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    ์ „ํ›„(ๆˆฐๅพŒ)์˜ ๋ถˆ๋ชจ์ง€์— ํ”ผ์›Œ๋‚ธ ์ „์ธ๊ต์œก(ๅ…จไบบๆ•Ž่‚ฒ)์˜ ๊ฝƒ: ํ˜ธ์žฌ(ๅฒตๅœจ) ํ•จ์žฌํ™(ๅ’ธ่ผ‰ๅผ˜) ์„ ์ƒ๋‹˜์˜ ํ—Œ์‹ ์  ์‚ฌ๋„(ๅธซ้“)์˜ ํ–ฅ๊ธฐ

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    ์•ผ, ์„ ์ƒ๋‹˜ ์˜ค์‹ ๋‹ค. ์„ ์ƒ๋‹˜โ€ฆโ€ฆ๋Œ๋ฉฉ์ด๊ฐ€ ๋“ฌ์„ฑ๋“ฌ์„ฑ ํŠ€์–ด๋‚˜์™€ ์žˆ๊ณ  ์•„์ง ์ž˜ ๋‹ค๋“ฌ์ง€ ์•Š์•„ ํ•™๊ต ์šด๋™์žฅ์ด๋ผ๊ณ  ํ•˜๊ธฐ์—๋Š” ๋„ˆ๋ฌด ์ž‘์€ ๊ณตํ„ฐ. ํ•œ ๊ฒจ์šธ ์˜ค์ „ ์ด๊ณณ์— ๋ชจ์—ฌ ๋†€๋˜ ์–ด๋ฆฐ์ด๋“ค์ด ๋ธŒ๋ผ์šด ์ƒ‰์˜ ๋‚™ํƒ€ ์™ธํˆฌ๋ฅผ ๊ฑธ์น˜๊ณ  ์„ฑํผ ์„ฑํผ ์ฒ ์กฐ๋ง ๊ต๋ฌธ์œผ๋กœ ๋“ค์–ด์„œ๋Š” ์„ ์ƒ๋‹˜์„ ๋ณด๊ณ  ์™ธ์น˜๋ฉฐ ๋‹ฌ๋ ค๊ฐ„๋‹ค. ์„ ์ƒ๋‹˜๊ณผ ์–ด๋ฆฐ์ด๋“ค์ด ํ•จ๊ป˜ ๋งจ์†์ฒด์กฐ๋ฅผ ํ•˜๊ณ ์„œ ๊ฐ€๋ณ๊ฒŒ ๋‹ฌ๋ฆฌ๊ธฐ๋ฅผ ํ•˜๋ฉฐ ๋ชธ์„ ๋ฐ์šด ๋’ค ๋“ค์–ด์„œ๋Š” ํŒ์ž ์ง‘ ๊ฐ€๊ต์‹ค. ์ถ”์šด ๊ฒจ์šธ๋ฐฉํ•™ ๋‚œ๋กœ๋„ ์—†๋Š” ๋งจ ํ™๋ฐ”๋‹ฅ์˜ ํŒ์ž ์ง‘ ๊ต์‹ค์— ์˜น๊ธฐ์ข…๊ธฐ ๋ชจ์—ฌ ๋ฌด์–ธ๊ฐ€ ์—ด์‹ฌํžˆ ํ•˜๊ณ  ์žˆ๋Š” ํ•ด๋ง‘์€ ๋ˆˆ์˜ ์ดˆ๋“ฑํ•™๊ต 4ํ•™๋…„ ๊ผฌ๋งน์ด๋“ค. ํ•œํŽธ์—์„  ๋„ํ™”์ง€์— ํฌ๋ ˆ์šฉ์œผ๋กœ ๊ทธ๋ฆผ์„ ๊ทธ๋ฆฌ๊ณ , ๋‹ค๋ฅธ ์ชฝ์—์„  ๊ธ€์ง“๊ธฐ๋ฅผ ํ•˜๊ณ , ๋ช‡๋ช‡์€ ํ•œ ๊ตฌ์„์—์„œ ์›…๋ณ€์—ฐ์Šต์„ ํ•˜๋Š” ๊ผฌ๋งน์ด๋“ค์˜ ์—ด๊ธฐ๋กœ ๊ฐ€๋“ ์ฐฌ ๊ต์‹ค. ์ด๋“ค ์–ด๋ฆฐ์ด ํ•˜๋‚˜ํ•˜๋‚˜๋ฅผ ๋ณด์‚ดํŽด ๊ณ ์ณ ์ฃผ๊ณ  ๊ฐ€๋ฅด์น˜๋ฉฐ ์ „์ธ๊ต์œก์— ๋ชฐ๋‘ํ•˜๋Š” 20๋Œ€ ํ›„๋ฐ˜์˜ ์˜ํ™”๋ฐฐ์šฐ์ฒ˜๋Ÿผ ์ž˜ ์ƒ๊ธด ์—ด์ •์— ๋„˜์นœ ์ฒญ๋…„๊ต์‚ฌ. ๋ฐ”๋กœ ์ด ์ฒญ๋…„๊ต์‚ฌ๊ฐ€ ํ•„์ž์˜ ์ดˆ๋“ฑํ•™๊ต 4ํ•™๋…„ 1๋ฐ˜๋ถ€ํ„ฐ ์กธ์—… ๋•Œ๊นŒ์ง€ 3๋…„๊ฐ„ ๋‹ด์ž„์„ ํ•œ ํ˜ธ์žฌ(ๅฒตๅœจ) ํ•จ์žฌํ™(ๅ’ธ่ผ‰ๅผ˜) ์„ ์ƒ๋‹˜์ด์‹œ๋‹ค. ํ•œ๊ตญ์ „์Ÿ์˜ ํœด์ „ํ˜‘์ •์ด ์ฒด๊ฒฐ๋œ ๋’ค 2๋…„ ํ›„์ธ 1955๋…„ 12์›” ํ•˜์ˆœ๊ฒฝ, ๋ถ€์‚ฐ ๋™๊ตฌ ์ˆ˜์ •๋™์˜ ์ˆ˜์ •์‚ฐ ์ค‘ํ„ฑ์— ์ƒˆ๋กœ ์„ธ์›Œ์ง„ ์ˆ˜์„ฑ์ดˆ๋“ฑํ•™๊ต 4ํ•™๋…„ 1๋ฐ˜์˜ ๊ฒจ์šธ๋ฐฉํ•™ ์ž์œจํŠน๋ณ„ํ™œ๋™ ์‹œ๊ฐ„ ๋ชจ์Šต์ด๋‹ค

    ์•ฝ๋ฌผ ์ „๋‹ฌ์— ์‘์šฉํ•˜๊ธฐ ์œ„ํ•œ 30Kc19๋ฅผ ์ด์šฉํ•œ ๋‹จ๋ฐฑ์งˆ ๋‚˜๋…ธ์ž…์ž์˜ ์ œ์กฐ ๋ฐ ํŠน์„ฑ ์—ฐ๊ตฌ

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    ํ•™์œ„๋…ผ๋ฌธ (๋ฐ•์‚ฌ)-- ์„œ์šธ๋Œ€ํ•™๊ต ๋Œ€ํ•™์› : ํ™”ํ•™์ƒ๋ฌผ๊ณตํ•™๋ถ€, 2015. 2. ๋ฐ•ํƒœํ˜„.30Kc19 protein is a member of the 30K protein family from silkworm, having molecular weights of around 30 kDa. 30Kc19 protein is the most abundant among 30K proteins in the hemolymph. In previous studies, 30K proteins exhibited anti-apoptotic effect in various cells by gene expression or addition of 30K proteins in recombinant form produced from Escherichia coli. 30Kc19 also enhanced productivity and glycosylation by expression of a 30Kc19 gene or supplementation with a recombinant 30Kc19 protein. Additionally, 30Kc19 exhibited enzyme-stabilizing and cell-penetrating abilities in vitro. In this study, it was hypothesized that supplemented 30Kc19 penetrated into the cell and enhanced the stability of the cellular enzyme, and investigated this using in vitro and cellular assessments. The activity of isolated mitochondrial complex I / III was enhanced with 30Kc19 in dose-dependent manner while initial reaction rate was unchanged, suggesting that 30Kc19 enhanced enzyme stability rather than specific activity. For intracellular enzyme activity assessment, mitochondrial complex II activity in HeLa cells increased more than 50% with 30Kc19. The enhanced mitochondrial complex activity increased mitochondrial membrane potential and ATP production in HeLa cells with 30Kc19, by over 50%. Then cell penetrating and enzyme stabilizing effect of 30Kc19 was exploited to efficient drug delivery. 30Kc19 and HSA were used as building block of protein nanoparticles to exploit both beneficial effect of 30Kc19 protein stability of HSA nanoparticles. 30Kc19-HSA nanoparticles were successfully prepared using the desolvation method, with uniform spherical morphology and stable dispersion. 30Kc19-HSA nanoparticles showed negligible toxicity when treated to cells, and 30Kc19-HSA nanoparticles also exhibited increase in cellular uptake compared with HSA nanoparticles. Because stable 30Kc19-HSA nanoparticles were successfully synthesized and characterized, nanoparticles loaded with model enzyme cargo to investigated effect of 30Kc19 on cargo enzyme. 30Kc19-HSA nanoparticles loaded with ฮฒ-galactosidase were uniformly spherical in shape, dispersed evenly in phosphate buffered saline and cell culture media, and released ฮฒ-galactosidase in a sustained manner. The 30Kc19-HSA nanoparticles had negligible toxicity to animal cells and exhibited enhanced cellular uptake and intracellular stability of ฮฒ-galactosidase in HeLa and HEK293 cells when compared with those of HSA nanoparticles. These results suggest that 30Kc19-HSA protein nanoparticles could be used as a versatile tool for drug delivery to various cells. Next, 30kc19-HSA nanoparticles were used to deliver actual therapeutic protein to cells. Fabry disease is a genetic lysosomal storage disease caused by deficiency of ฮฑ-galactosidase, the enzyme that degrades neutral glycosphingolipids transported to lysosomes. Enzyme replacement therapy (ERT) using recombinant ฮฑ-galactosidase is the only treatment available for Fabry disease. Because enhancing cellular delivery and enzyme stability is a challenge of ERT using ฮฑ-galactosidase to maximize treatment efficacy, 30Kc19-HSA protein nanoparticles were used to enhance delivery and intracellular ฮฑ-galactosidase stability. The 30Kc19-HSA nanoparticles had a uniform spherical shape and were well-dispersed. The 30Kc19-HSA nanoparticles had negligible toxicity to human cells. The nanoparticles exhibited enhanced cellular uptake and intracellular stability of the delivered ฮฑ-galactosidase in human foreskin fibroblasts. Additionally, the nanoparticles enhanced globotriaosylceramide degradation in fibroblasts from a patient with Fabry disease. It is expected that 30Kc19-HSA protein nanoparticles will be used as an effective tool for efficient delivery and enhanced stability of drugs.Contents Chapter 1. Research background and objectives 1 Chapter 2. Literature review 5 2.1 Nanoparticles for drug delivery 6 2.1.1 Terminology of nanoparticles 6 2.1.2 Classification of nanoparticles 7 2.2 Albumin nanoparticles 10 2.2.1 Albumins for nanoparticle production 10 2.2.2 Preparation of albumin nanoparticles 12 2.2.3 Surface modification of albumin nanoparticles 14 2.2.4 Uptake of albumin nanoparticles 18 Chapter 3. Experimental procedures 20 3.1 Production of recombinant 30Kc19 protein 21 3.2 Cell culture 21 3.3 Mitochondria isolation 22 3.4 Western blotting 22 3.5 Mitochondrial activity assay 22 3.6 Estimation of mitochondrial membrane potential and ATP generation 23 3.7 Preparation of nanoparticles 24 3.8 Size and zeta potential of the nanoparticles 24 3.9 Scanning electron microscopy (SEM) analysis of the nanoparticles 25 3.10 ฮฒ-galactosidase loading efficiency of the nanoparticles 25 3.11 In vitro ฮฒ-galactosidase release from nanoparticles 26 3.12 Cell viability assay 27 3.13 Cellular uptake of nanoparticles 27 3.14 Protein cargo activity of nanoparticle-treated cells 29 3.15 Globotriaosylceramide degradation 30 3.16 Statistical analysis 31 Chapter 4. Stabilization of cellular mitochondrial enzyme complex activity through supplementation of 30Kc19 protein 32 4.1 Introduction 33 4.2 Effect of 30Kc19 on in vitro mitochondrial enzyme stability 34 4.3 Intracellular and mitochondrial uptake of 30Kc19 35 4.4 Effect of 30Kc19 on intracellular mitochondrial enzyme stability 38 4.5 Effect of 30Kc19 on mitochondrial membrane potential and ATP generation 40 4.6 Conclusions 40 Chapter 5. Synthesis of protein nanoparticles using 30Kc19 protein and human serum albumin 42 5.1 Introduction 43 5.2 Preparation and characterization of 30K-HSA nanoparticles 45 5.3 Cellular toxicity of 30Kc19-HSA nanoparticles 49 5.4 Cellular uptake of 30Kc19-HSA nanoparticles 49 5.5 Conclusions 51 Chapter 6. Protein nanoparticles for protein cargo delivery using 30Kc19 protein and human serum albumin 53 6.1 Introduction 54 6.2 Characterization of ฮฒ-gal-loaded 30Kc19-HSA nanoparticles 55 6.3 ฮฒ-Galactosidase loading and in vitro release of 30Kc19-HSA nanoparticles 59 6.4 Cellular toxicity of 30Kc19-HSA nanoparticles loaded with ฮฒ-Galactosidase 62 6.5 Cellular uptake of 30Kc19-HSA nanoparticles loaded with ฮฒ-Galactosidase 64 6.6 Intracellular ฮฒ-galactosidase activity delivered by nanoparticles 66 6.7 Conclusions 69 Chapter 7. Protein nanoparticles for therapeutic protein delivery using 30Kc19 protein and human serum albumin 70 7.1 Introduction 71 7.2 Production and characterization of 30Kc19-HSA nanoparticles 72 7.3 Cellular toxicity of 30Kc19-HSA nanoparticles 76 7.4 Cellular uptake of nanoparticles 76 7.5 Intracellular ฮฑ-galactosidase activity delivered by nanoparticles 78 7.6 Globotriaosylceramide degradation activity in nanoparticle-treated Fabry disease fibroblasts 80 7.7 Conclusions 84 Chapter 8. Overall discussion and further suggestions 85 8.1 Overall discussion 86 8.2 Conclusion and further suggestions 92 References 96 ๊ตญ ๋ฌธ ์ดˆ ๋ก 110Docto

    Biomechanical characteristics of pelvis and lower limbs in Korean soccer players diagnosed with lumbar facet joint syndrome

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    ์˜ํ•™๊ณผ/์„์‚ฌ[ํ•œ๊ธ€] ๋งŒ์„ฑ์ ์ธ ์š”ํ†ต์˜ ๋Œ€ํ‘œ์ ์ธ ์งˆํ™˜์œผ๋กœ ํ›„๊ด€์ ˆ ์ฆํ›„๊ตฐ(facet joint syndrome)์ด ์žˆ๊ณ , ์ด๊ฒƒ์˜ ์›์ธ์œผ๋กœ ์ถ”์ • ๋˜๋Š” ๊ฒƒ์€ ์ฆ๊ฐ€๋œ ์š”์ฒœ์ถ” ์ „๋งŒ(hyper lordosis), ์•ฝํ•ด์ง„ ๋“ฑ/๋ณต๋ถ€ ๊ทผ์œก, ๋น„์ •์ƒ์ ์ธ ํ›„๊ด€์ ˆ ํ˜•ํƒœ ๊ทธ๋ฆฌ๊ณ  ํ•˜์ง€ ๊ธธ์ด์ฐจ ๋“ฑ์— ์˜ํ•œ ์š”์ถ” ํ›„๊ด€์ ˆ๊ฐ„ ์ŠคํŠธ๋ ˆ์Šค ์ฆ๊ฐ€(increased interfacet stress) ์ด๋‹ค. ํ•œํŽธ, ์žฅ๊ณจ๊ณผ ์ฒœ์ถ”์„ ํฌํ•จํ•œ ๊ณจ๋ฐ˜๊ณผ ์ œ 5์š”์ถ”๋Š” ํ›„๊ด€์ ˆ(์ œ 5์š”์ถ”/์ œ 1์ฒœ์ถ”๊ฐ„)์— ์˜ํ•ด ๋ฐ€์ ‘ํ•˜๊ฒŒ ์—ฐ๊ณ„๋˜์–ด ์žˆ์–ด ๊ณจ๋ฐ˜์˜ ๋น„์ •์ƒ์ ์ธ ์›€์ง์ž„์ด ํ›„๊ด€์ ˆ์˜ ์ŠคํŠธ๋ ˆ์Šค๋ฅผ ์ฆ๊ฐ€์‹œํ‚ฌ ์ˆ˜ ์žˆ๋‹ค. ์ฆ‰, ๊ณจ๋ฐ˜์˜ ํŽธ์ธก ํšŒ์ „, ๊ณผ๋„ํ•œ ๊ณจ๋ฐ˜์˜ ์ „๋ฐฉ ๊ธฐ์šธ์ž„, ๊ทธ๋ฆฌ๊ณ  ๊ณจ๋ฐ˜์˜ ์ขŒ์šฐ ๋†’์ด์ฐจ๊ฐ€ ์š”์ถ” ํ›„๊ด€์ ˆ์˜ ์ŠคํŠธ๋ ˆ์Šค๋ฅผ ์ฆ๊ฐ€ ์‹œํ‚ฌ ์ˆ˜ ์žˆ๋‹ค. ์ด์™€ ๊ฐ™์ด ๊ณจ๋ฐ˜์˜ ๋น„์ •์ƒ์ ์ธ ์›€์ง์ž„์„ ์ดํ•ดํ•˜๋Š” ๊ฒƒ์ด ์š”์ถ” ํ›„๊ด€์ ˆ ์ฆํ›„๊ตฐ์˜ ์œ ๋ฐœ ์›์ธ์„ ๋ถ„์„ํ•˜๋Š”๋ฐ ๋„์›€์ด ๋  ๊ฒƒ์œผ๋กœ ์ƒ๊ฐ ๋œ๋‹ค. ๋ณธ ์—ฐ๊ตฌ์—์„œ๋Š” ์š”์ถ” ํ›„๊ด€์ ˆ ์ฆํ›„๊ตฐ์„ ๊ฐ€์ง„ ์ถ•๊ตฌ ์„ ์ˆ˜๋“ค์„ ๋Œ€์ƒ์œผ๋กœ ๊ณจ๋ฐ˜๊ณผ ํ•˜์ง€์˜ ์›€์ง์ž„์„ ์ƒ์ฒด ์—ญํ•™์  ์ธก์ •์„ ํ†ตํ•ด ์–ป๊ณ , ์ด๊ฒƒ์„ ์š”ํ†ต์„ ๊ฐ€์ง€์ง€ ์•Š์€ ์„ ์ˆ˜๋“ค์˜ ๊ทธ๊ฒƒ๊ณผ ๋น„๊ตํ•˜๊ณ ์ž ํ•˜์˜€๋‹ค. ์š”์ถ” ํ›„๊ด€์ ˆ ์ฆํ›„๊ตฐ์œผ๋กœ ์ง„๋‹จ ๋ฐ›์€ ์ถ•๊ตฌ ์„ ์ˆ˜ 39๋ช…์„ ์—ฐ๊ตฌ ๋Œ€์ƒ์œผ๋กœ ํ•˜์˜€๊ณ , ๋Œ€์กฐ๊ตฐ์€ ์š”ํ†ต์„ ๊ฐ€์ง€์ง€ ์•Š์€ ์ถ•๊ตฌ ์„ ์ˆ˜ 18๋ช…์œผ๋กœ ํ•˜์˜€๋‹ค. ์ด๋“ค์„ ๋Œ€์ƒ์œผ๋กœ ์ƒ์ฒด ์—ญํ•™์  ๋ถ„์„์„ ์‹œํ–‰ํ•˜์˜€๋Š”๋ฐ ๊ณจ๋ฐ˜๋ถ€ ์ธก์ • ํ•ญ๋ชฉ ์„  ์ž์„ธ์—์„œ์˜ ๊ณจ๋ฐ˜์˜ ์ขŒ์šฐ ๋†’์ด์ฐจ๊ฐ€ ์žˆ์—ˆ๊ณ  ๋ฐœ/๋ฐœ๋ชฉ์˜ ์ธก์ • ํ•ญ๋ชฉ์€ ๊ธฐ๋ฆฝ์‹œ ์ข…๊ณจ๊ฐ ์ด์—ˆ๋‹ค. ์—ฐ๊ตฌ ๊ฒฐ๊ณผ, ๊ณจ๋ฐ˜ ์ขŒ์šฐ ๋†’์ด์˜ ๋น„๋Œ€์นญ(๊ธฐ๋ฆฝ ์ž์„ธ์—์„œ ์ขŒ์ธก์— ๋น„ํ•ด ์šฐ์ธก ๊ณจ๋ฐ˜์ด ๋‚ฎ์Œ), ๊ธฐ๋ฆฝ์‹œ ์ข…๊ณจ๊ฐ์˜ ๋น„๋Œ€์นญ(์šฐ์ธก ์ข…๊ณจ ๋‚ด๋ฐ˜๊ฐ ์ฆ๊ฐ€, ์‹ฌํ•œ ์ขŒ/์šฐ์ธก ์ข…๊ณจ๊ฐ ์ฐจ์ด)์†Œ๊ฒฌ์ด ๋ฐœ๊ฒฌ๋˜์—ˆ๋‹ค. ๋ณธ ์—ฐ๊ตฌ๋ฅผ ํ†ตํ•ด, ์š”์ถ” ํ›„๊ด€์ ˆ ์ฆํ›„๊ตฐ์„ ๊ฐ€์ง„ ์„ ์ˆ˜๋“ค์€ ๊ณจ๋ฐ˜๊ณผ ํ•˜์ง€์˜ ์ƒ์ฒด์—ญํ•™์  ์ด์ƒ(๋ถ€์ •๋ ฌ) ์†Œ๊ฒฌ์„ ๊ฐ€์ง€๊ณ  ์žˆ์Œ์ด ๋ฐํ˜€์กŒ๊ณ , ํ–ฅํ›„ ์ด๋“ค์„ ๊ต์ •ํ•˜๋Š” ๊ฒƒ์ด ์š”์ถ” ํ›„๊ด€์ ˆ ์ฆํ›„๊ตฐ ์น˜๋ฃŒ์— ๋„์›€์ด ๋  ๊ฒƒ์œผ๋กœ ์‚ฌ๋ฃŒ๋œ๋‹ค. [์˜๋ฌธ]Objective: To investigate and compare biomechanical characteristics in Korean soccer players diagnosed with lumbar facet joint syndrome with those in healthy Korean soccer players./Methods: We recruited thirty-nine Korean soccer players with lumbar facet syndrome that was confirmed by facet block and eighteen players without ailments. We performed biomechanical assessments in pelvis and lower extremities to all subjects. The following parameters were measured; pelvic level (obliquity angle) and resting calcaneal stance position. Results: The followings showed parameters with statistical differences between two groups in which the first set of values identifies facet joint syndrome group and the second set, the control: elevated pelvic level at left side(2.2ยฑ1.6; 0.6ยฑ0.9) and increased right calcaneal varus angle (2.8ยฑ4.0; -0.5ยฑ2.6). Conclusion: The asymmetry of pelvis and foot/ankle state in the facet joint syndrome group was identified and could be conclusively considered as one of the major causes of lumbar facet joint syndrome.ope

    (A) clinical study of high dose methotrexate, 5-fluorouracil and adriamycin combination chemotherapy in advanced stomach cancer

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    ์˜ํ•™๊ณผ/์„์‚ฌ[ํ•œ๊ธ€] ์—ฝ์‚ฐ๊ธธํ•ญ์ œ์ธ methotrexate (MTX)๋Š” ์ด์ˆ˜์†Œํ™” ์—ผ์‚ฐ ํ™˜์›์š”์†Œ๋ฅผ ์–ต์ œํ•˜์—ฌ ํ•ญ์•”ํšจ๊ณผ๋ฅผ ๋‚˜ํƒ€๋‚ด๋Š”๋ฐ 30mg/m**2์˜ ํ†ต์ƒ ์šฉ๋Ÿ‰์˜ ์น˜๋ฃŒ๋ฒ•์—์„œ ๋ฐœ์ „๋˜์–ด ๊ณ ์šฉ๋Ÿ‰(1-10g/m**2)์„ citrovorum factor(CF)์™€ ๋ณ‘์šฉํˆฌ์—ฌํ•˜์—ฌ ๊ณจ์œก์ข…, ์•…์„ฑ์ž„ํŒŒ์ข…, ๋‘๊ฒฝ๋ถ€์ข…์–‘ ๋“ฑ์—์„œ ๋†’์€ ๋ฐ˜์‘์œจ์„ ๋‚˜ํƒ€๋‚ด๊ณ  ๋ถ€์ž‘์šฉ์„ ์ค„์ผ ์ˆ˜ ์žˆ๋‹ค๊ณ  ์•Œ๋ ค์ ธ ์žˆ๋‹ค. ์ตœ๊ทผ Klein ๋“ฑ์€ ์ง„ํ–‰ ์œ„์•”์—์„œ high dose MTX (HDMT7)์™€ 5-FU๋ฅผ ์ฃผ์ถ•์œผ๋กœ ํ•˜๋Š” ๋ณตํ•ฉ ํ™”ํ•™์š”๋ฒ•์ด ๋†’์€ ๋ฐ˜์‘์œจ(63%)์„ ์–ป์„์ˆ˜ ์žˆ๋‹ค๊ณ  ๋ณด๊ณ ํ•œ๋ฐ”์žˆ๋‹ค. ์šฐ๋ฆฌ๋‚˜๋ผ์—์„œ ๊ฐ€์žฅ ํ”ํ•œ ์•”์ธ ์œ„์•”์—๋Š” 5-fluorouracil(5-FU), adriamycin(ADR), mitomycin-C ๋ณตํ•ฉ ํ™”ํ•™์š”๋ฒ•(FAM)์ด ์ฃผ๋กœ ์‹œํ–‰๋˜๊ณ  ์žˆ๋‹ค. ๊ทธ๋Ÿฌ๋‚˜ ์šฐ๋ฆฌ๋‚˜๋ผ์—์„œ๋Š” ์•„์ง HDMTX ์น˜๋ฃŒ์„ฑ์ ์— ๋Œ€ํ•œ ๋ณด๊ณ  ๋ฐ ์•ฝ๋™ํ•™์ ์—ฐ๊ตฌ๊ฐ€ ์—†์–ด ๋ณธ ์—ฐ๊ตฌ์ž๋Š” ์ง„ํ–‰ ์œ„์•” ํ™˜์ž์—์„œ HDMTXํˆฌ์—ฌ ์— ๋”ฐ๋ฅธ ํ˜ˆ์—ญ๋™ํ•™์  ์—ฐ๊ตฌ์™€ HDMTX, 5-FU ๋ฐ ADR์˜ ๋ณตํ•ฉ ํ™”ํ•™์š”๋ฒ•์˜ ํ•ญ์•”ํšจ๊ณผ, ๋…์„ฑ ์ •๋„๋ฅผ ์•Œ๊ธฐ ์œ„ํ•ด 1986๋…„ 1์›”๋ถ€ํ„ฐ 1986๋…„ 12์›”๊นŒ์ง€ ์—ฐ์„ธ๋Œ€ํ•™๊ต ์˜๊ณผ๋Œ€ํ•™ ๋ถ€์† ์—ฐ์„ธ์˜๋ฃŒ์› ๋ฐ ์—ฐ์„ธ์•”์„ผํ„ฐ์— ์ž…์›๋˜๊ณ  ์กฐ์ง๋ณ‘๋ฆฌํ•™์ ์œผ๋กœ ํ™•์ง„๋œ ์ง„ํ–‰ ์œ„์•” ํ™˜์ž 18์˜ˆ๋ฅผ ๋Œ€์ƒ์œผ๋กœ ๊ด€์ฐฐํ•˜ ์—ฌ ๋‹ค์Œ๊ณผ ๊ฐ™์€ ๊ฒฐ๊ณผ๋ฅผ ์–ป์—ˆ๋‹ค. 1) MTX 1.5 g/m**2 ํˆฌ์—ฌํ›„ MTX์˜ ํ˜ˆ์ค‘ ๋†๋„๋Š” ํˆฌ์—ฌ ์ข…๋ฃŒ 30๋ถ„ํ›„ 7.17 x 10**-5 ยฑ 3.62. x 10**-5 M(meanยฑS.D), 6์‹œ๊ฐ„ํ›„ 1.38 x 10**-5 ยฑ 0.75 x 10**-5 M, 12์‹œ๊ฐ„ํ›„ 3.71 x 10**-6 ยฑ 2.23 x 10**-6 M, 24์‹œ๊ฐ„ํ›„ 9.30 x 10**-7 ยฑ 1.12 ใ…Œ 10**-7 M, 48์‹œ๊ฐ„ํ›„ 1.9 9 x 10**-7 ยฑ 1.70 x 10**-7 M, ๊ทธ๋ฆฌ๊ณ  72์‹œ๊ฐ„ํ›„์—๋Š” 1.27 x 10**-7 ยฑ 1.25 x 10**-7 M๋กœ ์‹œ๊ฐ„๊ฒฝ๊ณผ์— ๋”ฐ๋ผ ๊ฐ์†Œํ•˜์˜€๋‹ค. ํˆฌ์—ฌ ์ข…๋ฃŒ 48์‹œ๊ฐ„์งธ 1 x 10**-7 M ์ดํ•˜์ธ ๊ฒฝ์šฐ๋Š” 50%์˜€๊ณ  72์‹œ๊ฐ„์งธ 1 x 10**-7 M ์ดํ•˜์ธ ๊ฒฝ์šฐ๋Š” 66.6%์˜€๋‹ค. 2) HDMTX, 5-FU ๋ฐ ADR ๋ณตํ•ฉ ํ™”ํ•™์š”๋ฒ•ํ›„์˜ ๋ฐ˜์‘์œจ์€ ํ™”ํ•™์š”๋ฒ•์„ ํˆฌ์—ฌ๋ฐ›์€ ๊ธฐ์™•๋ ฅ์ด ์žˆ๋Š” ํ™˜์ž๋Š” 11๋ช… ์ค‘ 1์˜ˆ(9.1%), ๋ฐ›์€์ ์ด ์—†๋Š” ํ™˜์ž 7๋ช…์ค‘ 1์˜ˆ(14.7%)๋กœ ์ด 18์˜ˆ์˜ ๋Œ€์ƒํ™˜์ž ์ค‘ 2์˜ˆ(11.2%)์—์„œ ๋ถ€๋ถ„๊ด€ํ•ด๋ฅผ ๋ณด์˜€๋‹ค. 3) HDMTXํˆฌ์—ฌ์— ๋”ฐ๋ฅธ ๋ถ€์ž‘์šฉ์€ ์น˜๋ช…์ ์ธ ๋ฐฑํ˜ˆ๊ตฌ๊ฐ์†Œ์ฆ์— ์˜ํ•œ ํŒจํ˜ˆ์ฆ์œผ๋กœ ์‚ฌ๋งํ•œ 1์˜ˆ๊ฐ€ ์žˆ์—ˆ์œผ๋ฉฐ ๊ทธ์™ธ ์˜ค์‹ฌ, ๊ตฌํ† , ๊ตฌ๋‚ด์—ผ, ๋ฐœ์ง„, ์„ค์‚ฌ๋“ฑ์ด ๋™๋ฐ˜๋˜์—ˆ์œผ๋ฉฐ ํ˜ˆ์ค‘ creatinine์˜ ์ƒ์Šน์„ ๋™๋ฐ˜ํ•œ ์˜ˆ๋Š” 1์˜ˆ๋ฟ์ด์—ˆ๋‹ค. ์ด์ƒ์˜ ๊ฒฐ๊ณผ๋กœ ๋ณด์•„ HDMTXํˆฌ์—ฌ์‹œ MTX์˜ ํ˜ˆ์—ญ๋™ํ•™์  ๋ณ€ํ™”๋Š” ์™ธ๊ตญ์˜ ๋ณด๊ณ ์™€ ์œ ์‚ฌํ•˜์˜€์œผ๋ฉฐ, CF๋„ ์ตœ์†Œ์ฐฌ MTXํˆฌ์—ฌ ์ข…๋ฃŒํ›„ 72์‹œ๊ฐ„ ์ด์ƒ ํˆฌ์—ฌํ•ด์•ผ ์•ˆ์ „ํ•œ ๊ฒƒ์„ ์•Œ์ˆ˜ ์žˆ์—ˆ๋‹ค. HDMTX, 5-FU ๋ฐ ADR ๋ณตํ•ฉ ํ™”ํ•™์š”๋ฒ•์˜ ์ง„ํ–‰ ์œ„์•”์— ๋Œ€ํ•œ ๋ฐ˜์‘์œจ์€ ๋งค์šฐ ๋‚ฎ์•˜๋‹ค. ๊ทธ๋Ÿฌ๋‚˜ ๋Œ€์ƒ ์˜ˆ๊ฐ€ ์ ์–ด ์ถ”๊ฐ€์ ์ธ ์—ฐ๊ตฌ ๋ฐ ํ‰๊ฐ€๊ฐ€ ํ•„์š”ํ•˜๋‹ค๊ณ  ์‚ฌ๋ฃŒ๋œ๋‹ค. [์˜๋ฌธ] The folic acid antagonists, methotrexate (MTX), were shown to have antitumor activity due to inhibition of the enzyme, dihydrofolate reductase. In the last two decades, the drug has been administered in conventional doses of 30mg/m**2; however during the last 10 years, very high doses of methotrexate in the range of 1-10g/m**2, coupled with citrovorum factor rescue, has been found to be strikingly more effective for chemotherapy of osteogenic sarcoma, malignant lymphoma, and squamous carcinoma of the head and neck. Klein(1983) reported a high response rate(63%) by MTX and 5-FU combination chemotherapy in cases with advanced stomach cancer. In Korea, the incidence of stomach cancer is higher than other tumors, and the usual chemotherapy program for advanced stomach cancer is a 5-fluorouracil, adriamycin and mitomycin-C combination regimen(FAM) ; but there is no pharmacokinetic study or clinical application of MTX. This paper presents a pharmacokinetic and clinical study of 18 cases with advanced stomach cancer, admitted from Jan. 1986 to Dec. 1986. The resells were as follows: 1) After intravenous infusion of MTX 1.5gm/m**2, the plasma MTX level were recorded as follows: At 30 min after discontinuation of MTX infusion, plasma MTX level was 7.17 x 10**-5 ยฑ 3.63 x 10**-5 M. At 6 hours, it was 1.38 x 10**-5 ยฑ 0.75 x 10**-5 M; at 12 hours, 3.71 x 10**-6 ยฑ 2.23 x 10**-6 M ; at 24 hours, 9.30 x 10**-7 ยฑ 1.02 x 10**-7 M ; at 48 hours, 1.99 x 10**-7 ยฑ 1.70 x 10**-7 M; and at 72 hours, 1.27 x 10**-7 ยฑ 1.25 x 10**-7 M. Forty-eight hours after discontining the drug, the plasma level of MTX fell below 1 x 10**-7 M in half of the cases. After 72 hours, 66.6% of the caes fell below the 1 x 10**-7 M level. 2) The response rate for the HDMTX, 5-FU and ADR combination chemotherapy was 11.2% in all cases. One case(9.1%) out of 11 cases with previous chemotherapy, showed a partial response; also, out of 7 case without previous chemotherapy, one case(14.2%) showed a partial response. 3) Toxicities with high dose MTX were : pancytopenia(1 case), nausea and vomiting(14 cases), stomatitis(8 cases), skin rash(2 cases) and diarrhea(2 cases). In our study the patient with pancytopenia died due to sepsis. There was only one case with an elevated creatinine level. In summary, the results of this study for pharmacokinetic changes of that MTX were similar to other reports. However, over 72 hours after discontinuation of high dose MTX and 5-FU combination chemotherapy, the risk of toxicity is reduced by the administration of CF. The response rates of HDMTX, 5-FU and ADR combination chemotherapy were low; therefore further studies should be done to elucidate a more exact response rate.restrictio
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