• Journal of Pharmaceutical Investigation
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• 제37권3호
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• pp.179-186
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• 2007

A simple, sensitive and selective liquid chromatographic/tandem mass spectrometric method (LC-MS/MS) was developed and validated for doxifluridine and 5-fluorouracil (5-FU) quantification in dog heparinized plasma. Sample preparation was based on liquid-liquid extraction using a mixture of isopropanol/ethyl acetate (1/9 v/v) to extract doxifluridine, 5-FU and 5-chlorouracil (5-CU, an internal standard) from plasma. Chromatography was performed on a C-18 analytical column and the retention times were 2.7, 1.5 and 1.7 min for doxifluridine, 5-FU and 5-CU, respectively with shorter analysis time within 5 min than previously reported methods. The ionization was optimized using ESI negative mode and selectivity was achieved by tandem mass spectrometric analysis by multiple reaction monitoring (MRM) using the transformations of m/z 244.8>107.6, 129.0>42.0 and 144.9>42.1 for doxifluridine, 5-FU and 5-CU, respectively. The achieved low limit of quantification was 20.0 ng/mL and the assay exhibited linear range of 20-2000 ng/mL ($R^2>0.99957$ for doxifluridine and $R^2>0.99857$ for 5-FU), using $100{\mu}L$ of plasma. Accuracy and precision of quality control samples for both doxifluridine and 5-FU met KFDA and FDA Guidance criteria of 15% for accuracy with coefficients of variation less than 15%. This method demonstrated adequate sensitivity, specificity, accuracy, precision and stability to support the simultaneous analysis of doxifluridine and 5-FU in dog plasma samples in pharmacokinetic and bioequivalence studies.

• 한국진공학회:학술대회논문집
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• 한국진공학회 2014년도 제46회 동계 정기학술대회 초록집
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• pp.432.1-432.1
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• 2014

Hydroxyapatite (Ca10(PO4)6(OH)2) is known as the main inorganic component of mature mammalian bones and teeth. Because of its biocompatibility, hydroxyapatite has attracted much attention due to its potential applications in many biomedical researches. Here, we tested a therapeutic potential for the use of hydroxyapatite as an anticancer drug delivery vector. We prepared various types of hydroxyapatite having different chemical contents and morphologies using hydrothermal synthesis. The capability of hydroxyapatite as drug delivery materials was examined by adsorption kinetics of 5-fluorouracil molecules, a common anticancer drug, in phosphate buffered saline. We find that hydroxyapatite with smaller crystal size and higher phosphate contents shows improved adsorption property. Given that hydroxyapatite provides a scaffold for bone regeneration, these results highlight a potential use of hydroxyapatite in therapies aimed at osteosarcoma.

• Archives of Pharmacal Research
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• 제12권3호
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• pp.186-190
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• 1989

The release rates of methotrexate (MTX) from MTX-human serum albumin (HSA) conjugate, and 5-fluorouracil (5-FU) from 5-FU acetic acid (AA)-HSA conjugate were determined after incubation of the conjugates in various conditions. The concentrations of 5-FU released from the conjugate increased monoexponentially, however those of MTX increased biexponentially in all studies. It indicated that there are two distinct types of MTX-HSA linkage, weakly and tightly bound linkages. The release rates of 5-FU were lower than those of MTX in all studies indicating that the bond of 5-FU-AA-HSA conjugate is very stable, which is supported by the higher value of activation energy (39. 9 vs 10. 7 Kcal/mole) using Arrhenius equation. The release rates of MTX and 5 -FU from the conjugates increased with incubation temperatures. Proteolytic enzyme and liver homogenates accelerated significantly the release rates of MTX and 5-FU. Approximately 1.30 and 22.0% of MTX were released after 12 hours of incubation in the absence and presence of protease, respectively. The corresponding values for 5-FU were released after 12 hours of incubation with rat liver homogenates which were diluted 6 times with phosphate buffer of pH 6.0. The MTX-HSA and 5-FU-AA-HSA conjugates were very stable in rat plasma.

• Biomolecules & Therapeutics
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• 제30권3호
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• pp.265-273
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• 2022

Resistance to chemotherapeutic drugs is a significant problem in the treatment of colorectal cancer, resulting in low response rates and decreased survival. Recent studies have shown that shikonin, a naphthoquinone derivative, promotes apoptosis in colon cancer cells and cisplatin-resistant ovarian cells, raising the possibility that this compound may be effective in drug-resistant colorectal cancer. The aim of this study was to characterize the molecular mechanisms underpinning shikonin-induced apoptosis, with a focus on endoplasmic reticulum (ER) stress, in a 5-fluorouracil-resistant colorectal cancer cell line, SNU-C5/5-FUR. Our results showed that shikonin significantly increased the proportion of sub-G₁ cells and DNA fragmentation and that shikonin-induced apoptosis is mediated by mitochondrial Ca²⁺ accumulation. Shikonin treatment also increased the expression of ER-related proteins, such as glucose regulatory protein 78 (GRP78), phospho-protein kinase RNA-like ER kinase (PERK), phospho-eukaryotic initiation factor 2 (eIF2α), phospho-phosphoinositol-requiring protein-1 (IRE1), spliced X-box-binding protein-1 (XBP-1), cleaved caspase-12, and C/EBP-homologous protein (CHOP). In addition, siRNA-mediated knockdown of CHOP attenuated shikonin-induced apoptosis, as did the ER stress inhibitor TUDCA. These data suggest that ER stress is a key factor mediating the cytotoxic effect of shikonin in SNU-C5/5-FUR cells. Our findings provide an evidence for a mechanism in which ER stress leads to apoptosis in shikonin-treated SNU-C5/5-FUR cells. Our study provides evidence to support further investigations on shikonin as a therapeutic option for 5-fluorouracil-resistant colorectal cancer.

• Journal of Digestive Cancer Research
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• 제5권1호
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• pp.58-61
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• 2017

5-FU로 인한 심장독성은 드물지만 협심증, 심근경색, 심지어 심장 돌연사까지 유발할 수 있다. 그러므로 약물치료를 계획하기 전 환자의 기저 심질환 여부를 정확히 평가해야 하며, 지연반응으로 인해 약물 투여와 증상 발생의 시간적 간격이 늘어날 수도 있으므로 증상과 EKG에서의 변화가 명확하다면 5-FU로 인한 관상동맥의 일시적인 연축으로 볼 수 있다. 심장효소의 상승과 관상동맥 조영술에서 심혈관의 협착 소견이 없더라도 약물을 중단하고 칼슘통로차단제 등의 혈관확장제를 사용하여야 한다. 그리고 재발의 위험성이 매우 높기 때문에 재투여는 피해야 한다.

• 약학회지
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• 제40권5호
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• pp.532-538
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• 1996

In cancer chemotherapy, it is necessary to control the phamacokinetic behavior of an antitumor drug for effective treatment. Therefore, two 5-fluorouracil derivatives synthesize d with N-a-cyloxycarbonyl derivatives {1-(N-t-butyloxycarbonyl)leucyloxymethyl-5-FU(BLFU) and 1-(N-t-carbobenzyloxymethyl)leucyloxymethyl-5-FU(CLFU)}. prodrugs of 5-fluorouracil, antitumor agent, were loaded into liposome of different lipid compositions. After liposomal drugs were injected intramuscularly, their pharmacokinetics and tissue distribution were assessed. The $AUC_{0{\to}{\infty}$ values were 1.29, 72.50, 85.57, 66.40 and 103.60${\mu}$g.hr/ml for 5-FU, BLFU, CLFU, BLFU- and CLFU-loaded liposome, respectively. 5-FU was distributed to spleen and liver with a maximal concentration after 1 hr and eliminated after 24 hr. But both prodrugs and dimyristoylphosphatidylcholine liposome entrapped prodrugs were distributed to spleen and liver at a lower concentration but maintained for a long time with a relatively high concentration in lung. Especially, liposome-entrapped CLFU was distributed to lung with a maximal concentration after 1 hr and redistributed to spleen increasingly, while the concentration of liposome-entrapped BLFU in lung reached a maximal level after 12 hr.

• Bulletin of the Korean Chemical Society
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• 제34권5호
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• pp.1349-1354
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• 2013

Twenty two new 5-fluorouracil (5-FU) derivatives, 2-butoxy-4-substituted 5-fluoropyrimidines, were synthesized and characterized by IR, $^1H$ NMR, MS, HRMS. All compounds were preliminarily evaluated by MTT assay on human liver BEL-7402 cancer cell line in vitro. Ten compounds were selected to test their cytotoxic activity against A549, HL-60 and MCF-7 cancer cell lines in vitro. These compounds were more sensitive to BEL-7402 than other cell lines, particularly, cytotoxic activity of compounds 6b, 6d-f, 6p, 6s-u were in sub-micromolar scale. The highest cytotoxic potency against A549, HL-60 and MCF-7 was shown by 2-butoxy-4-chloro-5-fluoropyrimidine (5) with $IC_{50}$ values of 0.10, 1.66 and $0.59{\mu}M$, respectively. Compounds 6d and 6e were effective against MCF-7 with $IC_{50}$ $9.73{\mu}M$ and HL-60 with $IC_{50}$ $8.83{\mu}M$, respectively.

• 한국임상약학회지
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• 제14권2호
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• pp.61-70
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• 2004

Heptaplatin is a new platinum derivative with antitumor activity against gastric cancer. Preclinical studies showed that it is less toxic than other platinum analogues. The purpose of this study is to evaluate the efficacy and toxicity of the combination therapy of heptaplatin and 5-fluorouracil in Korean advanced gastric cancer patients. This study was investigated retrospectively. The patients group consisted of 65 advanced gastric cancer patients with no prior radiotherapy. All patients received heptaplatin $400\;mg/m^2$ by 2-3 hour infusion on Day 1 and 5-FU $1000\;mg/m^2by 12-24 hour continuous infusion for 5 days. After the first cycle, subsequent doses were adjusted according to the toxicity. Courses were repeated every 28 days. As results, objective response occurred in 16 patients $(24.6\%)$. Two were complete and 14 were partial response. Median progression free survival was 32 weeks with $29\%$ of patients progression free at 1 year. The most common hematologic toxicity was anemia. Grade 3 or 4 anemia was seen at $2.7\%$ of treatment cycles. Grade 3 or higher leucopenia was seen at $1.2\%$ of cycles. Grade 3 or 4 neutropenia and thrombocytopenia occurred at $6.1\%\;and\;1.5\%$ of cycles, respectively. The most common nonhematologic toxicity was proteinuria. Though no patients experienced grade 3 or 4 proteinuria, proteinuria was a considerable factor for this chemotherapy. Grade 3 or higher gastrointestinal toxicities were nausea and vomiting ($4.6\%$ of patients) and diarrhea ($1.5\%$ of patients). Grade 2 renal toxicity with elevation of serum creatinine was seen in $0.3\%$ of cycles, which is less than that of other platinum analogues. This study showed that combination therapy of heptaplatin and 5-FU have modest antitumor activity against advanced gastric cancer without severe renal toxicity.

• Tuberculosis and Respiratory Diseases
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• 제59권5호
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• pp.536-540
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• 2005

저자들은 64세 남자 환자에서, 재발성 위암에 대한 oxaliplatin, 5-fluorouracil, leucovorin 병합화학요법 중에 발생한 폐섬유화증의 임상적 진단 및 스테로이등 충격 요법 치료 후 호전된 증례를 경험하였기에 문헌 고찰과 함께 보고하는 바이다.

• Maxillofacial Plastic and Reconstructive Surgery
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• 제20권2호
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• pp.158-165
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• 1998

This study was undertaken to observe the effects of the antineoplastic agent, 5-Fluorouracil(5 FU) on the hair in Sprague-Dawley white rats. Twenty four sprague-Dawley strain white rats, each weighing about 150-200 grams were used and divided into control and experimental groups. In the experimental group, eighteen rats were injected intraperitonially with 60 mg of 5-FU per killogram body weight with one time per two days, Six rats were injected with 0.5 cc of normal saline solution intraperitoneally as a placebo on this control group. Rats were serially sacrificed on the first, third, fifth, seventh, tenth and fourteenth day after 2 times of injection of 5-FU and saline. The hair were obtained and observed SEM. After examination and comparision of all specimens, the results of this study were as follows: 1. In the control group, the scale and cuticle of hair was observed smooth surface and equal interval 2. In the experimental group, the first day, scale change was seen from body of hair and crack was seen. from fifth day, and irregular scale and cuticle of hair was seen from 10, 14 days 3. The apperance of root of hair was not almost change From above results, 5-Fluorouracil was more effective on the hair body. The change was begun from first day and crack of scale was seen from fifth day and irregular scale and cuticle of hair was seen from 10,14 days. The.