• YAKHAK HOEJI
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• v.34 no.6
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• pp.395-400
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• 1990

The FU-fat conjugates(4a-e) as a prodrug have been synthesized by condensing various fatty acids(1a-e) via isocyanates(2a-e) as carbamoyl group at $N^1-position$ of 5-fluorouracil and their structures characterized. Preliminary testing for their antitumor effect was carried out on leukemia L1210 cells in culture. Most of them(4a-d) like the parent FU exhibited less than 50% inhibition on grouth of the cultrued cells at the concentration of $1\;{\times\;10^{-7}M$. Only a dicarboxylic acid derivative, 4e, showed over 50% inhibition at the same level.

• Biomolecules & Therapeutics
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• v.24 no.6
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• pp.604-609
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• 2016

5-fluorouracil (5-FU) is a chemotherapeutic agent commonly used for treatment of solid tumors, including colorectal cancer. However, chemoresistance against 5-fluorouracil (5-FU) often limits its success for chemotherapy and, therefore, finding out appropriate adjuvant(s) that might overcome chemoresistance against 5-FU bears a significant importance. In the present study, we have found that ${\alpha}$-mangostin can sensitize 5-FU-resistant SNUC5/5-FUR colon cancer cells to apoptosis. Exposure of ${\alpha}$-mangostin induced significant DNA damages and increased the intracellular 8-hydroxyguanosine (8-OH-G) and 4-hydroxynonenal (4-HNE) levels in SNUC5 and SNUC5/5-FUR cells. Western blot analysis illustrated that ${\alpha}$-mangostin-induced apoptosis was mediated by the activation of the extrinsic and intrinsic pathways in SNUC5/5-FUR cells. In particular, we observed that Fas receptor (FasR) level was lower in SNUC5/5-FUR cells, compared with SNUC5 cells and that silencing FasR attenuated ${\alpha}$-mangostin-mediated apoptosis in SNUC5/5-FUR cells. Together, our study illustrates that ${\alpha}$-mangostin might be an efficient apoptosis sensitizer that can overcome chemoresistance against 5-FU by activating apoptosis pathway.

• YAKHAK HOEJI
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• v.37 no.1
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• pp.89-94
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• 1993

In order to find out a proper connecting bridge between 5-fluorouracil(5-FU) and a macromolecule such as a polypeptide, potentially hydrolytic N$^{1}$-derivartives of 5-FU have been systhesized and evaluated for their biological activity. When tested with in vitro leukemic L$_{1210}$ cells all the obtained derivartives exhibited slightly higher antitumor activity than the parent 5FU. Among them the N$^{1}$ -carbamoyl analogue 2 and N$^{1}$-acetamido analogue 6b showed 50% inhibition of the L$_{1210}$ cell growth at the concentrations of 5.01$\times$10$^{-8}$M and 1.03$\times$10$^{-7}$M, respectively. When tested against sarcoma 180 tumor cells inoculated into mice, the compounds 2 and 6b exhibited, respectively, 62% and 54% inhibition of the solid tumor growth at the 5-time doses of 100 mg/kg/day. Both compounds, N$^{1}$-carbamoyl analogue 2 and N$^{1}$-acetamido analogue 6b, realeased the parent 5-FU when incubated in the L$_{1210}$ cell cultural media for 5 hrs.

• Korean Journal of Clinical Pharmacy
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• v.14 no.1
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• pp.1-10
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• 2004

Studies of oxaliplatin, 5-fluorouracil and leucovorin in pretreated metastatic colorectal cancer showed that oxaliplatin dose intensity is important prognostic factor for objective response rates and progression-free-survival (PFS). To evaluate response rates, PFS and toxicity according to oxaliplatin dose intensity, we retrospectively analyzed data from patients with metastatic colorectal cancer received oxaliplatin,5-fluorouracil, leucovorin regimens. Sixty-three patients were reviewed in this study, 42 patients received low dose intensity oxaliplatin (LDI: $\leq85\;mg/m^2/2wks$) and 21 patients high dose intensity oxaliplatin (HDI: $>85\;mg/m^2/2wks$). Objective responses occurred in 10 $(47.7\%)$ HDI patients and 9 $(21.4\%)$ LDI patients (p = 0.014). Median PFS was 24.7 weeks in HDI group, with $45.1\%$ of HDI patients progression free at 6 months, and 20.5 weeks in LDI group, with $33.5\%$ of LDI patients progression free at 6 months (p = 0.344). Increased oxaliplatin dose intensity was not associated with neutropenia, thrombocytopenia, neuropathy, nausea and vomiting. This study showed that oxaliplatin dose intensification significantly improves objective response rate in pretreated metastatic colorectal cancer without increasing severe toxicity.

• Nutrition Research and Practice
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• v.14 no.2
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• pp.95-101
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• 2020

BACKGROUND/OBJECTIVES: Folate plays a critical role in DNA synthesis and methylation. Intracellular folate homeostasis is maintained by the enzymes folylpolyglutamate synthase (FPGS) and γ-glutamyl hydrolase (GGH). FPGS adds glutamate residues to folate upon its entry into the cell through a process known as polyglutamylation to enhance folate retention in the cell and to maintain a steady supply of utilizable folate derivatives for folate-dependent enzyme reactions. Thereafter, GGH catalyzes the hydrolysis of polyglutamylated folate into monoglutamylated folate, which can subsequently be exported from the cell. The objective of this review is to summarize the scientific evidence available on the effects of intracellular folate homeostasis-associated enzymes on cancer chemotherapy. METHODS: This review discusses the effects of FPGS and GGH on chemosensitivity to cancer chemotherapeutic agents such as antifolates, such as methotrexate, and 5-fluorouracil. RESULTS AND DISCUSSION: Polyglutamylated (anti)folates are better substrates for intracellular folate-dependent enzymes and retained for longer within cells. In addition to polyglutamylation of (anti)folates, FPGS and GGH modulate intracellular folate concentrations, which are an important determinant of chemosensitivity of cancer cells toward chemotherapeutic agents. Therefore, FPGS and GGH affect chemosensitivity to antifolates and 5-fluorouracil by altering intracellular retention status of antifolates and folate cofactors such as 5,10-methylenetetrahydrofolate, subsequently influencing the cytotoxic effects of 5-fluorouracil, respectively. Generally, high FPGS and/or low GGH activity is associated with increased chemosensitivity of cancer cells to methotrexate and 5-fluorouracil, while low FPGS and/or high GGH activity seems to correspond to resistance to these drugs. Further preclinical and clinical studies elucidating the pharmocogenetic ramifications of these enzyme-induced changes are warranted to provide a framework for developing rational, effective, safe, and customized chemotherapeutic practices.

• Journal of Gastric Cancer
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• v.13 no.2
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• pp.121-125
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• 2013

Gastric cancer patients with acute disseminated intravascular coagulation experiences a rare but severe complication resulting in a dismal prognosis. We report a case of advanced gastric cancer complicated with disseminated intravascular coagulation with intractable tumor bleeding which was successfully treated with chemotherapy consisting of 5-fluorouracil and oxaliplatin. The patient was a 63-yearold man who complained of abdominal pain, melena, and dyspnea on 24 November 2010. We diagnosed stage IV gastric cancer complicated by disseminated intravascular coagulation. Gastric tumor bleeding was not controlled after procedures were repeated three times using gastrofiberscopy. With the patient's consent, we selected the 5-fluorouracil and oxaliplatin combination chemotherapy for treatment. After one cycle of 5-fluorouracil and oxaliplatin therapy, symptoms of bleeding improved and the disseminated intravascular coagulation process was successfully controlled. The primary tumor and multiple metastatic bone lesions were remarkably shrunken and metabolically remitted after eight cycles of chemotherapy. In spite of progression, systemic chemotherapy is effective in disease control; further, the patient gained the longest survival time among cases of gastric cancer with disseminated intravascular coagulation.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.9
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• pp.5263-5267
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• 2013

Background: The aim of this study was to evaluate the efficacy and tolerability of a gemcitabine, 5-fluorouracil and leucovorin (GEMFUFOL) chemotherapy regimen as first line treatment of metastatic biliary tract cancer. Materials and Methods: All patients received folinic acid $400mg/m^2$ on day 1, 5-fluorouracil bolus $400mg/m^2$ on day 1, IV infusion of 5-fluorouracil $2400mg/m^2$ over 46 hours, and gemcitabine $1250mg/m^2$ on day 1. Results: A total of 29 patients with metastatic biliary tract cancer received GEMFUFOL regimen as the firstline treatment. The mean follow-up was 22.1 months (95%CI, 12.5-31.8). One patient (3.4%) achieved complete response, 5 (17.2%) had partial response, and 4 (13.8%) had stable disease. The median progression-free survival was 3.3 months (95%CI, 2.9-3.7), and the median overall survival was 8.8 months (95%CI, 3.5-14). The 1-year and 2-year survival rates were 58.6% and 30%, respectively. Grade 3 and 4 toxicity included neutropenia in 4 patients (13.7%), thrombocytopenia in 2 (6.8%), anemia2 (6.8%), and alopecia in 1 (3.4%). Two patients (6.8%) developed febrile neutropenia. A dose reduction was achieved in 8 patients (27.6%) while 5 patients had extended-interval dosage (17.2%) for toxicity. Conclusions: The GEMFUFOL chemotherapy regimen was generally efficacious and tolerable as a first-line treatment of metastatic biliary tract cancer.

• YAKHAK HOEJI
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• v.53 no.4
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• pp.184-188
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• 2009

Fluorouracil (5-FU) is one of the most widely used chemotherapeutic drugs in the treatment of advanced colorectal cancer patients. Capsaicin (N-vanillyl-8-methyl-alpha-nonenamide), a spicy component of hot pepper, is a homovanillic acid derivative that preferentially induces cancer cells to undergo apoptosis. The purpose of the present study is to examine whether capsaicin enhances the anticancer effect of 5-fluorouracil in HT-29 human colon cancer cells by inducing apoptosis, and whether PPARgamma is involved in the capsaicin action in combination treatment with 5-FU. Treatment of the cells with either 5-FU or capsaicin alone for 48 h had little effect on the cell viability up to $50{\mu}M$ concentration, whereas co-treatment of the cells with capsaicin in the presence of 5-FU for 48 h significantly decreased the cell viability in a concentration-dependent manner. In addition, caspase-3 activity, a marker enzyme for apoptosis, was significantly increased by the combined treatment with 5-FU and capsaicin compared to the 5-FU or capsaicin alone treatment. Also, treatment with troglitazone, a peroxisome proliferator-activated receptor gamma ($PPAR{\gamma}$) agonist, further enhanced the effect of the combination treatment on the cell viability and caspase-3 activity, and bisphenol A diglycidyl ether (BADGE), a $PPAR{\gamma}$ antagonist, blocked the effect of the combination treatment. These results suggest that the combination treatment of HT-29 cells with 5-FU and capsaicin induces apoptotic cell death at relatively low concentration than each drug alone, and the combination treatment may be associated with the $PPAR{\gamma}$ pathway activation.

• Molecules and Cells
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• v.25 no.1
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• pp.119-123
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• 2008

Pyrimidine antagonists including 5-Fluorouracil (5-FU) have been used in chemotherapy for cancer patients for over 40 years. 5-FU, especially, is a mainstay treatment for colorectal cancer. It is a pro-drug that is converted to the active drug via the nucleic acid biosynthetic pathway. The metabolites of 5-FU inhibit normal RNA and DNA function, and induce apoptosis of cancer cells. One of the major obstacles to successful chemotherapy is the resistance of cancer cells to anti-cancer drugs. Therefore, it is important to elucidate resistance mechanisms to improve the efficacy of chemotherapy. We have used C. elegans as a model system to investigate the mechanism of resistance to 5-FU, which induces germ cell death and inhibits larval development in C. elegans. We screened 5-FU resistant mutants no longer arrested as larvae by 5-FU. We obtained 18 mutants out of 72,000 F1 individuals screened, and mapped them into three complementation groups. We propose that C. elegans could be a useful model system for studying mechanisms of resistance to anti-cancer drugs.

• Journal of Pharmaceutical Investigation
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• v.24 no.3
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• pp.33-39
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• 1994

We have studied the effect of loading amount and particle size on the rate of release of 5-fluorouracil (5-FU) from ethylene-vinyl acetate (EVA) matrix. Release rate increased as the loading amount and particle size increase. We also studied the effect of additives (lactose and algin) on the rate of release of 5-FU. Both algin and lactose promoted the rate of release. The ability to increase the rate is in the order of algin>lactose>5-FU. Scanning electron microscope study clearly shows that large cavities and cracks are created. The results imply that, by the proper combinations of the amount of the additive, $EVA_c$ and drug, the rate of drug release can be modulated over a wide range of values.