bone marrow is a controversial side effect of this drug. This study is to evaluate the effect of Juakium-derivative on aplastic anemia induced by 5-FU on mice. Forty 5-week old ICR mice were divided into four groups: normal, 5-FU only, 5-FU+Juakium-derivative and Juakium-derivative. 100mg/Kg of 5-FU was administered to induce aplastic anemia in the 5-FU only group. And 1000mg/kg of Juakium derivative was supplementarily administered in the 5-FU+Juakium-derivative group. Hematologic findings, body weight, organ weight and histopathological findings were observed. In mouse body weight, the weight of Juakium-derivative+5-FU group and 5-FU only group was decreased compared to the normal group. But the weight of the Juakium-derivative+5-FU group was higher than that of the 5-FU only group. In the hematologic study, the Juakium-derivative+5-FU group showed improvement in WBC, RBC, Hbc, Hct, and PLT compared with the 5-FU only group. The weight of extracted spleen and thymus in the Juakium-derivative+5-FU group was significantly higher than that of the 5-FU only group. The weight of extracted live and heart exhibited no significant difference between the Juakium-derivative+5-FU group and the 5-FU only group. In the histopathologic findings, compared with 5-FU only group, the Juakium-derivative+5-FU group showed few megakaryocytes in the cortex of the spleen and well-preserved lymphatic nodules. Furthermore the atrophy of the thymus was milder in the Juakium-derivative+5-FU group than in the 5-FU only group. Juakium-derivative has a therapeutic effect on aplastic anemia induced by 5-FU, and it is expected that combined administration of Juakium-derivative and 5-FU can decrease the side effects of 5-FU. Therefore, Juakium-derivative is recommendable for clinical use in the treatment of aplastic anemia. Further study on the supplemental herbs in this prescription is required.

5-플루오로우라실 프로드럭의 제조, 물리화학적 성질 및 항암효과

지웅길,이계원 충남대학교 약학대학 의약품개발연구소 1996 藥學論文集 Vol.12 No.-

To assess their stability as a prodrug of 5-fluorouracil (5-FU), four N-acyloxycarbonyl derivatives (1-(N-tert-butyloxycarbonyl)glycyloxymethyl-5-FU:BGFU. 1-(N-tert-butyloxycarbonyl)-leucyloxymethyl-5-FU:BLFU, 1-(N-tert-carbobvenzylloxymethyl)glycyloxymethyl-5-FU:CGFU and 1-(N-tert-carbobenzyloxymethyl)leucyloxymethyl-5-FU:CLFU) possessing differently protected amino acids, and two acetic acid derivatives (5-FU-1-acetylpentane:FUAP and 5-FU-1-acetylhexane:FUAH) were synthesized and their physicochemical properties, hydrolysis kinetics, acute toxicity and antitumor activity were evaluated. The lipid-water partition coefficients of six 5-FU prodrugs were higher than that of 5-FU and their aqueous solubilities were in the following rank order: BGFU>FUAP>CGFU>BLFU>CLFU??FUAH. The hydrolysis of N-acyloxycarboyl derivatives, greater at higher pH, was enhanced in presence of liver homogenate or human plasma. Meanwhile, acetic acid ester dervatives, very stable, were hydrolyzed by liver homogenate. Absorption rate constants were 0.181, 0.121, 0.111, 0.168, 0.168, 0.116 and 0.125 hr^-1 for 5-FU, BGFU, BLFU, CGFU, CLFU, FUAP and FUAH, respectively. The cytotoxicity of N-acyloxycarbonyl derivatives was 4 to 5 times lower than that of 5-FU, but that of acetic acid ester derivatives was negligeble. The LD_50 values were 204, 325.97 (133.59, amount as 5-FU), 708.16 (262.13), 663.50 (211.77), 382.33 (192.54) and 272.33 (130.09) ㎎/㎏ for 5-FU, BGFU, CGFU, CLFU, FUAP and FUAH, respectively. While N-acyloxycarbonyl derivatives showed enhanced antitumor activity and therapeutic ratio (3.30, 3.06, 4.19, 3.11 and 1.81 for BGFU, BLFU, CGFU, CLFU and 5-FU, respectively), FUAH and FUAP showed a smaller therapeutic ratio (0.79 and 0.83).

CHP-100 Ewing"s 육종세포에서 5-fluorouracil에 의한 G1 arrest 유도 및 apoptosis 유발에 관한 연구

김성옥(Sung Ok Kim),최영현(Yung Hyun Choi) 한국생명과학회 2016 생명과학회지 Vol.26 No.9

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. 5-fluorouracil (5-FU), a pyrimidine analog, is a widely used anticancer drug, which works through irreversible inhibition of thymidylate synthase. In the present study, it was investigated the anti-proliferative effects and molecular mechanisms of 5-FU using Ewing"s Sarcoma CHP-100 Cells. The present data indicated that treatment of 5-FU to CHP-100 cells induced a G1 phase arrest of the cell cycle in a time-dependent manner. 5-FU-induced G1 arrest was correlated with the accumulation of the hypophosphorylated form of the retinoblastoma protein (pRB) and association of pRB with the transcription factors E2F-1 and E2F-4. Although 5-FU treatment did affect the levels of cyclin-dependent kinases, the levels of cyclin A and B were markedly down-regulated as compared with the untreated control group. In addition, 5-FU-induced G1 arrest of CHP-100 cells was also associated with the induction of apoptosis, as determined by apoptotic cell morphologies, degradation of poly(ADP-ribose) polymerase and Annexin V staining. Furthermore, 5-FU induced the loss of mitochondrial membrane potential with up-regulated pro-apoptotic Bax expression, down-regulated anti-apoptotic Bcl-2 expression and cytochrome c release from mitochondria to cytosol. Collectively, the data suggest that 5-FU is effective in inducing cell growth reduction and apoptosis, in part, by reducing phosphorylation of pRB and activating mitochondrial dysfunction in CHP-100 cells.

5-플루오로우라실 프로드럭의 제조, 물리화학적 성질 및 항암효과

지웅길(Ung Kil Jee),이계원(Gye Won Lee) 대한약학회 1996 약학회지 Vol.40 No.3

To assess their stability as a prodrug of 5-fluorouracil (5-FU), four N-acyloxycarbonyl derivatives (1-(N-tert-butyloxycarbonyl)glycyloxymethyl-5-FU :BGFU, 1-(N-tert-butyloxycarbonyl)-leucyloxymethyl-5-FU:BLFU, 1-(N-tert-carbobenzyloxymethyl) glycyloxymethyl-5-FU:CGFU and 1-(N-tert-carbobenzlyoxymethyl)leucyloxymethyl-5-FU:CLFU) possessing differently protected amino acids, and two acetic acid derivatives (5FU-1-acetylpentane:FUAP and 5-FU-1-acetylhexane:FUAH) were synthesized and their physicochemical properties, hydrolysis kinetics, acute toxicity and antitumor activity were evaluated. The lipid-water partition coefficients of six 5-FU prodrugs were higher than that of 5-FU and their aqueous solubilities were in the following rank order; BGFU>FUAP>CGFU>BLFU>CLFU=FUAH. The hydrolysis of N-acyloxycarboyl derivatives, greater at higher pH, was enhanced in presence of liver homogenate or human plasma. Meanwhile, acetic acid ester derivatives, very stable, were hydrolyzed by liver homogenate. Absorption rate constants were 0.181, 0.121, 0.111, 0.168, 0.168, 0.116 and 0.125 hr-1 for 5-FU, BGFU, BLFU, CGFU, CLFU, FUAP and FUAH, respectively. The cytotoxicity of N-acyloxycarbonyl derivatives was 4 to 5 times lower than that of 5-FU, but that of acetic acid ester derivatives was negligeble. The LD50 values were 204, 325.97 (133.59, amount as 5-FU), 708.16 (262.13), 663.50 (211.77), 382.33 (192.54) and 272.33 (130.09) mg/kg for 5-FU, BGFU, CGFU, CLFU, FUAP and FUAH, respectively. While N-acyloxycarbonyl derivatives showed enhanced antitumor activity and therapeutic ratio (3.30, 3.06, 4.19, 3.11 and 1.81 for BGFU, BLFU, CGFU, CLFU and 5-FU, respectively), FUAH and FUAP showed a smaller therapeutic ratio (0.79 and 0.83).

노인에 있어서 양한방 병용치료에 대한 인식도 조사 및 상호작용 연구

김익균 ( Ekyune Kim ) 대구가톨릭대학교 자연과학연구소 2016 자연과학연구논문집 Vol.14 No.1

The goal of this study is to develop a liquid chromatography-mass spectrometry (LC/MS/MS) quantification method that proved reliable and had high sensitivity to 5-FU and eloxatin. This method was then used to analyze 5-FU and eloxatin in invivo rat samples. In order to evaluate the effect single Ginseng and Atractylodes Formula (GAF) dose on the pharmacokinetics of 5-FU and eloxatin, a single dose of puredistilled water and acolloidal suspension of distilled water and GAF were administered to the control and test groups, respectively. After 5min, both the groups were orally administered 5-FU and eloxatin. Present study was evaluated the pharmacokinetic changes observed in 5-FU and eloxatinin the control and test groups. No statistically significant differences were observed in the pharmacokinetics of 5-FU and eloxatinin both the groups. These findings demonstrated that a single dose of orally-administered GAF did not affect the pharmacokinetics of 5-FU and eloxatin. Nor did the repeated administration of 5-FU and eloxatin an hour after the administration of GAF influence the pharmacokinetics of the two anticanceragents. In order to investigate the effects of repeated administration of GAF on the pharmacokinetics of 5-FU and eloxatin, distilled water and a colloidal suspension of distilled water and GAF were administered for seven days to the control and test groups, respectively. On day 7, 5-FU and eloxatin were intravenously administered to both the control and test groups after 5 min of GAF administration, and changes in the pharmacokinetics of 5-FU and eloxatin were evaluated. No statistically significant intergroup differences were observed. These experimental results verified that repeated administration of GAF did not have an effect on the pharmacokinetics of 5-FU and eloxatin.

Curcumin Reduces Cytotoxicity of 5-Fluorouracil Treatment in Human Breast Cancer Cells

Jeannette E. Ferguson,Robert A. Orlando 한국식품영양과학회 2015 Journal of medicinal food Vol.18 No.4

Antimetabolites have proven successful as therapeutics for advanced-stage breast cancers, but are often accompanied by severe side effects that can limit treatment regimens. 5-Fluorouracil (5-FU), an antimetabolite that inhibits cell proliferation, has served an important role in standard chemotherapy protocols for a variety of solid tumors. Although reasonable response rates have been reported for 5-FU, continued exploration is necessary to improve clinical outcomes and reduce cytotoxic side effects that are an inherent problem for chemotherapeutic interventions. Because of its diverse anticancer properties, we explored whether by combining the natural product curcumin with 5-FU, synergistic improvements in preventing breast cancer cell proliferation and/or provide protection against 5-FU-induced cytotoxicity could be achieved. Indeed both curcumin and 5-FU inhibit DNA synthesis in MDA-MB-231 cells using BrdU incorporation assays; however, combined treatment showed no synergistic improvement. We next established the cytotoxicity profile for 5-FU in MDA-MB-231 cells using a tetrazolium-based cell viability assay and obtained an LD50 value of 28 lM. When 5-FU incubations were repeated with the addition of curcumin, the LD50 value increased to 200–300 lM, representing a 7–10-fold protection by curcumin against 5-FU cytotoxicity. These findings suggest that the addition of curcumin as an adjuvant therapy during 5-FU treatment might enhance the chemotherapeutic effectiveness of 5-FU by protecting normal cells from reduced viability and thus permitting higher dosing or longer treatment times. This would be especially important to those individuals who are plagued with severe cytotoxicities and require frequent interruptions, or even early termination of their treatment regimens.

5-Fluorouracil 투여 방법이 백서의 공장 점막에 대한 방사선 효과에 미치는 영향 : on lipids and Hormone Receptors m PostinenoTjWomen

박경란,고창만,정순희 연세대학교 원주의과대학 1993 원주의대논문집 Vol.6 No.1

흰쥐 생체시료 중 5-플루오로우라실 및 테가푸르의 안정성

장지현,박종국,강진형,정석재,심창구,구효정 한국약제학회 2004 Journal of Pharmaceutical Investigation Vol.34 No.3

5-Fluorouracil (5-FU) is an antimetabolite anticancer agent active against many types of solid tumors. Tegafur (TF), a prodrug of 5-FU, is frequently used in combination with uracil as dihydropyrimidine dehydrogenase (DPD) inhibitory fluoropyrimidine. We studied the stability of 5-FU and TF in biological fluids of rats and determined their bioavailability (BA) and excretion into bile, and urine. The drug concentrations were analyzed by an HPLC method. At room temperature, there was a 14-30% decrease in the concentration of 5-FU and TF in bile, urine, and plasma specimen at 10 and 100 μg/ml over 240 min. No significant difference was noted among the sample types or between two different concentrations of 10 and 100 μg/ml. The decrease in drug concentration was significantly less in samples kept on ice (6-12%) for both drugs. These data indicate that biological fluid samples containing 5-FU or TF in plasma, urine, or bile should be placed on ice during the sample collection. Following these storage guidelines, samples were collected after administration 50 ㎎/㎏ of each drug via i.v. or oral route. BA was 1.5 folds greater for TF (60%) than that of 5-FU (42%). Approximately 0.52 and 3.3% of the i.v. doses of 5-FU and TF was excreted into bile, respectively. Renal clearance of 5-FU was about 16% of its total body clearance. These results suggest that instability of 5-FU and TF in biological fluids should be considered in pharmacokinetic or pharmacogenomic studies.