五倍子酸誘發大細胞肺癌細胞株NCI-H460凋亡之機轉研究; The mechanism(s) of gallic acid-induced apoptosis in large cell carcinoma (NCI-H460)

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(1)! τ ୦ ᙫ!ᛧ ά Ꮩ ᖆ㣊ᙫᏙ࣫‫܃ة‬ ᅱΪᏙՆፌЅ ύ।ήᇿᇟพάಉऔ‫ޛ‬ᕅಉऔਪ NCI-H460 উ΢χᐉᙦ࣫‫ة‬ The mechanism(s) of gallic acid-induced apoptosis in large cell carcinoma (NCI-H460). ࡧ Ꮫ ௩ ௛ Ǳৡ ݊ ፬ ௩ ௛ ҼӌࡧᏛ௩௛Ǳᗒ ඪ ҷ ௩ ௛. ࣫ ‫ ة‬ҊǱࣾ ࢹ ለ. τ๥Ѿ୦·Γ΅Ӻ΅Ћ.

(2) ग!ᖫ! ! ਋ҷ૕णǫΉӺ‫ވ‬ᅱΪਜ਼Ꮩཧղஉւ΂࢛ဌǫᖆ㣊ᙫᏙ࣫‫ވ܃ة‬Ꮩಕᙝ൛ Έ‫ב‬୮ᘬᆭᖆ㣊ᙫᏙ‫ތވ‬ᛴǫቭᗘΈԵθҊࢩΙ‫ވ‬ም୨ǫᡚ‫ވב‬ՀᙫҊనபЧ ‫ת‬кбძԭౘऄǭ! !!!!ፌЅ‫ְވ‬Ԃǫय़Һव༹ᖫৡ݊፬௩௛ǫσ༥ఌ‫ވב‬౸‫ܖ‬ԭᜢ༷Ᏻұ‫ࡧވב‬ Ꮫԫ৚ǰЧϮᗒඪҷ௩௛ǫӞ‫ב‬༴൳෻ծ਋Ϯ਋Փз඙Ђǫᜢ༷ࡧᏛ‫޺ב‬නσ Ԃዌ‫ة࣫ވ‬Ϯඓ٥ძᡄ‫ו‬ೃΙ‫ވ‬Є඙ǭԓѝǫ༹ᖫᖆ㣊ᙫᏙ࣫‫ܼ!܃ة‬థయ‫܃‬ ߆ǫᗟ෼‫߆܃‬є௩‫΂ב‬ӺȟᙾᇕፌЅ૯ፌȠ‫ވ‬ፇสǫ߼ᡚ‫ב‬ᡆཥ‫΂ࢸفڀ‬Նᙫ ᏙτϿ‫ވ‬ᖆ㣊ᙫ৚ǫᓿ့σ॒ም୨ǫ਋਋бძᏙೃ‫ތ‬ᛴǫٗѦ֥‫ވ‬உᙫ৚ᆭԫ ৚‫ظވ‬ԼӔԭࢸ΂ǭәࢸ၎፝ᎥໃǫЧगመԫ৚ॱޯປ‫ת‬Ӥ਋໋ᆭᆉઊ٧௩ Ꮫǰ༹ᖫᅱΪਜ਼ӌᏙງຊǬ۱ដᆭಧ๥ᙫ৚Ӟ࣫‫ة‬Ι‫ࣣވ‬ό௫พǫ‫ࡹۿ‬Ҋࢩᗱ ᄷΙ‫ۭވ‬ԓ᜙Ͽǫᆭ፵਋ඓ٥Եθᝁຝ‫ط༷ވ‬ǭ! әࢸӞᙄ‫ވ‬᜙ߦǫ໡Ӟԓ੔ը༹ᐖჽϦ୮࿅௩ᙫଚᆭ઼๑ܼࣴታ໙Уұǫ ӌ༷‫ב‬೤‫ٶ‬Ӻ٧‫ވ‬Ӟᙄີॼǰ઼๑ࣴһᡆӌϏǫӞ‫ॼב‬ཧ਋ᜢ༷ϠᏳ‫ב‬ᖆ㣊Ι ‫ވ‬ηՙǫ੔ըህ༹ӞϿǭ! ടࡌǫ༹ᖫᑺ༻‫ވ‬ԫ୾‫ވ‬ЄࡤᆭႫᓧǫᖫᖫYoYoᆭMoMoӞ೤࢛਋໋೶ࡇ ٘ǭࣣߕ؉ԍ՚ॱǫ೤ዾፌЅᆭᏙཧ෻‫ݛ‬໠ժְԂǭ! ᙚЧԓዾፌЅᝏๆ‫܃‬ԍ᜙Ͽ‫ވב‬ΊǫٗᝏΙട૞ဿ‫ވ‬ઋᅴǭ! ! !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!ࣾࢹለ!!ᙚग‫!ܤ‬ !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!τ୦ᙫᛧάᏙ!ᖆ㣊ᙫᏙ࣫‫!܃ة‬ !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!τ๥Ѿ୦·Γ΅ӺϛЋΓЉ!. 0.

(3) ҕᒬ ज़Ԓ गᖫ. 0. ҕᒬ. 1. ა޻ҕԒ. 3. ౻ဝᆭᕤቡ. 6. τЅᄋव. 7. थЅᄋव. 9. ౺΂ഌ ߲‫ع‬. 11. ౺΂࿦ ࣫‫ة‬ऐඪ. 11. ౺Ή࿦ ࣫‫ة‬ҕ‫ވ‬. 42. ౺Ήഌ ࣫‫ة‬Ј‫ݛ‬. 44. ౺΂࿦ ࣫‫׮ة‬ਈ. 44. ౺Ή࿦ ࣫‫ة‬೒ष. 49. ౺Ζ࿦ ಄षЈ‫ݛ‬. 65. ౺Ζഌ ࣫‫ة‬฿ܷ. 66. ౺΂࿦ ύ।ήᇿჰΊᜡάಉऔ‫ޛ‬ᕅಉऔਪ‫ވ‬ቑҊ‫ڂפ‬ᆭಉऔࠗ 66. ᄁ‫צ‬ᠹ ౺Ή࿦ ύ।ήᇿӞΊᜡάಉऔ‫ޛ‬ᕅಉऔਪჰಉऔຳන (cell. 66. cycle)‫ވ‬ተ៓ ౺Ζ࿦ ᔗ෪ύ।ήᇿӞΊᜡάಉऔ‫ޛ‬ᕅಉऔਪࡹոౙҊࢩ‫ۻ‬ਲ਼ Ϧ‫(ݹ‬Reactive oxygen species). 67. ౺ћ࿦ ύ।ήᇿჰΊᜡάಉऔ‫ޛ‬ᕅಉऔጙ႔Ն (Mitochondrialmembrane potential)‫ވ‬ተ៓. 67. ౺ύ࿦ ύ।ήᇿჰΊᜡάಉऔ‫ޛ‬ᕅಉऔχເᙽήកзተ៓. 68. 1.

(4) ౺ϛ࿦ ժҋቴࡺ္ᡄ(Comet assay)ᡷჯύ।ήᇿჰΊᜡάಉऔ 68. ‫ޛ‬ᕅಉऔχ DNA ໵ৄสࡂ ౺΅࿦ ժҋDAPIࢀԼᡷჯύ।ήᇿჰΊᜡάಉऔ‫ޛ‬ᕅಉऔχಉ. 69. औউ΢ ౺΍࿦ ժҋࢣӻಉऔሱᔗ෪ύ।ήᇿჰάಉऔ‫ޛ‬ᕅಉऔχಉऔ উ΢ࣣ᜙ಿҒ፝Caspase-3ǬCaspase-8ϮCaspase-9. 70. ౺·࿦ ժҋՂЈᎷᗱ‫ݛ‬ᔗ෪ύ।ήᇿӞΊᜡάಉऔ‫ޛ‬ᕅಉऔτ ჰ caspase ಿҒᆭಉऔউ΢ፊொಿҒ޻౓ຽ‫ވ‬ተ៓. 70. ౺ћഌ ૯ፌ. 73. ౺ύഌ ฿ፌᆭࡃᝳ. 78. ୍ԬЅᝏ. 79. !. 2.

(5) ა޻ҕԒ! ज़Ԓ ა 1.1. ᛜГᡭጜЌΙ‫ظވ‬।ᜡᙔ㓆ȇύ।ήȈ. 15. ა 1.2. ᛧ‫׮‬ύ।ή)‫ر‬।Ȉ. 15. ა 1.3. ഹშᇿχ฿ᄣӻ. 16. ა 1.4. ύ।ήᇿχ฿ᄣӻ. 17. ა 1.5. ಉऔউ΢ၘৠ. 32. ა 2.1. ύ।ήᇿ gallic acid ჰΊᜡάಉऔ‫ޛ‬ᕅ NCI-H460 ಉऔӯ ࢩ౎ϮᇟᏛಉউ΢‫ڠ‬ಉऔຳනଭᅀძᡄࢅᄣ. 50. ა 2.2. MMP ೣᡆ‫ވ‬Ϡ݂ა. 56. ა 2.3. ROS ೣᡆϠ݂ა. 58. ა 2.4. ເᙽήೣᡆϠ݂ა. 60. ა 2.5. Caspase-3 ೣᡆϠ݂ა. 61. ა 3.1. σӌᐑࡂχύ।ήᇿ gallic acid ಷ౒ NCI-H460 ಉऔ 24 β 87. ਋ӯࢩ౎ ა 3.2. σӌᐑࡂχύ।ήᇿ gallic acid ಷ౒ NCI-H460 ಉऔ 48 β ਋ӯࢩ౎. 87. ა 3.3. ժҋ॰ҜӻࣣՆ৘ᡀ༵ᜋᡷჯಉऔ‫ࠗވ‬ᄁ. 88. ა 3.4. σӌᐑࡂχύ।ήᇿ gallicaicd ჰ NCI-H460 ಉऔಉऔຳන 90. Ϡՠተ៓-12 β਋ ა 3.5. σӌᐑࡂχύ।ήᇿ gallicaicd ჰ NCI-H460 ಉऔಉऔຳන 92. Ϡՠተ៓-48 β਋ 3.

(6) ა 3.6. ժҋࢣӻಉऔषኞሱຈՎΊᜡάಉऔ‫ޛ‬ᕅಉऔ࿭Ҏๆω 250ǋM χύ।ήᇿӞσӌ਋໋‫܃‬೮Ԃ ROS ౙҊ‫ވ‬ተ៓. ა 3.7. Ίᜡάಉऔ‫ޛ‬ᕅಉऔ࿭Ҏๆωᐑࡂ 250ǋM χύ।ήᇿ‫܃‬ ೮Ԃ౿ဆᡆጙ႔ՆȇƩƺmȈᠹ୆χຽϦა. ა 3.8. 98. ࿭Ҏσӌᐑࡂ‫ވ‬ύ।ήᇿಷ౒Ίᜡάಉऔ‫ޛ‬ᕅಉ 48 β਋ ࡌǫЧቴࡺ္ᡄϠ݂‫ٸ‬ჰಉऔ DNA ໵ৄ‫ވ‬สࡂ. ა 3.10. 96. Ίᜡάಉऔ‫ޛ‬ᕅಉऔ࿭Ҏๆωᐑࡂ 250ǋM χύ।ήᇿ‫܃‬ ೮ԂເᙽήᐑࡂΙϩ‫ވ‬ຽϦა. ა 3.9. 94. 99. σӌᐑࡂ‫ވ‬ύ।ήᇿಷ౒Ίᜡάಉऔ‫ޛ‬ᕅ NCI-H460 ಉऔ 24 β਋ࡌ DAPI ࢀԼᡷჯ. 100. ა 3.11. ύ।ήᇿჰჰΊᜡάಉऔ‫ޛ‬ᕅಉऔ caspase-3 ࢩ‫ۻ‬χተ៓. 101. ა 3.12. ύ।ήᇿჰჰΊᜡάಉऔ‫ޛ‬ᕅಉऔ caspase-8 ࢩ‫ۻ‬χተ៓. 103. ა 3.13. ύ।ήᇿჰჰΊᜡάಉऔ‫ޛ‬ᕅಉऔ caspase-9 ࢩ‫ۻ‬χተ៓. 104. ა3.14. ժҋՂЈᎷᗱ‫ݛ‬ᡷჯᆭ apoptosis ԍ᜙‫ ވ‬FasǬFas-LǬFADD 105. ‫ވ‬ಿҒ޻౓ຽᠹϦ ა3.15. ժҋՂЈᎷᗱ‫ݛ‬ᡷჯᆭ apoptosis ԍ᜙‫ ވ‬cytochrome cǬ AIFǬApaf-1 Ϯ caspase-9 ‫ވ‬ಿҒ޻౓ຽᠹϦ. ა3.16. ժҋՂЈᎷᗱ‫ݛ‬ᡷჯᆭapoptosisԍ᜙‫ވ‬GADD153ǬGRP78 4. 105.

(7) ಿҒ޻౓ຽᠹϦ. ა3.17. 106. ժҋՂЈᎷᗱ‫ݛ‬ᡷჯᆭ apoptosis ԍ᜙‫ވ‬ caspase family ಿҒ޻౓ຽᠹϦ. ა 3.18. ժҋՂЈᎷᗱ‫ݛ‬ᡷჯᆭ apoptosis ԍ᜙‫ ވ‬Bcl-2 family ಿҒ 107. ޻౓ຽᠹϦ ა 3.19. ޻ 1.1. 106. ύ।ήᇿᇟᏛΊᜡάಉऔ‫ޛ‬ᕅ NCI-H460 ಉऔਪಉऔຳන ଭᅀϮಉऔউ΢χၘৠა. 108. ፊொಉऔຳනχຳනಿҒϮ‫ٸ‬ᐖ䁐. 20. ޻ 1.2 !! ಉऔউ΢ᆭಉऔᚦԔχୋը. 23. ޻ 1.3. ѝӞೳৠχԔ΢‫ڐ‬ᡆȇdeath receptorsȈ. 26. ޻ 2.1. ύ।ήᇿχ଒ᇐ. 51. 5.

(8) ౻ဝᆭᕤቡ! AIF: apoptosis inducing factor Apo2L: apoptosis-inducing ligand 2 APAF1: apoptotic peptidase activating factor 1 BAD: BCL2-antagonist of cell death BAX: BCL2-associated X protein BCL2: B-cell chronic lymphocytic leukemia/lymphoma 2 BCLXL: (BCL2L1)BCL2-like 1 BID: BH3 interacting domain death agonist CAD: (DFFB)DNA fragmentation factor, 40kDa, beta polypeptide CHOP: C/EBP homologous protein GADD153: growth arrest and DNA damage-inducible gene 153 DAXX: Death-associated protein 6 DIABLO: direct inhibitor of apoptosis protein DISC: death-inducing signal complex FADD: Fas (TNFRSF6)-associated via death domain FAS: CD95 FAF1: Fas (TNFRSF6) associated factor 1 FLIP: FLICE (FADD-like interleukin 1́-converting enzyme) inhibitory protein GRP78: glucose regulated protein 78 IAP: inhibitor of apoptosis PUMA, p53-upregulated modulator of apoptosis Smac: second-mitochondria-derivated activator of carspase TRAIL: tumor necrosis factor-related apoptosis-inducing ligand. 6.

(9) τЅᄋव ᕅ੨΂‫޿ࡹދ‬ΓӺ୦ΊΓάԔә‫ވ‬౺΂ՆǫҎ‫ܤ‬ᕅಉऔ‫ވ‬ଦࣸᠹ‫ۻ‬ǬԿᅼ ཛྷҊ੔‫ۻ‬ᆭଦᙦ౴‫ۻ‬ǫ٣பᕅ੨‫ٷ‬ԍࣣྴ᜛‫ވ‬ౢᘧ‫ۻ‬ǫΟәԓ೑Ӥᕅ੨ࣣ᜙‫ވ‬ ࣫‫֘ޚة‬ᐿཬൟ‫תכ‬ԍਆС‫ת‬ӳһ‫דވ‬ᕅᛧ‫ݹ‬ǭϕϱǫ΂ॸӞ‫ܦ‬Љೆᇘࢸ‫ٷ‬ԍ τࡂगᕅ‫ވۻ‬ϦӔ‫ݹ‬-ύ।ήᇿǫ೯ၯΈ΂ٛ࣫‫ة‬ᡀҙ‫ٸ‬шિࢸ΂ॸ‫ٷ‬ԍ኿Α ‫דވ‬ᕅᛧ‫ݹ‬ǫѣшЧᏛगΊᜡ‫ޛ‬ဆᕅಉऔ‫ވ‬Ԕ΢ǫ՗Զϕ‫ۏ‬෻࣫‫ة‬உύ।ήᇿ (gallic acid)ᓿҋ‫ܤ‬άಉऔ‫ޛ‬ᕅ(large cell carcinoma)‫ة࣫ވ‬ΙǫԭС‫דٸ‬ᕅࢩ ‫ވۻ‬ᐉᙦΟ‫ۏ‬ѹೆథཨ‫ވ‬ോᏛၯǭ Ѹዾ࣫‫ࢸة‬ժҋϱ෼ස‫ݹ‬τ‫ވ‬ύ।ήᇿಷ౒Ίᜡάಉऔ‫ޛ‬ᕅ NCI-H460 ಉ औਪ‫ވ‬ՙҋᐉᙦǭЧࢣӻಉऔषኞሱ٧ଷ෪ಉऔ‫ވ‬ӯࢩ౎ǫพ౓ᒶ๨ᛧ‫ݹ‬ᐑࡂ ‫ވ‬Ιϩ‫ڠ‬кᛧ਋໋‫߆ۦވ‬ǫያძཥ‫ڂפ‬ಉऔӯࢩ౎ǭЧ॰ҜӻՆࣣ৘ᡀ༵ᜋ٧ ᡷჯಉऔࠗᄁΙ‫צވ‬ᠹǫ฿ܷพ౓ԍಉऔࠗᄁσְᏵǬಉऔጙዢᕤǬᆭ‫ݧޓ‬Ϧ ‫౓ވ‬ດǭЧࢣӻಉऔषኞሱ٧ଷ෪ಉऔຳනǫพ౓Ӟ G0/G1 න‫ވ‬ಉऔБ٦Ιϩǫ ࡱύ।ήᇿཥ೮Ԃಉऔຳන‫ ވ‬G0/G1 න‫ވ‬ଭЎǫٗԍಉऔউ΢(apoptosis)‫౓ވ‬ ດౙҊǭЧࢣӻಉऔषኞሱ٧ଷ෪౿ጌᡆጙ႔Ն(mitochondrial membrane potential)ǫพ౓౿ጌᡆጙ႔ՆΗॕǫࡱ௙෪ύ।ήᇿཥᇟพಉऔጙϵၧ‫ވ‬ѱ ້ǫԭᏛग౿ጌᡆጙ႔ՆΗॕǭЧࢣӻಉऔषኞሱ٧ଷ෪ເᙽή(Ca2+)ᐑࡂǫ พ౓ເᙽήᐑࡂϩଦǫࡱ௙෪ύ।ήᇿཥ࿭Ҏ౿ጌᡆកзເᙽήີΌϚጙǫ೮ ԂເᙽήᐑࡂϩଦǭЧቴࡺ္ᡄଷ෪ಉऔ‫ ވ‬DNA ཕ໵(damage)ǫพ౓Ӟଦᐑ ࡂύ।ήᇿಷ౒ࡌǫ೮Ԃಉऔ‫ވַܝ‬Б٦ടࢸ‫ܫ‬ᡀǫ޻ҙԍ DNA ཕ໵‫౓ވ‬ດǭ ԭࡌЧՂЈᎷᗱ‫(ݛ‬Westernblotting)٧ଷ෪ಿҒ޻౓ຽ‫צވ‬ᠹǫพ౓ FasǬ Fas-LǬcaspase-3ǬBaxǬCytochrome c ಿҒ޻౓ຽቑкǫԭ Bcl-2ǬBcl-xlǬ ಿҒ޻౓ຽෞ϶ǭ ᆌӔЧΙ฿ܷพ౓ǱЧύ।ήᇿಷ౒Ίᜡάಉऔ‫ޛ‬ᕅ NCI-H460 ಉऔǫཥ 7.

(10) Ꮫग DNA ཕ໵ǫີԭࢩϦ p53ǫີԭ٣ಉऔଭЎӞ G0/G1 නǭFas ᆭ Fas-L ᗍ ฿ǫٗࢩϦΗ෕‫ ވ‬caspase-8Ǭcaspase-3ǫᇟพಉऔউ΢ǭ౿ጌᡆϚ‫ ވ‬Bcl-2 ৅௳ಿҒෞ϶ǫм࡫ Bcl-2 ᆭ Bcl-xlǫٗ‫ٿ‬ᐖ౿ጌᡆ Bax ቑкǫԓ਋ಉऔϚ፝ ᆒཥកзເᙽήǫٗ೮Ԃ౿ጌᡆጙ႔ՆΗॕǫԭ౿ጌᡆҤཥកз cytochrome cǫٗࢩϦΗ෕‫ ވ‬caspase-9Ǭcaspase-3ǫ೮Ԃ DNA ຂဵǫട಍೮ԂಉऔԔ΢ǫ ີԭ‫ڂפ‬άಉऔ‫ޛ‬ᕅಉऔ‫ވ‬ӯࢩ౎ǭ. 8.

(11) Abstract Cancer is the leading cause of death for decades in Taiwan. Due to the genomic instability, cancer cells acquire many malignant characteristics including high growth ability, high metastatic property and inducement of angiogenesis, which may lead to the poor cure of cancer. As a result, more and more investigators are trying to discover anti-cancer drugs with high effective and low toxicity. Today, a compound called gallic acid is found to exhibit anti-cancer activity. It can induce human lung adenocarcinoma cells apoptosis. However, gallic acid is not applied to the study of large cell carcinoma yet and its molecular mechanism(s) of anti-cancer effect is also not well-investigated. In this study, we have addressed the cytostatic and apoptosis effects of gallic aicd on human large cell carcinoma cell lines (NCI-H460). Treatment of NCI-H460 cells with gallic aicd resulted in the inhibition of cell proliferation , arrest of cell cycle in G0/G1 phase and commitment to apoptosis. Inhibition of cell proliferation was examined by flow cytometry. The inhibition effect is dose-dependent manner. The effects on cell cycle phases were determined at 50-300 ǋM of gallic aicd using flow cytometry detected by morphological cell changes, sub-G1 peak occurrence. Gallic aicd also induced the levels of Ca2+ concentration and decreased the levels of mitochondria membrane potential in NCI-H460 cells. The DNA damage of NCI-H460 cells indeuced by gallic aicd was observed by Comet assay. The results also demonstrated that gallic acid up-regulate the expression of apoptotic factors FasΕFas-L andʳcytodhrome c. The active form of apoptosis key enzyme caspase-3 was increased and the apoptosis inhibitors Bcl-2 and Bcl-xl were down-regulated.The apoptosis inducer Bax were up-regulated. Overall, we proved gallic acid induced cell cycle arrest and apoptosis in 9.

(12) human large cell carcinoma cells in our study. This suggest a plausible utilization of this compound as an anti-proliferative agent in cancer therapy.. 10.

(13) ౺΂ഌ. ߲‫ع‬. ౺΂࿦ ࣫‫ة‬ऐඪ ‫ޛ‬ᕅ΂૊ࡧ‫ޛࡹވ‬ძ፝೴‫ވ‬ᕅ੨ǫ೦஛σм֍‫ٸ‬ЫӬԲጙ૽྄‫ވ‬τऍቢင ዝȇmesotheliomaȈǫ‫ٸޚۿ‬Ы൵‫ۻ‬ငዝӬᜡᕅȇcarcinoidȈǬ൵‫ۻ‬ధϺዝ ȇmalignant lymphomaȈǫ‫ࡹۿ‬ᙦ౴Ե‫ٸ‬Ы٧྄‫ވ‬ငዝǭәԓЧΗ‫܃ॱב‬ᇜ ‫ޛވ‬ᕅ,ࡹࡧ٧Ե‫ܤ‬ЄਲᅼȇbronchialȈ‫ۿ‬ಉЄਲᅼȇbronchiolarȈ޻ғಉऔ ȇepithelial cellȈ‫ވ‬൵‫ۻ‬ငዝǫՕΈ‫ޛ‬ძ፝൵‫ۻ‬ငዝ‫ ވ‬90-95%!)Merck Manual Professional Edition*ǭ‫ד‬ᕅᛧ‫ݹ‬ჰߑβಉऔ‫ޛ‬ᕅਆܷσ୳Ӫȇ஛ҋ‫דވ‬ᕅᛧ‫ݹ‬ ЧഹᏁ‫ݦ‬ᕄჰβಉऔᆭߑβಉऔ‫ޛ‬ᕅ‫ވ‬ϯᓿ౎ԍ΂।ЧΙ‫ވ‬৘ౝǫమӔ٣ҋ‫ވ‬ ᕄਆ‫ࣣת‬৘ၩћ।χӤȈǫҽкΙ‫ד‬ᕅᛧ‫ݹ‬ԍ‫ڂפ‬೮ԿлિȇӬࣽǬҒԿ౑Ϯ Կβܿኞҕॕ՜ǫ೮ԂೝԿǬ༹ࢀϮзԿȈϮཕ໵‫ٸ‬ЫᏋ‫ۋ‬ȇӬ⧂ϿǬჄӎǬ ௕ᎪǬफ़ቼσ৸Ǭ੩१෻ΑǬΨ๑ዄᅣาȈ‫ܫވ‬ᡀୂՙҋǫ᜻ॐ਋࣎ԶཥӉৄ ‫ڀ‬Ҋ‫ވڥ‬ӳһ)Hamilton et al.,2005*ǭҎ‫ܤ‬Ϧᕄਆܷԍ॒ǫΕபШзࣣྴ‫ވ‬Э ሴȇୂՙҋȈǫЧ۪Ԭት‫ڀ‬Ϧᕄ਋σ՗ԍ਋੧Ίᇎ‫ـ‬σ߲ǫ೨ᙫҊΟཥ᝱பΑ σ஬Ͽ)Clegg et ai., 2002*ǭәԓǫ‫כ‬з‫࣫ۿ‬พз΂ᅶિ୳‫ޛڂפ‬ᕅಉऔٗ٣ ‫ٸ‬ԵՀಉऔউ΢ȇapoptosisȈǫСσཥౙҊၯӤୂՙҋ‫ވ‬ᛧ‫ݹ‬ǫࡹѯ෼‫ވ‬ᖶ໿ǫ Οࡹ‫ټ‬σ৉ጎ‫΂ވ‬ໟηสǭ ЧΗൠ‫ޛ‬ᕅǬύ।ήᇿǬಉऔຳනᆭಉऔউ΢ᐉᙦՙऐඪϠ݂ϖಆǱ. ΂Ǭ‫ޛ‬ᕅ ‫ޛ‬ᕅҕ߲ࡹһП࣑ᕅ੨Ԕә‫ވ‬౺΂ӓǫ1995 ӺһП࣑ԍ 60 ࿛ΊԔ‫ޛܤ‬ ᕅǫԭС‫׹‬ӺΊኞ೶ӞΙϩǭЧऄ୦ࢸ٦ǫ2005 ӺԔ‫ޛܤ‬ᕅ‫ވ‬Ίኞँ 163,500ǫ ೤БάကᕅǬٙᕅǬ߲ҿဆᕅΖᅶᕅ੨‫ވ‬Ԕ΢Ίኞᕫ‫ ڠ‬127,500 ᗂवଦ)WHO, 2006*ǭԭέ‫ۻ‬ப‫ޛڀ‬ᕅ‫ވ‬พҊ౎Ϸ‫ٸ‬ԍΙϩ‫ވ‬ᖶ໿(National Lung Cancer Partnership,2006).ǭ 11.

(14) ਜᏬՀࡰଚጸҊ࿶ϝѩȟ2006 Ӻ୦ΊΓάԔәȠ಄षǫ൵‫ۻ‬ငዝȇᕅ੨Ȉ ‫ވ‬Ԕ΢Ίኞф౎ຣၯԤϠχΉΓ΍ǫ౺ΉΓύӺᙓᕻᄝय़ǫѪ֘‫׹‬ΓΖϠύΓ ࣵൠԍ΂ΊԔ‫ܤ‬ᕅ੨ǭ2006 Ӻ୦ΊУवΓάԔә٠‫ࢸ־‬Ǳᕅ੨ȇԤϠχΉΓ ΍ᗱ΂ȈǬဇԿᅼ੦੧ȇԤϠχ·ᗱΖȈǬϿ᠃੦੧ȇԤϠχ·ᗱ΂ȈǬᑎֶ ੧ȇԤϠχ΅ᗱΉȈǬٚࡱ໵ৄȇԤϠχύᗱ·ȈǬ‫ݰޛ‬ȇԤϠχћȈǬᄃ‫ۻ‬ ‫خ‬੧Ϯ‫خ‬ฦϦȇԤϠχΖᗱ΅ȈǬ๔‫ݰ‬ȇԤϠχΖᗱύȈǬԵగȇԤϠχΖᗱ ΖȈϮଦԿᓯ‫ۻ‬੦੧ȇԤϠχ΂ᗱΖȈǭ୦Ίәᕅ੨Ԕ΢ᕫΊኞၩΖ࿛΅Φ· Ԥ·Γ΍Ίǫ߲ΓάУवᕅ੨໠Նࢸ‫ޛ‬ᕅǬ‫خ‬ᕅǬ฿က‫ދ‬ကᕅǬέ‫ۻ‬ٙᕅǬऎ ᕅǬΨ๑ᕅǬឡឿဆᕅǬήেᓄᕅǬफ़ၧᕅǬષ᠃ᕅǫ໠Ն௟ӓᆭ 2005 Ӻࣣ ӌ)ጸҊ࿶һ୦ጸҊ಄ष၎૲ᆒ 2005-2006*ǭ П࣑ጸҊಋᘺ‫ވ‬಄षǫട޿ΉΓӺ٧һП࣑‫ވ‬ᕅ੨Ԕ΢౎Ѽ‫׍‬೩Ιϩǫ‫ٸ‬ τЧ‫ޛ‬ᕅ‫ވ‬Ԕ΢౎ቑкട‫)׍‬WHO, 2006*ǭჰ‫ޛܤ‬ᕅพҊ‫੶ވ‬Ѽ঑ә, ҕ߲‫ۏ‬ ѹְһ‫ܫ‬ᕌ, ՗ჰᏛग‫ޛ‬ᕅχӉᒷәટǰӬѝ٧әટ)‫ྖܓ‬Ǭ‫ޓ‬ਲԝࢀ*Ϯᒡ໱ әήιԍࣣྴ‫ވ‬Έဵ)Vaporciyan et al., 2000*ǭ ‫ޛ‬ᕅ‫ވ‬Ԃәшિσࡹഹ΂әટǫԭࡹӤәટ೮Ԃ‫ވ‬ǱӬ‫ܓ‬๟ǬΉЂ๟Ǭ৅ ௳ѕǬᚳ្‫ܤ‬ᕀდτ‫ވ‬गᕅ‫ݹ‬፝ǭӞ‫ۻء‬τǫ‫ܓ‬๟ࡹᏛग‫ޛ‬ᕅ‫ވ‬ടУवԂәǫ 90%‫ޛވ‬ᕅࡹә‫ܓ‬๟ԭϾ૽‫ވ‬ǭӞέ‫ۻ‬τǫ80%‫ޛވ‬ᕅࡹә‫ܓ‬๟ԭϾ૽‫ވ‬ǫ‫ء‬Ǭ έ‫ۻ‬Ѫ֘ࡹ 87%ǭ σ‫ܓ‬๟ǫ߼߆නօΌȱΉЂ๟Ȳ‫ވ‬ΊΟӌኣཥ፸‫ڐ‬໵ৄǫ ਜᏬ಄षԔ‫ޛܤ‬ᕅ‫ँވ‬ԍ 4%‫ۻءވ‬ЧϮ 22%‫ވ‬έ‫ۻ‬ǫ‫ޛٸ‬ᕅУәΆߦᆭօΌ ΉЂ๟ԍ᜙ǭ‫ܓ‬๟‫ڷވޚ‬ήԔ‫ޛܤ‬ᕅ‫ވ‬ᐉ౎ࢸߑ‫ܓ‬๟‫ڷޚ‬ή‫ٶވ‬।ԶΖ।χ ໋ǭԭօΌΉЂ๟‫ޛٸޚ‬ᕅᑘல౎वБ؉օΌΉЂ๟‫ވ‬Ίଦз 30%ǭ ѝ࣑ᕀ დग‫ޛ‬ᕅәટǫӬ‫ޓ‬ਲԝࢀǫօΌҘᆖǬᙶǬ੿Ǭ‫ܢ‬ো‫ۻ‬ᱵਲาǫΟ೶шિᏛ ग‫ޛ‬ᕅǭτ୦फ़‫ݹ‬ല៶‫ࢽݟ‬ǬᐟǬྕ‫܃‬ౙҊ‫ޓވ‬ਲԝࢀ, шિᆭ‫ޛ‬ᕅพҊԍ᜙ǭ ѓ΂‫ޓ‬ਲԝࢀࡹ‫܃‬٣ҋᐦਈ‫܃‬ౙҊ࠲Ϛ‫ޓ‬ਲԝࢀԍ᜙)Chiu et al., 2006*ǭ ‫ޛ‬ᕅ‫ׅ‬Ԃ‫ވ‬ၯสτ, ടԇҎगᕅәήϾพ୮ә໵ৄࡌ‫ڀ‬ळԂᕅಉऔ਋໋ ࣣྴᅇ߆ǭҎ΂ॸᕅಉऔळҊ‫ॸ΂ڀ‬ᕅಉऔ࿹‫܃‬መ਋໋Ҥࣣྴᅇ߆, ՗ࡹ΂Ѷ 12.

(15) ᕮळԂ΂ॸᕅಉऔ࿹ߵᘀජ೩ࡂൠߑ஛‫׍‬, ‫ݦ‬ᕄਆܷߑ஛σӪ, ‫܃‬Чႚْ‫ޛ‬ᕅ ‫ވ‬Ј‫ݛ‬, єԍӞႚْ‫ׅٸ‬ԂΙկΑ-ෞ϶‫ޓ‬ਲԝࢀǬ࿚ྖǬෞ϶‫ٸ‬Ыᕀდԝࢀǭ ‫ޛ‬ᕅ‫ވ‬ಉऔᅶᜡ ‫ޛ‬ᕅ೦஛ϠԂ‫ٶ‬άᜡࠗǱβಉऔ‫ޛ‬ᕅᆭߑβಉऔ‫ޛ‬ᕅǭ 1. βಉऔ‫ޛ‬ᕅǱӤพҊ‫ۻءܤ‬ǫСᆭ‫ܓ‬๟৩৩ࣣ᜙ǫՕһ೴‫ޛ‬ᕅ‫ ވ‬12%‫ ڀ‬25%ǭ βಉऔ‫ޛ‬ᕅҊ߆பࡇ‫׍‬ǫС৉‫ވ׍ࡇܧ‬ᘀජ‫ٸڀ‬ѣᏋ‫ۋ‬ǭ 2.ߑβಉऔ‫ޛ‬ᕅǱ Бβಉऔ‫ޛ‬ᕅ஛‫ط‬ǫՕһ೴‫ޛ‬ᕅ‫ ވ‬75%‫ ڀ‬88%ǭߑβಉऔ‫ޛ‬ᕅ‫ވ‬Ҋ߆ၟᄃǫ ‫ٸ‬ᘀජᙦ౴‫ވ‬พҊΟၟᄃǭਜᏬငዝಉऔ‫ࠗވ‬ᄁшϠԂΖᅶǱဆᕅǬᡉ‫ݺ‬ಉऔ ᕅϮάಉऔᕅǭ ‫ޛ‬ᕅ೦஛ཥࡇ‫ވ׍‬ᘀජ‫߇ޛڀ‬Ǭᕬᆧ๑‫ވ‬ధϺ฿‫઼ۿ‬๑ߌ޿ ‫ٸވ‬ѣಋᘺǫΟ৉‫ވ׍ࡇܧ‬ᘀජᙦ౴‫فڀ‬ᡆ‫ٸވ‬ѣᏋ‫ۋ‬ǫ٦Ӭဇ೴Ǭ‫ۿ᠃خ‬ଥ ᓇǬଥᡅาǭ ‫ޛ‬ᕅ٠ಋᘺࠗᄁೆϠԂβಉऔ‫ޛ‬ᕅ)small cell lung cancer*ᆭߑβಉऔ‫ޛ‬ ᕅ)non-small cell lung cancer*‫ٶ‬άᜡࠗǫ߲‫ँޚ‬ՕԤϠχΓύǫࡌ‫ߵޚ‬м࡫ ဆ ᕅ )adenocarcinoma* ȇ ँ Օ 30-40% Ȉ Ǭ ᡉ ‫ ݺ‬ಉ औ ᕅ )squamous cell carcinoma*ȇँՕ 20-30%ȈϮάಉऔᕅ)large cell carcinoma*ȇँՕ 10-15%Ȉ ΖᅶУवᜡࠗǫҼँՕԤϠχ΍ΓύǭϠԂ೤‫ٶ‬άᜡࠗ‫ވ‬Уव঑әࡹ෻ፌӞҊ ‫ݹ‬੔፝Ǭᖆ‫౓޻׀‬ᆭჰ‫ݦ‬ᕄ‫ވ‬௬༹ࡂЈॖǫѣॱχ໋೶ԍࡇά‫ވ‬৘ౝ(Travis et al.,1995)ǭ βಉऔ‫ޛ‬ᕅ‫ވ‬౺΂ጌ‫ݦ‬ᕄࡹЧϦᕄࢸУ)Murray et al., 2006*ǭᆭβಉऔ ‫ޛ‬ᕅࣣБǫߑβಉऔ‫ޛ‬ᕅ‫ވ‬ቑҊǬᘀජၟᄃǫჰϦᕄ௬༹ࡂ՜ǫਜ‫ވݦ‬ᒛ‫ࡹݛ‬ ຤ԇ‫י‬ငዝְһϡଟ(Clegg et al., 2002)ǭш஽‫ࡹވ‬шЧ້Ώְһϡଟ‫ވ‬ԇන ੧லȇ౺΂ǬΉනϮ౺ΖනԇනȈσ‫ڀ‬ΖԂǫԭЂೃࡌ‫ވ‬൱พ౎Οσ՜)Strand 2007*ǰ౺΂නȇ‫ִޛ‬೴χβငዝȈँԍћϠχ΂ǰ౺Ήනȇ‫ޛ‬ငዝၟάǫ‫ۿ‬ βငዝ՗ᅇ‫߇ޛڀۦ‬ధϺ฿Ȉшિຣၯ΂сǰ౺Ζනԇනȇ‫ޛ‬ငዝᗟάǫ՗؉ ԍߖ҄‫ڀ‬УवԿᅼϮϚ᠃ǫǫٗшિຣຢ‫߇ޛ‬ᅇ‫ڀۦ‬ӌସ‫ވ‬ᕬႍధϺ฿Ȉ‫ת‬ଦǫ ၩћϠχΖǭ೤ٛ൱พ‫ވ‬੧٦ǫσፌනըଦ՜ǫ‫ٸ‬τ΍Ԃ֘ԍᇲಷᙦ౴ǫԭ೤ ٛᙦ౴ӞЂೃχ߲ᓿιพҊǫ߼әࢸϳβԭଷ෪σз٧ǭ٠ԓࣥ٧ǫσᅼࡹβ 13.

(16) ಉऔ‫ߑࡹۿ‬βಉऔ‫ޛ‬ᕅǫ೶ᓿ့ೆྴՙһ‫ވۻف‬੦੧٧Ԭት੧Ί‫ݦވ‬ᕄǫԭव ‫ޛ๊צ‬ᕅ‫ݦވ‬ᕄ౎ǫִ೴ᆭһ‫ݦވۻف‬ᕄ΂ኣ‫ވ‬ॐवǫ೶σિ۰຅ǭ. ΉǬύ।ήᇿ ύ।ήᇿࡹഹშᇿ‫ވ‬Дဵౙ‫ݹ‬ǫԭഹშᇿࡹτᛧ‫ވ‬ύ।ή)gallnut*‫ވ‬Уव ԂҴǫәԓӞϖಆύ।ήᇿχ߲ǫҺᇜ‫ܫ‬ύ।ήᆭഹშᇿǭ. ΂Ȉύ।ή ȇ΂ ύ।ήΕᅷ؉फ़ήǫँӞ‫ٶ‬ΦӺ߲ǫȟεਾ࿭Ƞղԍ૭ၠτ୦ઉҺჰ‫ܤ‬ ύ । ή ‫ ވ‬ժ ҋ ǭ Ҏ ᆖ 㓆 ૦ ࣴ ȇ Pemphigidae Ȉ ‫ ވ‬। ૦ ᙔ ‫ ٿ‬ᐖ ᅁ ᐂ ࣴ ȇAnacardiaceaeȈᅁᐂឝȇRhusȈස‫ݹ‬ಋᘺǫ ‫ׅ܃‬Ԃ‫ވ‬ᙔ㓆ᅷࢸύ।ήǭύ ।ή‫ׅވ‬ԂଟΈመԍরஃУȇᅁᐂឝස‫ݹ‬Ȉѝǫ ᗂመवӞౙ㓆ස‫ވݹ‬Ҋ‫ز‬ӝ ߌ޿ԍеஃУȇ੔‫ۊ‬ាᜡȈ‫ވ‬ӯӞǭ ύ।ήࡡᙔ㓆‫ׅވ‬ᄁш཮Ϡࢸ‫ظ‬।Ǭ‫ر‬ ।Ϯ।ޯᜡǭύ।ή൛֍ഹშᇿǫ шቭ‫ݨ‬ᓿҋ‫ܤ‬ᙫᛧǬᐉఊǬ୦ْϮफ़ࠋา ౙཧǭτ୦άഃι࣫พΊη୲‫וز‬ೃǫ ඓଦύ।ήౙຽЧ‫๊צ‬ၤ‫ׯ‬࿭ᔥǭϠ ѩ‫ܤ‬ᆬᡳһ৕ε᜵‫ވ‬ᛜГᡭጜЌǫ Ҥшพ౓ࢸኞσ϶‫ވ‬ύ।ήǫԇӺදԍτ ᛧ୏϶ຽ௝໚ǫூ‫ٸ‬ժҋ኿િ‫້ࡈۏ‬พǭΊᜡჰ‫ܤ‬ᙔ㓆‫ވ‬ժҋǫ‫ܤڿ‬Ѿߢҋೳǭ ӞΓ΅Пࣾǫथ୦ࢸΈታઋրУࡰᡆ‫ࡗވ‬൱ǫ ‫׹ܤ‬Ӻ‫ވ‬㇒㓆࿦ȇoak apple dayȈǫΊѾཥ଒ᔅᙔ㓆ǫ ٗЧ㓆ϚҊ‫ވݹ‬ӑໟ޻ቲфΔѹ٧΂Ӻၤٚ‫ވ‬ӊϟǭ Γ·Пࣾ޺ǫ ኲࢡ‫ת‬ҎτܶάຽີΨᙔ㓆ǫЧඓྙ㓆ᡆ‫֍܃‬χഹშᇿǫᇐ೮ ᎷДǬࢀਈϮᙫᛧǭ ԓѝǫഹშᇿ‫ۏ‬ԍగ๬Ϯк೩‫ׅ‬Ԃᘧ໵ಋᘺ‫ވ‬лҋǫо ऄӈӝӳΊϡ້ᖎᖑΙ‫ވ‬ᙔ㓆ǫ ࿳‫ܤ‬ЌѸස‫ވݹ‬ϡΨΙǫЧժᘧ໵ಋᘺ‫ׅވ‬ Ԃǭ τ୦ժҋ૦ᙔ‫ܤ‬ᡭጜЌᜡස‫ݹ‬Ι‫ׅ܃‬Ԃ‫ވ‬ᙔ㓆ȟύ।ήȠྴՙԆᔐᏁǫ Ο ԍ޿‫ٶ‬ΦӺ‫ވ‬ᐌѕ)཯఩ᐡา๨ǫᆬᡳ‫ވ‬ස‫ݹ‬㓆*ǭ. 14.

(17) ა 1.1 ᛜГᡭጜЌΙ‫ظވ‬।ᜡ. ა 1.2 ᛧ‫׮‬ύ।ή)‫ر‬।Ȉ. ᙔ㓆ȇύ।ήȈ)ཛྷПࣾᆒๅፇสࡃ೒ηส τ偆 Ꮩ* )཯఩ᐡา๨Ǳᆬᡳ‫ވ‬ස‫ݹ‬ 㓆*!!!!!. (Ή)ഹშᇿ ഹშᇿǫΕᅷഹშ‫ۿ‬φშǫथЅӓ Tannin ᚃᇿ‫ۿ‬ᚃ፝ǫࡹස‫ݹ‬τ ΂ᅶْጸҋϦᏙԂϠǫҋ٧࠵ᙰ૦ᙔ‫ވ‬Ψ๑ЧԆْЎ૦ᙔ‫קވ‬ᔇχਆǭഹშᇿ УवшЧϠࢸшДဵ‫ވ‬ഹშᇿᆭᆢӔ‫ވ‬ഹშᇿ‫ٶ‬ᅶǭ ౝӓǱᚃᇿǬഹშǬύ।ήഹშᇿǭ ‫ݺۻ‬Ǳఠ໪ԼԶతපԼચѺǫԍ੔ਯਲ‫ڑ‬ǫ‫ཬڑ‬ᔫǭྂ‫ ܤ‬1 Ҵ‫ވ‬Д‫΃ۿ‬፾ǫྂ ‫ܤ‬О✀ǫσྂ‫ිܤ‬Ҧ‫⾯΃ۿ‬ǭ ଱‫୔ړ‬ә๞‫ڎ‬਋ǫкΌᎀᇿႀ‫ވ‬঑әǫ‫ٸ‬ҕ‫ވ‬ ࡹࢸΈଟчഹშᇿ೤ᜡ‫ވ‬ԍԼᙾ፝ǭ ഹშࡹဖ๲଑τ‫֍܃‬ԍ‫ވ‬Ήᅶ⇃ϦӔ‫ٸݹ‬τ‫΂ވ‬ᅶ‫ݹ‬፝ǫϷ‫ٸ‬Ӟࣽဖ๲଑τ֍ ຽၟӤǫԍੲ‫ܤ‬Ͽ᠃Կᅼ੦੧‫ވ‬ႚْǭဖ๲଑τ‫ވ‬ഹშ΂૊ࡹҎဖ๲ࣻǬғϮ ఉ਽‫ݧ‬พᇾԭ٧ǫ‫ࡹޚۿ‬әࢸӯ‫ܤ‬ᐅЌఆϚԭ๞‫ڎ‬ᐅЌϚ‫ވ‬ഹშԭ٧ǭഹშ‫ވ‬ Ӥ϶шЧ‫ۊ؃‬଑‫ވ‬ड़‫ڑ‬Ǭ฿ᄣᆭ፝ӝǭ઩Хഹშ‫ࣽވ‬଑፝ӝᇯᖊǫ؉ԍ߽ძ‫ވ‬ ༹᝱ǫᖊ଑๩ࣽ଑ൠࡹ‫ࠗٹ‬Э޻ǭഹშᙝ൛‫ࣽވ‬଑шЧӯ‫ܢ‬࿭ӺǫٗС೫ᅃᗈ ᡟзॠ፾ಉጆ‫ވ‬ംӺड़‫ڑ‬ǭྴဖ๲଑ΌΨࡌΨ๑༹᝱ପᔫǫΨ๑ᗰጙཥԍᖠዢ ༹ǫَߘࡹഹშӞ૽ՙҋǭ ฿ᄣӻǱ 15.

(18) ა 1.3 ഹშᇿχ฿ᄣӻ. ȇΖȈύ।ήᇿ ύ।ήᇿӞᖆ‫׀‬Ιш଱ࢸЎԿ‫ވ‬ԆᔐᏁǫ೑Ӥ‫ݦ‬ᕄЛғ៽Ϯ౟ዟᛧᆦ‫ވ‬Ԃ Ҵࣚ֍ԍύ।ήᇿǭύ।ήᇿ‫ٷ‬ԍ‫ד‬ਲ਼Ϧ‫ވ‬ՙҋǫિᓼծಉऔ‫דܙ‬ਲ਼Ϧ‫ވ‬ཕ ᚦǫԓѝ࣫‫ة‬Οᡀҙύ।ήᇿિ‫ڂפ‬ᕅಉऔ‫ވ‬ಉऔ࢜‫ۻ‬ǫ՗߼σཥ໵ৄ‫ڀ‬Ѽ஛ ‫ވ‬ಉऔǭ थЅӓ gallic acid monohydrate ըӓǱ؉फ़ήᇿ ϦᏙӓǱ 3,4,5-trihydroxybenzoic acid monohydrate ϠήӻǱC6H2(OH)3COOH ϠήຽǱ188.14 ᅐᗱǱ251°C Дྂ‫ۻ‬Ǳ15 g/l (20°C) ฿ᄣӻ: 16.

(19) ა 1.4 ύ।ήᇿχ฿ᄣӻ. ස‫ݹ‬٧྄Ǳά೴Ҵ‫ވ‬ස‫֍ࣚݹ‬ԍύ।ήᇿǫ‫ٸ‬τ൛֍ύ।ήᇿ‫ވ‬ස‫ݹ‬ԍύ।ή )gallnuts*Ǭ૘ထǬ ဖ๲Ǭಹക૒)hops*Ǭᄤܷ)witch hazel*Ǭᅁᐂ)sumac* ᆭᐅᐂғ)oak bark*ǭ ΉǬಉऔຳනᆭಉऔຳනፊொәή ஬঑‫ڿ‬ᑺЭಉऔີՀಉऔϠຂǫϠຂ‫ׅ‬Ԃ‫ॸٶ‬ήЭಉऔ‫ވ‬ၯส਋໋ǫᅷࢸ: ಉऔຳනǭᘸഹ٧ᇜൠࡹϠຂಉऔ஬ԍไϠຂ฿‫ڀ׫‬ΗԒԍไϠຂ฿‫ވ׫‬ၯ สǭྴτшϠࢸΖॸ਋න:ಉऔҊ߆නǬDNAጻᇐනǬಉऔϠຂනǭಉऔຳනш ϠࢸInterphase(G0ǬGlǬS‫ڠ‬G2)ϮMitosis(M)phaseǭ ҭЎන)G0න*Ǳಉऔಷ‫ܤ‬ᓀЎ‫ݺވ‬ᄁǫшિࡹአ਋ҭ੷‫ࡹޚۿ‬ҀΝ‫ۻ‬ҭ੷ǫመ वԍ፵ྴ‫૲ވ‬৩ǫ٣ಉऔີΌಉऔຳන‫ۿ‬ϠϦGlනǭ Ϡຂࡌන)G1න*Ǳಉऔ້‫ڿ‬Ѽ஛ЭᖫٗСҊ߆ǫٗౙҊRNAϮಿҒ፝ǫಉऔᡆ ᐿཥቑкǫGl න‫ࢀވ‬Լᡆኞҕࡹ2NǭԭӞີΌS(synthesis) ਋නχ߲ཥᔗࢎࢀԼ(chromosome)DNAࡹո‫੾ڀڐ‬ᚦιີ Հॼိ‫ވ‬ηՙǫԓ਋නመवޯΓ‫ڀ‬ΓΉβ਋ǭԓࢸӔԂ߲නǭ DNAӔԂන(Sන)ǱಉऔີՀϛ‫ڀ‬΍β਋DNAӔԂϮஉ঑Ѹ‫ވ‬ ΉΓΖჰࢀԼᡆጻᇐѓ΂ҴǭԓࢀԼᡆኞҕ2N~4Nχ໋ǭϠ. 17.

(20) ຂ߲න(G2න)ǱಉऔີΌG2නመवޯΖ‫ڀ‬ћβ਋ǫࢀԼᡆ஬ 2Nᠹ4NǭଟΈᝠឲҊ߆ٗСӔԂಿԵ፝χѝǫӞಉऔवີΌ Mනχ߲ཥऻ೙ᔗࢎࢀԼᡆDNA‫ވ‬ጻᇐࡹոְᏵЧժີՀԍ ไϠຂȇmitosisȈǭ ԍไϠຂනȇMනȈǱԓ਋නєԍ΂β਋ǭཥଭЎಉऔҊ߆ϮಿҒ፝ӔԂǭҎ ΂ॸѽಉऔᠹԂ‫ॸٶ‬ήಉऔǫጻᇐְԂ‫ࢀވ‬ԼᡆཥӑԵϠ ଒‫ڀ‬ήಉऔϚǫ٣ήಉऔϚ‫ࢀވ‬Լᡆᆭѽಉऔְһ΂ኣǫ ཛྷಉऔӞԓනְԂǭ Ӟಉऔຳනτǫ‫ॸ׹‬໏࢛‫ۿ‬਋නң࣑೶ԍ‫܃‬ᒆ‫ވ‬ȟᔗࢎᗱȇcheckpointȈȠǫ ྴDNA damage਋ǫߵcell cycle෻‫ݛ‬೦ၯᔗࢎᗱԭ೮ԂଭᅀȇarrestȈǫԓ਋ཥ ೮ԂDNAॼ൱ǫྴॼ൱ְ਋πபЧີΌΗ΂ॸ਋නǭG1໏࢛‫܃‬ᅨ෪‫ࢸވ‬ಉऔॸ ᡆ‫ވ‬άβǫӞಉऔԂ߆ၯสτǫಉऔਘᒡ໱‫ݹ‬፝ठԍ‫ڐ‬ѝ࣑ଦિᒖোጌ‫ۿ‬ϦᏙ ‫ݹ‬፝‫ވ‬ተ៓ԭࣸᠹǫߵ௫୆ॼ൱‫ت‬಄ǭS໏࢛ߵࡹӞີՀDNAጻᇐǫԭG2໏࢛ УवӞᔗࢎ‫܃‬ԍࢀԼᡆDNAࡹո೶ೆጻᇐС॒‫΂ܤ‬Ԓǫठ΂ϡ೶Ѽ஛πિີΌ ടࡌಉऔϠຂMනǭ՗ठࡹၭ‫ڀ‬෻‫ވိॼݛ‬ᒨ‫ݹ‬਋ǫಉऔߵཥ‫ؿ‬Ӓषด‫ۻ‬উ΢ (apoptosis)ǭ ੶ਘ‫ވ‬ಉऔຳනτિ٣ಉऔѼ஛ೌࡊ‫ີވ‬Հǫྴτԍॸፊொ‫ت‬಄ǭԓፊொ ‫ت‬಄Ҏ٠ᒏ‫ۻ‬ಿᐖ䁐CDKs(cyclin dependent kinases)Ϯຳනಿ䁐(cyclins) ፊொ әήǭшЧѼӒፊொಉऔຳනǭ՗ࡹྴDNA damageǬϠϦ‫ڠ‬ԫϦ਋ǫ ཥߝ٣ Cdk ‫ޚڂפވ‬ԍӒऻӒፊொಉऔຳනǫԭ೮Ԃ‫ڂפ‬ಉऔቑҊ (Senderowicz, 2004ʼΖ. ȇ΂Ȉ ຳනಿҒȇcyclinsȈ Ӟ cyclin ৅௳‫ٸ‬Ԃঠι‫ތ‬ԍ8ᅶǫϠըࢸǱ AǬB1ǫ2ǫ3ǬD1ǫ2ǫ3ǬEǬ FǬGǬHǭσӌ‫ވ‬ຳනಿҒǫӞಉऔຳන‫ވ‬σӌ਋න‫ވ౓޻܃‬ຽԍ‫܃‬σӌǫ‫ٸ‬ 18.

(21) ୱՀ‫ވ‬лિΟԍ‫܃‬σӌǫӬᆭG1 phaseࣣ᜙χcyclinࢸcyclin DϮEǫS phaseࡹ cyclin AǫԭᆭG2/M phaseࣣ᜙‫ࢸߵވ‬cyclin AϮBǭԭcyclin AᆭBೆᅷࢸmitotic cyclinsǫ‫ٸ‬ᛐ‫ވۊ‬ӯӞ‫ܤ‬interhaseǫ՗Ӟmitosisන਋ཥ‫ه‬೩Ϡဵǭ‫܃‬ԍ‫ވ‬ຳන ಿҒӞ฿ᄣΙ೶֍ԍ΂࢛ࣣՖ‫ވ‬Ủ୮ᇿ‫־‬ҿǫᅷࢸcyclin boxǫऻ೙ᒚᇘσӌ‫ވ‬ cyclin-dependent kinasesȇCdksȈٗᆭχ฿Ӕǫ‫ׅ‬Ԃcyclin-CdkጻӔᡆǫӞಉ औຳන‫ވ‬σӌ਋න޻౓зσӌ‫ۻࢩވ‬ǭ. ȇΉȈCyclin-dependent kinasesȇCdksȈ Cdksࢸserine/threonine protein kinaseǫ‫ٸ‬฿ᄣΙшϠࢸcatalytic subunit Ϯcyclin regulatory subunitǫшᙍҎᆭຳනಿҒχ฿Ӕ٧ፊ࿦‫ۻࢩٸ‬ǭCdksӞ ಉऔຳන‫ވ‬ӑॸ਋න޻౓ຽࡹ΂ग‫ވ‬ǫ՗ѯ໡ᆭ੔‫ۊ‬਋න‫ވ‬ຳනಿҒ฿Ӕࡌπ ཥ‫ٷ‬ԍࢩҊǫ‫܃‬ЧӞσӌ‫ވ‬਋නǫCdks‫ߵۻࢩވ‬σӌȇMorgan, 1997ȈǭCdks ш೯ၯჰ‫ٸ‬੔‫ڐۊ‬፝‫ވ‬ᕎᇿϦ٧ፊொಉऔຳනχີՀǭ Cdk৅௳ιพ౓ٗ‫ڥ‬ӓ ‫ވ‬ԍ7ᅶǫϠըࢸ:Cdh1(cdc2)ǬCdk2Ǭ3Ǭ4Ǭ5Ǭ6Ǭ7ǭຳනಿҒDᆭCdk4/6 ‫ׅ‬ԂχጻӔᡆǫຳනಿҒEᆭCdk2‫ׅ‬ԂχጻӔᡆᆭG1න‫ີވ‬Հԍ᜙ǫԭຳනಿ ҒE‫౓޻ވ‬Ϯ‫ٸ‬ᆭCdk2‫ވ‬฿ӔߵࡹಉऔຳනີΌSන‫܃‬ѯ໡‫ވ‬ǫຳනಿҒAᆭ Cdk2ߵУᏛSනχີՀǫԭຳනಿҒBᆭCdk1ߵ‫ڠ‬ಉऔີΌMන‫ވ‬ፊொԍ᜙ ȇSherr, 1996ǰSherr, 2000ǰHo and Dowdy, 2002Ȉǭ. 19.

(22) ȇΖȈ Cyclins-dependent kinases inhibitors᧤CdkIs᧥and p53 CdkIsિᆭCdks฿Ӕ‫ׅ‬Ԃᛐ‫ۊ‬฿ᄣԭш‫ڂפ‬Cdksχࢩ‫ۻ‬ǫࢸჰCdks‫ވ‬ՙҋີ ՀऻӒፊொ‫ވ‬ಿҒ፝ǭCdkIsУवшϠࢸ‫ٶ‬άᜡ: ౺ ΂ ᜡ ࢸ KIP/CIP(CdK inhibitory protein)family ǫ Ԃ ঠ м ֍ ԍ p21Cip1/Waf1/Sdi1/Sap20Ǭp27Kip1Ϯp57Kip2ȇSherr and Roberts,1999ȈǫԓᜡಿҒ ፝шӌ਋‫ڂפ‬cyclin E-Cdk2Ǭcyclin A-Cdk2Ǭcyclin D-Cdk4‫ވ‬ՙҋǫີԭ‫ڂפ‬ ಉऔຳනχີՀǫԭp57Kip2УवࡹᆭಉऔϠϦၟ‫ࣣٷ‬᜙‫ۻ‬ǭԭp21. Cip1/Waf1/Sdi1. ࡹҎtumor suppressor gene p53‫ܤ‬DNA‫ڐ‬ཕ਋ᇟᏛз٧ǫУवཥ‫ڂפ‬cyclin E-Cdk2χࢩ‫ۻ‬ԭ٣ಉऔଭᅀ‫ܤ‬G1නǭҎ‫ܤ‬೤ΖॸಿҒ฿ᄣτ‫ވ‬Ủ୮ᇿѺᅻԍ੔ ‫ۊ‬ᄣࠗિᆭcyclin-CdK฿Ӕǫ‫ׅ‬Ԃcyclin-Cdk-CdkI‫ވ‬ᛐ‫ׅۊ‬ӻǫәԭ෻‫ࢩݛ‬Ϧ Η෕әήԭ‫ڂפ‬ಉऔຳනǭ ѓ΂ᜡಿҒ፝ࢸINK4ȇinhibitors of kinase 4Ȉfamilyǫм֍p16INK4a Ǭ p15INK4bǬp18INK4cϮp19INK4dȇSherr and Roberts, 1999ȈǫჰCdk4Ϯ6‫ٷ‬ԍᒞ Ꮾ‫ڂפۻ‬ՙҋǫཥᆭcyclin D᝘‫ݵ‬฿Ӕǫ٣cyclin D෻‫ࢩݛ‬ϦCdk4Ϯ6ǫີ΂‫׸‬ ‫ڂפ‬RbȇretinoblastomaȈ‫ވ‬ᕎᇿϦǫԭ٣பಉऔຳනଭᅀ‫ܤ‬G1χԇනԶτන ȇMcConnell et al., 1999Ȉǭp53ࢸငዝ‫ڂפ‬әήǫિ୳ْЎಉऔᕅϦǫԭ‫ܤ‬ Ίᜡ‫ވ‬ᕅ੨τǫԍ80ʏ‫ވ‬ᕅ੨ᆭp53‫ࣸވ‬ᠹԍ᜙ǭ. ޻1.1 ፊொಉऔຳනχຳනಿҒϮ‫ٸ‬ᐖ䁐 Cell cycle stage. Cyclins. CDKs. G0 /G1 phase. Cyclin D. Cdk4, Cdk6. Late G1 phase. Cyclin E. Cdk2. S (synthesis) phase. Cyclin A. Cdk2. G2/M phase. Cyclin B. Cdk1. 20.

(23) ȇћȈ pRbϮE2F families pRB ȇ retinoblastoma protein ‫ ۿ‬pocket protein Ȉ families м ֍ pRB ȇpRB1,P110ȈǬpRB2/p130ᆭp107Ζ‫ޚ‬ǫԭE2F ȇearly gene 2 factorȈfamilies ߵм֍E2F-1ԶE2F-6ȇDyson 1998Ȉǭ E2Fࢸᙦᒬәήȇtranscription factorȈǫྴ‫ٸ‬ᆭRbಿҒ፝฿Ӕ਋σ‫ٷ‬ԍࢩ ‫ۻ‬ǫ՗ྴRbೆcyclin-CdkጻӔᡆᕎᇿϦ਋ǫߵཥಜᙽE2Fǫ٣ப‫ٷ‬ԍE2Fࢩ‫ۻ‬ǭ pRBࡹᆭE2F-1,2,3฿ӔǫԭpRb2/p130ᆭp107ࡹᆭE2F-4,5฿ӔӞ΂૽ǫ՗E2F-6 ߵࡹᆭpolycomb group proteinsȇPcGȈ฿Ӕǭ ΂૊ᇘࢸE2F-4,5ᆭpRB2/p130ϮE2FᆭPcGχ฿Ӕǫ‫ܤ‬G0Ϯearly G1න‫ס‬ᄴ transcription repressors‫ظ‬Լǫ՗E2F-1,2,3ߵࢸtranscription activatorsǫՙҋ ‫ܤ‬late G1ϮSනȇStevaux and Dyson, 2002Ȉǭ. ΖǬಉऔউ΢ȇapoptosisȈ ಉऔԔ΢ԍ‫ٶ‬ᅶೳৠǫ΂ᅶࢸಉऔᚦԔȇnecrosisȈǫѓ΂ᅶࢸಉऔউ΢ǭ ಉऔ፸‫ڐ‬ѝ٧‫ٿ‬ᐖӬִ೴઩ԿǬ઩ਲ਼‫ۿ‬ϦᏙ࢜‫ۻ‬า‫܃‬Ͼ૽χಉऔԔ΢ǫУ वࡹ࿭ҎಉऔᚦԔχೳৠǫԓၯสཥ೮Ԃಉऔ౿ဆᡆင๕ǫϚ፝ᆒౙҊД‫ݧ‬Ǭ ಉऔጙχְᏵ‫ۻ‬ೆ੾ᚦԭџчҊ౒ᐉિǫಉऔәԭஔဵǫԓၯสཥក‫ܢ‬зᖶϦ ‫ۻ‬ಉऔϚ৉‫ݹ‬ǫϾ૽‫ڣ‬൅ಉऔ‫ۻݰ‬ϯᓿǭ. ȟಉऔউ΢Ƞ(apoptosis) ΂ຉടԇࡹӞ1972 ӺҎ੧౒Ꮩ৅John Kerr‫܃‬. ඓзǭಉऔউ΢ΕೆᅷࢸҊ౒Ι‫ވ‬ಉऔԔ΢(physiological cell death) ‫ࡹۿ‬ ಉऔषด‫ވۻ‬Ԕ΢(programmed cell death)ǫࡹ΂ᅶѼ஛Ҋ౒‫ۻ‬ಉऔԔ΢ǫ ΂ᅶԵ෼‫ވ‬Ҋ‫౓ڥ‬ດǫҕ‫ࢸވ‬ଟчσव‫ۿވ‬ι෻ҋ‫ވ‬ಉऔǰၯสτҎ੔‫ވۊ‬ಿ Ғ፝Ϯᇾટፊொǫ൲‫־‬ᅃີ٣ಉऔԔ΢ǭ‫ٸ‬੔ቲࢸಉऔ๱ᕤȇshrinkageȈǬಉ 21.

(24) औጙ‫ׅ‬Ԃ‫ݺݧޓ‬ȇmembrane blebbingȈǬಉऔਘχࢀԼ፝ᐑࢀСጆஆ ȇchromatin condensationȈǬDNAᘇຂԂβЙ࢛ȇinternucl eosomal fragmentationȈǫີԭಉऔጙϚഇஉಉऔϠഡࢸӤॸԍмጙмᙖχউ΢βᡆ ȇapoptotic bodyȈǫടࡌҎ፺޿χնᏏಉऔऔնᏏǫԭз౓ಉऔউ΢౓ດχ ಉऔߵϠජ‫ܤ‬ಋᘺτǫ‫ٸ‬ಉऔጙٗσཥ੾ຂǫࡱσཥϾ૽‫ۻݰ‬ϯᓿǭ ΂૊ᇘࢸᇟᏛಉऔີՀಉऔউ΢ࡹၟӪ‫דވ‬ᕅᐉ‫ڂ‬ǫшᙍԓෞ϶ᛧ‫ݹ‬шϾ ૽‫ୂވ‬ՙҋǭ ठҊ‫ݹ‬ᡆσિѼ஛ີՀಉऔউ΢ǫߵཥϾ૽σѼ஛‫ވ‬ቑҊ‫ۿ‬Ꮫ गᕅಉऔ‫ވ‬พҊǭѓ΂Јॖǫಉऔউ΢ࡹಉऔჰѝ٧੧࢜‫קވ‬ᔇ‫੾ۿ‬ᚦ‫΂ވ‬ᅶ Ԕ΢ኪӻǫྴಉऔউ΢џፊ਋ǫм࡫σࡕྴ‫ࢩވ‬Ϧ‫ࣚڂפۿ‬ཥᏛग੦੧‫ވ‬พ ҊǫႴࡹߊ૖ਾᓟ੨ȇAlzheimer diseaseȈȇBehl et al., 2000ȈǬAIDSǬԵᡆ դࣔ੦੧าǭ. 22.

(25) ޻1.2 !ಉऔউ΢ᆭಉऔᚦԔχୋը!)տ‫!ֲ׊‬ᅱΪፌЅ-!2003*! Apoptosis উ΢. Necrosis ᚦԔ ·ಉऔጙְᏵ‫ۻ‬ളџ ·ಉऔϮ౿ጌᡆ๕ά ·ᏵॸಉऔϠဵ ·෻ಉऔβ‫ׅݧ‬Ԃ ·औᏋϠဵ. Morphological features ·ᆙࡤְᏵ‫ۻ‬ǫಉऔጙพ‫౓ݧ‬ດ ·ಉऔਘ chromatinᆢ໚Ꮐᕤ ·ಉऔጙዢᕤϮਘᏀᕤ ·ಉऔਘϠထՙҋ‫ׅ‬Ԃβᡆ ·ਘጙᜇጋβ‫ׅݧ‬Ԃ (apoptotic bodies) ·౿ጌᡆ‫ׅ‬Ԃຂᕪ(bcl-2 familyࣣ ᜙) Biochemical features. ·ᙽήѪᑴളџ ·෻መિຽ ·DNAᒶ༷ϡᘇ (smear ) ·ಉऔྂဵࡌ DNA fragmentation (Ԕ΢௸න). ·ொ‫ڂ‬ၯสੂϮࢩϦՙҋϮ enzymatic steps ·መિ Energy (ATP)-dependent ·ഹ΂‫ۿ‬Ӥ।‫ވ‬ਘβᡆ߆ࡂ DNAЙ ࢛(ladder pattern ) ·ಉऔྂဵ߲ DNA fragmentation · ౿ጌᡆក‫ܢ‬ಿҒີΌಉऔ፝ (cytochrome C ,AIF) ·caspase cascade ࢩϦ ·ಉऔጙჰᅷ‫צۻ‬ᠹ ( phosphatidylserineϯᙦ). Physiological significances ·ተ៓፺޿Ᏽ࿹ಉऔ ·Ͼ૽ߑҊ౒‫ۻ‬మ໭ (ိᡆ‫ק‬ᔇ, ੧࢜ྂဵ, ઩ਲ਼,Э ᖫ࢜‫ݹ‬ౙҊ) ·macrophages ୱՀնᏏՙҋ ·Ͼ૽พ‫ݰ‬ϯᓿ. ·ተ៓ॸըಉऔ ·ᇟᏛҊ౒‫ٿۻ‬ᐖ (growth factors σ‫ـ‬, hormonal environment ‫צ‬ᠹ) ·ࣣ፺ಉऔ or macrophages ֘ш ՀնᏏՙҋ ·σϾ૽พ‫ݰ‬ϯᓿ. 23.

(26) )΂*!ಉऔউ΢‫ވ‬੔ቲ ಉऔউ΢‫ވ‬ၥՙǫм֍๨੔‫ވۊ‬Ҋ‫ݹ‬ϦᏙᠹϦǫΟᆭಉऔ‫ވ‬ᚦԔᄉ෼σ ӌǭәԓǫ΂ٛࠗᄁᏙ‫ۿ‬ҊϦᏙ‫ވ‬੔ቲǫшҋ٧ՙࢸ்૯ᛧ‫ࡹݹ‬ո೮Ԃಉऔউ ΢‫ࡧވ‬ከǫ٦Ӭউ΢ၯสτཥԍǫಉऔࠗᄁ‫צ‬ᠹȇcellular morphology changeȈǬಉऔጙϚቢ‫ ވ‬phosphatidylserineȇ PS Ȉ ‫ވ‬ѝᙃǬಉऔ๱ᕤ ( Shrinkage ȈǬDNA ᘇຂȇoligonucleosomal DNA cleavageȈǬಉऔਘዢᕤ ȇnuclear shrinkageȈϮࢀԼ፝Ꮐ฿ȇchromatin condensationȈǫີԭಉऔጙ ϚഇஉಉऔϠഡࢸӤॸмጙмᙖχ উ΢βᡆȇapoptoic bodyȈǫҽೆ፺޿‫ވ‬նᏏಉऔ‫܃‬նᏏǫٗ෻‫ݰ‬੨ϯᓿౙҊǭ ࡱ΂૊ᇘࢸᇟพಉऔີՀapoptosis ࡹ΂ᅶၟӪ‫דވ‬ᕅᐉ‫ڂ‬ǫᙍԓෞ϶ᛧ‫ݹ‬ш િϾ૽‫ୂވ‬ՙҋǭ‫ܤ‬ᡆѝ୲᎝ә෻ѥᏏಉऔǫউ΢ಉऔട಍ϔཥ‫ؿ‬ӒᚦԔ ȇnecrosisȈȇFadok et al., 1992ȈǭࢩϦউ΢ࣣ᜙‫ވ‬ಿҒ፝Ϯᇾટǫѣॱԍ ‫୍ވ‬ᆭ‫צ‬ᠹ౿ဆᡆጙ‫ְވ‬Ᏽ‫ۻ‬٣౿ဆᡆ18ጙ႔ՆȇƩƺmȈΗॕǫԍ‫ވ‬ୱՀϠဵ ಿҒ፝‫ۿ‬࿭੔ਯፊொࢩϦਘᇿᇾટЧДဵDNA٣ࢀԼᡆᘇຂǫшЧີՀTUNEL ȇTerminal deoxynucleotidyltransferase UTP NickEnd LabelingȈǬDAPI staining assayǬcomet assay ϮDNA ႔‫ݑ‬Ϡ݂ᔗ෪ǫ೤ٛࠗᄁᏙ‫ۿ‬ҊϦᏙ‫ވ‬ ᠹϦΙ‫ވ‬ᔗ෪೶ࡹ࣫‫ة‬apoptosis ‫ވ‬୮ᘬǭԓѝǫಉऔউ΢Οཥ௫୆΂‫ت‬ҿ‫ވ‬ ૲৩໱ᇷՄᕻȇsignal transduction cascadeȈተ៓ӑ໏࢛‫ີވ‬Հǫᆉஆӝፊொ ส‫ۻ־‬Ԕ΢‫ވ‬ਆܷǭ. ȇΉȈಉऔউ΢χၘৠ A. ѝӞೳৠ—Ԕ΢‫ڐ‬ᡆ௫୆ၘৠȇDeath receptor initiated pathwayȈ ಉऔጙΙԔ΢‫ڐ‬ᡆၘৠߵࡹ࿭ҎࢩϦಉऔጙΙFasǬTNFR-1‫ۿ‬TRAIL receptorาԔ΢‫ڐ‬ᡆᆭಉऔጙΙ‫ވ‬surface receptor฿Ӕǫក‫ܢ‬ಉऔউ΢૲ဝࡌ ້௫ǭಉऔউ΢௫୆ࡌཥ‫ދ‬௎ࢩϦcaspase cascadeǫԭ٣ಉऔࡇ‫׍‬ப‫ؿ‬Ӓউ΢ǭ. 24.

(27) 1. Fas/FasLȇCD95/CD95LȈ Fasឝ‫ܤ‬TNFȇtumor necrisis factorȈ receptor superfamilyτtype Iጙಿ ҒǫԭFasLࢸTNF receptor superfamilyτtype˟ጙಿҒǫྴFasᆭFasL฿Ӕǫ ཥࢩϦFas receptorǫٗີՀtrimerizationǫٗօϾFADDȇFas-associated death domainȈ฿ӔԶreceptor Ն‫ܤ‬ಉऔ፝τ‫ވ‬domainǰѓ΂ЈॖǫFADDཥີ΂‫׸‬ օϾӤϠή‫ވ‬procaspase-8 ‫ׅ‬Ԃ‫ވ‬DISCȇdeath-inducing signaling complexȈǫԓ਋procaspase-8ཥәᄣ‫צވׅ‬ᠹ‫ڠ‬ᐑࡂ‫ވ‬ඓଦԭࢩϦԂ caspase-8ǫ‫ٷ‬ԍְᏵࢩ‫ވۻ‬caspase-8 шࢩϦcaspase-3 ‫ڠ‬caspase-7ǫԭ caspase-3ཥҽࢩϦcaspase-6ǫ೤ٛeffector caspaseȇм࡫caspase-3Ǭ6Ǭ7Ȉ ཥີ΂‫׸‬чተ៓΂೨Մ‫ވ‬caspase substrateȇBratton et al.,2000Ȉǰ‫ޚۿ‬ caspase-8‫ࢩވ‬Ϧߝ٣Bcl-2৅௳ԂঠBid‫ވ‬ຂဵǫtBidՆ౴Զ౿ጌᡆǫߝ٣౿ጌ ᡆក‫ܢ‬зcytochrome c ௎๨ࢩϦcaspase-9 ‫ڠ‬caspase-3 ടࡌ٣ಉऔʗ apoptotic deathȇBudihardjo et al., 1999Ȉǭ. 2. TNFR1ȇtumor necrosis factor receptor 1Ȉ TNFࡹҎࢩϦ‫ވ‬ѥᏏಉऔ‫ࢀ༹ۿ‬ϯᓿҊԂ‫ވ‬Tಉऔ‫܃‬ౙҊ‫ވ‬ǫTNF‫ڠ‬ಉऔጙ ޻ॖ‫ވ‬TNFR1฿ӔࡌǫཥօϾTRADDȇTNFR-associated death domainȈ฿Ӕ ԶreceptorጙϚ‫ވ‬domanǫີԭࢩϦcaspase-8ǫग٣ಉऔউ΢ǰѓ΂Јॖǫཥ օϾRIPȇreceptor interacting proteinȈϮTRAF2ȇTNF-associated factor 2Ȉ ᆭχ฿ӔǫࢩϦNF-ǉBߝ٣ಉऔӯࢩȇDerradji and Baatout, 2003Ȉǭ. 25.

(28) ޻1.3. ѝӞೳৠχԔ΢‫ڐ‬ᡆȇdeath receptorsȈ Receptors. Ligands. CD95(Fas, Apo1). CD95L. TNFR1(p55, CD120a). TNF/ lymphotoxin. TNF gene. DR3(Apo3, WS-L1,. Apo3L(TWEAK). super. TRAMP, LARD). family. DR4. Apo2L(TRAIL). DR5(Apo2, TRAIL-R2,. Apo2L(TRAIL). TRICK2,KILLER). 3. TRAILȇTNF-related apoptosis inducing ligandȈ TRAIL ‫܃‬೮Ԃ‫ވ‬apoptosis ၘৠ‫ڠ‬Fas ࡇࣣՖǫ୛΂ၖFas ᐉ‫ڂ‬σϳ΂ኣ ‫ࡹވ‬FasL ‫౓޻ވ‬वT cell ᆭNK cell ‫ࢩވ‬ϦǫԭTRAIL ‫ࢩވ‬ϦшЧᙍҎ೑Ӥಋ ᘺ‫ٿ‬ᐖ٧޻౓ǭTRAIL ‫ވ‬receptor ࡹDR4 ‫ۿ‬DR5ǫྴTRAIL ᆭDR4 ‫ۿ‬DR5 ฿ ӔࡌཥօϾDR4/DR5 Death domain ฿ӔǫີԭࢩϦcaspase-8Ǭ10ǫԭີՀ ಉऔউ΢ϯᓿȇMarsters et al., 1997Ȉǭ ԭಉऔጙΙԍ‫ٶ‬ᅶreceptor ཥᆭDR4/DR5 ᝘‫ݵ‬TRAIL ‫ވ‬฿ӔՆ࿳ǫൠࡹDcR1 ᆭDcR2ǫྴTRAIL ᆭDcR1 ‫ۿ‬DcR2 ฿Ӕࡌǫߵσཥ௫୆ಉऔউ΢ϯᓿǭ. B. ϚӞೳৠ—౿ဆᡆၘৠȇMitochondrial pathwayȈ ѓѝ΂ᅶಉऔউ΢ၘৠߵࡹ࿭Ҏ౿ጌᡆχ‫צ‬ᠹԭϾพ‫ވ‬উ΢ǭ೤ٛϾ૽౿ ጌᡆ‫ވ‬Ԕ΢૲৩шЧࡹDNA ‫ڐވ‬ཕǬເᙽήᐑࡂ‫ވ‬σѪᑴǬROS (reactive oxygen species) ‫ވ‬ౙҊǫ‫܄ࡹۿ‬௎٧Ե‫ܤ‬Ԕ΢௎‫ڐ‬ᡆࢩϦ‫܃‬໱ᇷ‫૲ވ‬ဝาǭ ྴ౿ጌᡆ௎Ԇ‫ڀ‬Ԕ΢૲৩χࡌǫ౿ጌᡆ‫ވ‬ጙ೦೯‫ۻ‬шિཥᠹά (mitochondrial membrane permeabilization, MMP) ǫ ౿ ጌ ᡆ ጙ ႔ Ն ৘. (mitochondrial. transmembrane potential)Οԍшિളџǫߝ٣೑Ӥ౿ጌᡆϚ‫ݹވ‬፝ក‫ܢ‬Զಉ 26.

(29) औ ፝ ྴ τ ǫ ‫ ٸ‬τ м ࡫ ೑ Ӥ ߝ উ ΢ ‫ ވ‬ಿ Ғ ǫ ٦ Ӭ Ǳ (1) cytochrome c Ǭ (2) caspasesǬ(3) Smac/DIABLO (Second Mitochondrial Activator of Caspases/Direct IAP Binding protein with Low pI)Ǭ(4)HtrA2/OmiǬ(5) AIF (apoptosis inducing factor)ǬϮ (6) Endo G (endonuclease G)ǭ೤ٛಿҒш‫ދ‬௎‫໋ۿ‬௎ߝີಉऔউ΢χ‫ׅ‬Ԃǭ Cytochrome c ࡹҎಉऔਘϚ୮ә࿭ᙦᒬǬᙦ᝶ԭӔԂ‫ވ‬ಿҒǫӞ޺‫ׅ‬Ԃ਋ࢸ ΂ॸσ‫߲ވۻࢩٷ‬ៗ‫ݹ‬ǫᅷࢸapo-cytochrome cǭApo-cytochrome c ӞӔԂࡌ ࡇ‫׍‬ӝཥೆၥଃ‫ڀ‬౿ጌᡆϚǫԭӞີΌ౿ጌᡆ‫ވ‬ӌ਋ǫapo-cytochrome c ཥ ࿭ Ҏ cytochrome c lyase ‫ ވ‬໴ Ϧ ԭ ‫ ڠ‬hem moiety ฿ Ӕ ǫ ີ ΂ ‫ ׸‬ӝ ‫ ׅ‬Ԃ holo-cytochromecǫٗӯӞ‫ܤ‬౿ጌᡆ‫ވ‬Ϛѝጙχ໋ (intermembrane space)ǭ Cytochrome c ‫ވ‬Ѽ஛лિࢸ႔ήχអஜ‫ޚ‬ǫшЧ໱ᇷ႔ή‫ܤ‬႔ή໱ᇷᜏτ complex III ‫ڠ‬complex IV χ໋ǭ՗ࡹLiu าΊӞ1996 Ӻพ౓Ӟ΂ॸcell-free ‫تވ‬಄τǫcaspase-3 መवԍdATPЧϮholo-cytochrome c ‫ވ‬ӯӞπિ୳ೆࢩ ϦǭӞࡌឲ‫ވ‬Ѕᝏྴτࡇ‫׍‬ӝൠೆᛵძǫྴcytochrome c ஬౿ጌᡆೆក‫ڀܢ‬ ಉ औ ፝ τ ਋ ǫ ཥ ၖ Apaf-1 (apoptoticprotease-activating factor-1) Ч Ϯ caspase-9 ฿Ӕٗ‫ׅ‬ԂጻӔ‫ݹ‬ǭӞdATP ӯӞχ‫ݠݺ‬Ηǫcaspase-9 шЧೆᄉ ϡԭࢩϦٗີ΂‫׸‬ᄉϡΗ෕‫ވ‬caspase-3 ٣‫ࢩٸ‬Ϧǫߝ٣ಉऔີΌউ΢ǭଟΈ cytochrome c χѝǫcaspase ΟшિՆ‫ܤ‬౿ጌᡆϚǫ‫ދ‬ԶಉऔᗃΌউ΢߲π ೆក‫ܢ‬Զಉऔ፝τǭ1998 ӺMancini าΊЧդࣔࢀԼχЈ‫ݛ‬ǫժҋҼೢ෹ᡀ ༵ᜋ (confocal microscope) ЧϮ႔ήᡀ༵ᜋ (electron microscope)ǫᡷჯЧ UVBǬC2-ceramide ЧϮsaturosporine า‫ݹ‬፝Ͼ૽ಉऔউ΢ࡌǫcaspase-3 ߲ ៗ‫ވݹ‬ϠՠՆ࿳ǭ฿ܷพ౓ӞѼ஛஺‫ݠ‬Ηǫcaspase-3 ߲ៗ‫ݹ‬Ն‫ܤ‬౿ጌᡆϚѝ ጙχ໋ǫᒶ๨ಉऔউ΢‫ވ‬ౙҊǫ౿ጌᡆϚ‫ވ‬caspase-3 ߲ៗ‫ߘݹ‬ཥᒶχෞ϶ǭ Ыॱәԓ௙ፌǫcaspase-3 ߲ៗ‫ݹ‬шિӞಉऔউ΢‫ވ‬ၯสྴτǫཥ஬౿ጌᡆೆ ក‫ܢ‬Զಉऔ፝ϚǫٗೆࢩϦԭᏛगಉऔউ΢ǭӞ‫ٸ‬ЫΊ‫ة࣫ވ‬τшЧพ౓‫ڀ‬ caspase-9 ЧϮcaspase-2 ΟԍᜡՖ‫ࢩވ‬Ϧၯสǭྴcaspase Ӟಉऔ፝з౓‫ވ‬ 27.

(30) ਋ ॹ ǫ ٗ σ Э ޻ ಉ औ ΂ ‫ ۊ‬ཥ ᗃ Ӓ উ ΢ ‫ ވ‬σ ᘓ ၘ ǭ ә ࢸ ԍ ΂ ࿹ ಄ ᅷ ࢸ IAPs (inhibitor of apoptotsis proteins) ‫ވ‬ಿҒǫшЧᙍҎ‫ڠ‬caspase ฿Ӕٗ‫ڂפ‬ caspase ࢩ ‫ ۻ‬ԭ ߋ Ў ಉ औ উ ΢ ǭ ೤ ΂ ᜡ ‫ ވ‬ಿ Ғ ԍ XIAP Ǭ c-IAP1 Ч Ϯ c-IAP268-71ǭ೤ٛಿҒ೶֍ԍ΂ॸЧΙᅷࢸBIR (baculovirus IAP repeat) ‫ވ‬ ୋ༞ǫࡹУव‫ڠ‬caspase ଱ᗍ฿ີԭ‫ڂפ‬caspase ࢩ‫ވۻ‬ୋ୨ǫ՗ࡹ‫ٸ‬ያϡ‫ވ‬ ᐉ‫ڂ‬ҕ߲ϔѹΓϠథཨǭҕ߲ι‫ތ‬BIR ϠՠՆ࿳χσӌǫჰσӌ‫ވ‬caspase ‫ٷ‬ σӌสࡂχஈ΂‫ۻ‬ǭЧXIAP ࢸ٦ǫ౺ΖॸBIR ୋ୨Уवࡹ‫ڂפ‬caspase-9 χ ࢩϦǫԭӞ౺΂ॸ‫ڠ‬౺ΉॸBIR ୋ୨χ໋ǫߵшЧ‫ڂפ‬caspase-3 ‫ࢩވ‬Ϧ69ǭ ϯχǫ΂ٛ٧Ե౿ጌᡆϚ‫ވ‬উ΢ϠήǫӬǱSMAC/DIABLOЧϮHtrA2/Omiǫ߼ િ‫ڂפ‬IAPsԭ٣பcaspase ೆࢩϦǫີԭ٣ಉऔີΌউ΢ǭSMAC/DIABLOӞӔ Ԃࡌཥ࿭ҎN ᅻMLS (mitochondrial localization sequence) ‫ވ‬ஜምԭᙦ౴‫ڀ‬ ౿ጌᡆ‫ވ‬Ϛѝጙ໋ǫٗ࿭ҎᇾટᄉϡஉMLS ౴ଟǭӞԔ΢૲৩χ‫ٿ‬ᐖΗǫSMAC /DIABLOཥ஬౿ጌᡆྴτೆក‫ڀܢ‬ಉऔ፝ϚǫٗшЧ‫ڠ‬IAPs ฿Ӕԭ౴ଟIAPs ჰcaspase ࢩ‫ڂפވۻ‬ǭЧXIAP ࢸ٦ǫྴSMAC /DIABLO ‫ڠ‬XIAP ฿Ӕ਋ǫш Ч‫ڂפ‬XIAP‫ڠ‬caspase-9 ฿Ӕ‫ވ‬િΑǫٗߝີಉऔউ΢72ǭHtrA2/Omi ‫ڠ‬ smac/DIABLO ԍ೑Ӥ‫ވ‬ᜡՖᗱǱ(1) ӔԂࡌӌኣ࿭ҎN ᅻ‫ވ‬MLS ஜምԭᙦ౴ ‫ڀ‬౿ጌᡆ‫ވ‬Ϛѝጙχ໋ǫٗ࿭ҎᇾટᄉϡஉMLS ౴ଟǰ(2) ‫ޚٶ‬χN ᅻ‫־‬ҿߑ ஛ࣣ޿ǰ(3) ӞԔ΢૲৩‫ٿވ‬ᐖχΗǫཥ஬౿ጌᡆྴτೆក‫ڀܢ‬ಉऔ፝Ϛǫٗ шЧ‫ڠ‬IAPs ฿Ӕԭ‫ڂפ‬IAPs ‫ވ‬ՙҋǭ՗Бၟ੔ը‫ࡹވ‬ǫӞ౿ጌᡆѝHtrA2/Omi ‫ވ‬ၯࡂ޻౓(overexpression)۪۪ཥ೮Ԃ΂ᅶ‫ڠ‬ಉऔউ΢ౚࢸσӌ‫ވ‬Ԕ΢౓ ດǭԔ΢‫ވ‬ಉऔϔ෼‫ڠ‬উ΢‫ވ‬ಉऔ΂ኣǫಉऔ፝ཥԆᕤԭ٣பಉऔᠹ༔ǫᗟ෼ ϔ෼ߜԍಉऔጙ‫ְވ‬Ᏽ‫ۻ‬ǫ՗ࡹಉऔጙσཥౙҊዢᄐǫΟσཥౙҊಉऔউ΢β ᡆǫ࣎Զಉऔਘ‫ވ‬ᠹϦΟ೶ְһ਺џǭଟԓχѝǫղ٣ࡹӞ઩ХApaf-1 ЧϮ caspase-9 ‫ވ‬ಉऔྴτၯࡂ޻౓HtrA2/Omiǫ΂ኣΟшЧ೮ԂಉऔԔ΢ǫ೤޻ ҙHtrA2/Omi шЧσ࿭Ҏ‫ڂפ‬IAPs ‫ވ‬Јӻߘિߝ٣ಉऔີΌউ΢ǭSuzuki า 28.

(31) Ίพ౓ǫठवְһ਺ଟHtrA2/Omi ߝີಉऔউ΢‫ۻࢩވ‬ǫଟΈ౴ଟ‫ٸ‬N ᅻ‫־‬ҿ (‫ڂפٷ‬IAP ࢩ‫ۻ‬χୋ୨)χѝǫᗂመवஉ‫ٷ‬ԍserine-protease ࢩ‫־ވۻ‬ҿ౴ଟ ௕74ǭәԓǫHtrA2/Omi шિ࿭Ҏ‫ٶ‬ᅶЈӻߝີಉऔউ΢ǫ΂ᅶࡹ࿭Ҏ‫ڂפ‬IAPs ԭࢩϦcaspaseǫѓ΂ᅶߵࡹ‫ٸڠ‬Ѹ‫ٷف‬serine-protease ‫ۻࢩވ‬ԍ᜙ǭ AIF ЧϮEndo G ࡹБၟ੔ը‫ߝވ‬উ΢ಿҒǫѣॱшЧ஬౿ጌᡆកзٗ‫ދ‬ ௎ີ‫ڀ‬ಉऔਘྴτǫᄉϡDNA ԭ٣ಉऔີΌউ΢ǭәԓǫѣॱѸ‫ٷߘف‬ԍDNA ᄉϡᇾટ (nuclease) ‫ވ‬лિǫٗσመव࿭ၯࢩϦcaspase ‫׸ވ‬ᡦ٧ߝີಉऔ উ΢ǭAIF ‫ڠ‬SMAC /DIABLO ϮHtrA2/Omi ࣣӌǫ΂ኣӞӔԂࡌǫ࿭ҎMLS ஜ ምີΌ౿ጌᡆ‫ވ‬Ϛѝጙ໋ǰԭEndo G ߵࡹҎ౿ጌᡆϚ‫ވ‬୮ә࿭ᙦᒬǬᙦ᝶ԭ ӔԂ‫ވ‬ǭAIF ЧϮEndo G ‫ڠ‬caspase ࣣБӌኣшЧϾ૽౿ጌᡆጙ႔Ն‫ވ‬ള џǫϮಉऔጙΙPS (phosphatidylserine) ‫ވ‬ѝᙃǫЧϮࢀԼ፝‫ވ‬Ꮐᆢา౓ດǭ Endo G ᄉϡ‫ׅ܃‬ԂχDNA Й࢛‫ڠ‬caspase ࢩϦ໋௎‫܃‬೮ԂχDNA Й࢛άβ ৘σӤǫ෼ԭAIFᄉϡ‫ׅ܃‬Ԃ‫ވ‬DNA Й࢛‫ܫ‬ᡀၟάǫάँԍ50 kb61,80ǭ. ȇΖȈಉऔউ΢χፊொᐉᙦ! A. Caspase ᇾટ৅௳ ApoptosisၯสτǫཥࢩϦ΂࿹ಿҒДဵ䁐ȇproteaseȈ٧ୱՀউ΢χ୆ՙǭ ղ caspase ȇ cysteine aspartyl-specific proteaseȈ ࡹ ‫ ٷ‬ԍ ஈ ΂ ‫ ވ ۻ‬cysteine proteaseǫஈ߇ϡഡaspartic acid residuesȇAlnemri et al., 1996ȈǭCaspase ಿ Ғ‫ت‬ҿ֘‫ٷ‬ԍࣣՖ‫ވ‬਴୮ᇿ‫־‬ҿǬ฿ᄣ‫ڠ‬ஈ΂‫ۻ‬ǫ೶ࡹ࿭ߑࢩϦᄁ‫ވ‬ pro-caspaseȇँ30-50 kDaȈχຂဵ‫܃‬गǭ೤ٛpro-caspase м֍ΖॸУव‫ވ‬ ೴ՆȇdomainȈǱNH2 terminalǬlarge subunitǬsmall subunitǭPro-caspaseࢩϦ਋ѯ໡Һ࿭Ҏ‫ٸ‬Ыcaspases ີՀ΂ ೨ՄಿҒϠဵǫຂဵ೤ٛdomainǫ౴ଟpro-domain ‫ڠ‬linker regionǫ٣பάǬ βsubunit฿Ӕ‫ׅ‬ԂጻӔᡆǫԂࢸࢩϦᄁ‫ވ‬caspaseȇNicholson et al., 1997Ȉǭ CaspaseΕшϠࢸinitiator caspase‫ڠ‬effector caspaseǫinitiator caspase‫ڀڐ‬ѝ 29.

(32) ٧‫ۿ‬ಉऔϚউ΢૲৩໱ᇷࢩϦࡌǫӞີ΂‫ࢩ׸‬Ϧeffector caspaseǭinitiator caspaseм֍ԍcaspase-2Ǭ8Ǭ9Ǭ10ǰԭeffector casapseм֍ԍcaspase-3Ǭ6Ǭ 7ǭ‫ܤ‬౿ጌᡆၘৠτǫcyrochrome cកзᆭApaf-1฿ӔǫࢩϦcaspase-9ǫີԭ ࢩϦcaspase-3Ǭ6Ǭ7ǭ฿ܷ೮ԂಉऔਘጙಿҒȇlaminȈ‫ވ‬ϠဵǬPARPȇpoly ȇADP-riboseȈpolymeraseȈຂဵǫPARP‫ٷ‬ԍॼ൱‫ڐ‬ཕDNA‫ވ‬ՙҋǫྴcaspase-3 ࢩϦཥຂဵPARPǫߵཥҎ116 kDaຂဵԂ85kDaǫԭџчॼ൱лિǭЧϮࢩϦ ‫ވ‬casapse-3ཥஉICADȇInhibitor of CADȈϡଟ‫ܢ‬зCADȇcaspase-activated DnaseȈǫԭ೮ԂDNA fragmentationǫີԭᏛगಉऔউ΢ǭ. B. Bcl-2 ৅௳ಿҒχፊொ Ҏ‫޿ܤ‬න‫ྴة࣫ވ‬τǫ້‫ڿ‬พ౓Ӟԍٛউ΢‫ވ‬ಉऔτǫ‫ٸ‬౿ጌᡆٗσ΂‫ۊ‬ ཥз౓ᅄά੾ຂ‫౓ވ‬ດǫәԓԍΈ౺Ζᅶ௙ፌǫᇘࢸӞಉऔউ΢ၯสྴτǫཥ ԍ‫ݹ‬፝ᆢ໚Ӟ౿ጌᡆѝጙΙٗ‫ׅ‬Ԃϵࢧǫәԓ౿ጌᡆϚѝጙχ໋‫ݹވ‬፝ߘபЧ កз‫ڀ‬ಉऔ፝ྴτǭBcl-2 ৅௳ಿҒ (Bcl-2 family protein) ߘࡹ΂࿹шЧᆢ໚ Ӟ౿ጌᡆѝጙٗ‫ׅ‬Ԃϵࢧ‫ވ‬ॐवϠήǭਜᏬ฿ᄣЧϮлિ‫ވ‬σӌǫBcl-2 ৅௳ ಿҒϠࢸΖᅶǱ (1). ‫ד‬উ΢ಿҒ࿹ (anti-apoptotic subfamily). (2). Ӥୋ༞ߝউ΢ಿҒ࿹(multi-domain pro-apoptotic subfamily). (3). ഹୋ༞ߝউ΢ಿҒ࿹ (BH3 only protein subfamily)ǭ ‫ד‬উ΢ಿҒ࿹м֍Bcl-2ǬBcl-xLǬBcl-wǬMcl-1 ЧϮA1(Bfl-1)ǰ೤ٛಿҒ. ࣚ֍ԍ4 ॸBcl-2 homology (BH) ୋ༞ (BH1 ‫ڀ‬BH4)ǭӤୋ༞ ߝউ΢ಿҒ࿹м֍BaxǬBakǬMtd (Bok) ЧϮBcl-ramboǰѣॱ֍ԍ3 ॸBH ୋ ༞ (BH2 ‫ڀ‬BH4)ǭԭഹୋ༞ߝউ΢ಿҒ࿹ߵм֍Bik (Nbk)ǬBadǬBidǬ Bim(Bod)ǬHrk (DP5)ǬNoxaǬBlkǬBnip3 (Nix)ǬBnip3LǬPumaǬp193ǬBmf ЧϮBcl-G าǰ฿ᄣτє֍ԍBH3 ୋ༞ǫ՗٠෼‫ٷ‬ԍߝউ΢χлિǭБၟ‫ॸٶ‬ ߝউ΢ಿҒ࿹χߝউ΢‫ۻ‬਋ǫӤୋ༞ߝউ΢ಿҒՖЦ‫ס‬ᄴ‫ދ‬௎χፊொ‫ظ‬Լǭә 30.

(33) ࢸ઩ХBax ЧϮBak ‫ވ‬ԫႬǫჰ‫ܤ‬ಉऔউ΢૲৩‫ٿވ‬ᐖΓϠσ௬༹ǫղ٣ࡹ‫ދ‬ ௎ๆωBid ‫ۿ‬Bim ೤ٛє‫ٷ‬ԍBH-3 ୋ༞‫ވ‬ಿҒǫ೤ٛԫႬϔ෼σཥີՀಉऔ উ΢88-89ǭBax Ѫ஛ࡹЧഹᡆ (monomer) ‫ׅވ‬ӻଭ੥Ӟಉऔ፝ྴτ90-91ǫ ԭBak ߵࡹ঑ѸൠՆ‫ܤ‬౿ጌᡆ‫ވ‬ѝጙΙǰྴಉऔ‫ڀڐ‬উ΢‫ٿ‬ᐖ਋ǫBax ߘཥ஬ ಉऔ፝τ౴Զ౿ጌᡆѝጙΙ92ǫ‫ڠ‬Bak ࣣӌӝǫ‫צ‬ᠹ঑Ѹ‫ވ‬฿ᄣ93-94 ٗᆢ໚ ‫ׅ‬ԂჩӔᡆ (oligomer)95-97ǭԓჩӔᡆшЧൡΌ౿ጌᡆѝጙǫԭີ΂‫ވ׸‬Ӟ ౿ጌᡆѝጙΙ‫ׅ‬ԂϵࢧǫᏛग౿ጌᡆϚѝጙτ໋‫ވ‬ಿҒபЧកзԶಉऔ፝τ 98-99ǭΟԍЅᝏࡧзBax шЧॕ՜ᕎશ፝ཬ‫( ۻ‬polarity) ‫ވ‬ᛐ‫ࡂۊ‬ǫᏛगѝ ጙ‫ڐ‬ཕǫәԓǫBaxшિѸ‫ٗف‬σ΂‫ۊ‬መवЧ‫ׅ‬Ԃ೦ၧχ‫ׅ‬ӻǫ೮Ԃ౿ጌᡆѝ ጙ೦೯‫ۻ‬χቑкǭѓѝΟԍ΂ٛЅᝏࡧзǫBax ‫ࡹۿ‬Bak шЧ‫ڠ‬VDAC ฿Ӕǫ ٗ࿭ၯࢃٛѹ‫ވތ‬ᐉ‫ߝڂ‬٣VDAC ѱ້ີ΂‫׸‬٣౿ጌᡆϚ‫ݹވ‬፝កзǭ෼ԭ VDAC χ້Ӕٗσ΂‫ܤۊ؃ۊ‬Bax χӯӞᆭոǫәࢸԍ࣫‫ة‬ᡀҙղ٣ӞBax ؉ ԍ஬ಉऔ፝ᙦ౴‫ڀ‬౿ጌᡆ‫ވ‬஺‫ݠ‬ΗǫROS ҤшЧ‫ދ‬௎ߝີVDAC ѱ້ٗ٣ப ౿ጌᡆϚ‫ݹވ‬፝ೆកзǭഹୋ༞ߝউ΢ಿҒ࿹‫ވ‬лિ‫ڠ‬উ΢૲৩χ௎Ԇᆭ໱ᇷ ԍ᜙ǭ೤ٛಿҒѪ஛೶Ն‫ܤ‬ಉऔ፝τǫ‫ڀڐڀދ‬Ԕ΢૲৩‫ٿވ‬ᐖ਋πཥౙҊ‫צ‬ ᠹٗ౴୆Զ౿ጌᡆߌ ޿ǭЧBid ࢸ٦ǫ‫ٸ‬ѯ໡࿭Ҏcaspase-8 ‫ۿ‬granzyme B உ‫ٸ‬N ᅻ౴ଟχࡌπ ཥԍ౴୆‫ڀ‬౿ጌᡆ‫ވ‬୆ՙǭBad ӞѼ஛਋ॹཥೆᕎᇿϦٗၖ14-3-3 ฿Ӕԭଭ ੥Ӟಉऔ፝ྴτǫчᕎᇿϦࡌπཥ‫ڠ‬14-3-3 Ϡ້ԭ౴୆‫ڀ‬౿ጌᡆǭԭBim Ч ϮBmf ߵϠըཥ‫ڠ‬ಉऔଥࢅτ‫༵ވ‬βᅼ (microtubule) ЧϮԳ୆ಿҒ (actin) ฿Ӕԭଭ੥Ӟಉऔ፝ྴτǭԍٛഹୋ༞ߝউ΢ಿҒߵࡹӞ௎‫ڀڐ‬Ԕ΢૲৩‫ٿ‬ᐖ χࡌπཥӔԂǫ٦ӬྴDNA ‫ڐ‬ཕԭࢩϦp53 ‫ވ‬਋ॹǫNoxa ЧϮPuma πཥિ ࿭Ҏ໱ᇷ૲৩ๆӤୋ༞ߝউ΢ಿҒǫࢩϦӤୋ༞ߝউ΢ಿҒٗᏛगಉऔີΌউ ΢ǭDesagher าΊӞ1999 Ӻพ౓ǱӞHeLa ಉऔτǫЧstaurosporine Ͼ૽ ಉऔউ΢਋ǫBid ཥ஬ಉऔ፝ྴτ౴୆‫ڀ‬౿ጌᡆΙǫ‫ڠ‬Bax ᗍ฿ٗີ΂‫׸‬ӝࢩ ϦBax ኡ្‫ٸ‬N ᅻ฿ᄣǫԭࡌ٣ப౿ጌᡆϚ‫ވ‬cytochrome c ೆកзǭԭWei า 31.

(34) ΊӞ2000 Ӻ‫ة࣫ވ‬พ౓Bid ჰBak Ο‫ٷ‬ԍࣣᜡՖ‫ވ‬ՙҋǭ‫ד‬উ΢ಿҒ࿹χл િшિࡹ࿭Ҏ‫ڠ‬Ӥୋ༞ߝউ΢ಿҒ࿹‫ࡹۿ‬ഹୋ༞ߝউ΢ಿҒ࿹฿Ӕǫٗ‫ڂפ‬೤ ٛಿҒ঑Ѹߝີಉऔউ΢‫ވ‬лિǭԍ࣫‫ة‬ᡀҙBax वౙҊ฿ᄣΙ‫צވ‬ᠹٗࢩϦ χࡌǫπཥ‫ڠ‬Bcl-2 ԍ฿Ӕ‫ވ‬୆ՙǫәԓǫ‫ד‬উ΢ಿҒ࿹шિєཥ‫ࢩڠ‬Ϧ‫ވ‬Ӥ ୋ༞ߝউ΢ಿҒ࿹ (٦ӬǱBax) ฿ӔǭԓѝǫӬஉBcl-xL‫ڠ‬Bax ᗍ฿‫ވ‬ୋ୨੾ ᚦǫBcl-xL ٠෼шЧ‫ڂפ‬ಉऔ‫ވ‬উ΢ǫәԓǫ‫ד‬উ΢ಿҒ࿹‫ވ‬лિшЧσᙍҎ ‫ڠ‬Ӥୋ༞ߝউ΢ಿҒ࿹ᗍ฿ԭพ඗ǭ‫ד‬উ΢ಿҒ࿹‫ވ‬лિшિᗂ‫ڠ‬ഹୋ༞ߝউ ΢ಿҒ࿹฿Ӕԍ᜙ǫᙍҎ‫ڂפ‬ഹୋ༞ߝউ΢ಿҒ࿹໱ᇷ૲৩ๆӤୋ༞ߝউ΢ಿ Ғ࿹χЈӻǫີԭ‫ڂפ‬ಉऔউ΢ǭԓѝǫ‫ד‬উ΢ಿҒ࿹ΟшЧσ࿭Ҏ‫ڠ‬Ӥୋ༞ ߝউ΢ಿҒ࿹‫ࡹۿ‬ഹୋ༞ߝউ΢ಿҒ࿹฿Ӕߘ‫ٷ‬ԍ‫ڂפ‬ಉऔউ΢‫ވ‬િΑǫ‫ٸ‬ш િ‫ڂפڠ‬VDAC ‫ވ‬ѱ້ԍ᜙ǫәࢸHuang าΊพ౓உBcl-2 ‫ވ‬BH4 region ࣸ ᠹཥЮBcl-2 ‫ڂפ‬ಉऔউ΢‫ވ‬лિְһ҈ဵ௕ǫ՗ࡹҎ‫ٸܤ‬BH3 region ϔ෼ӯ Ӟǫәԓᗂࡹཥ‫ڠ‬BaxǬBakǬBikǬBidǬBim ЧϮBcl-2฿ӔǭೆᙦᒬǬᙦ᝶ԭ ޻౓ǭҕ߲ჰ‫ܤ‬ഹୋ༞ߝউ΢ಿҒ‫ވ‬ՙҋᐉᙦٗσథཨǫ޺‫׸‬ᇘࢸш. ა1.5 ಉऔউ΢ၘৠ 32.

(35) (Ashkenazi A, 2002) C. ౿ጌᡆ೦೯‫צވۻ‬ᠹϮ‫ٸ‬ፊொ Ҏ‫ܤ‬౿ጌᡆ೦೯‫ۻ‬χ‫צ‬ᠹӞಉऔᗃΌউ΢ၯสτǫσ՗᜙ᗍС‫ࡧٷ‬ከ‫ۻ‬ǫ әԓԍ᜙ࢸՍ‫ٸ‬೦೯‫ۻ‬ཥ‫צ‬ᠹີԭᏛगಉऔউ΢χ࣫‫ߑة‬஛Ӥǭҕ߲‫܃‬ඓзχ ମᇜԍΗҿ൪ᅶǭ. 1/!VDAC (voltage-dependent anion channel) ടԇඓз‫ވ‬ମᇜᇘࢸӞಉऔউ΢ၯสྴτǫVDAC (voltage-dependent anion channel) ཥ᜙೿ԭᏛग౿ጌᡆϚ‫ވ‬ATP ෻‫ڠݛ‬ಉऔ፝ྴτ‫ވ‬ADP ң ඛǫәԓF1F0-ATPase ‫ߘۻࢩވ‬ཥೆ‫ڂפ‬ǫٗ٣பH+ᆢ໚‫ܤ‬౿ጌᡆχϚѝጙ ໋ǫ෻‫ݛ‬Ӛ‫ڀ‬౿ጌᡆ‫ވ‬୮፝ (matrix) ྴτǫ ԭᏛग౿ጌᡆϚጙ‫ވ‬ጙ႔Նၯཬ Ϧ(hyperpolarization)ǫӌ਋H2O ϠήҤཥәࢸ୮፝ (matrix) τχଦᅍ೯ᓯԭ ӒϚӚࢣǫᏛग౿ጌᡆ‫ވ‬୮፝ᅄάٗߝີ౿ጌᡆ‫ވ‬Ϛጙೆኍ້ǭҎ‫ܤ‬౿ጌᡆ‫ވ‬ Ϛጙ֍ԍ೑Ӥ‫ވ‬ዢᄐ (cristae)ǫәԓྴѣೆኍ້਋ߘԍ‫޻ވ୳ـ‬ॖᐿшЧஉ౿ ጌᡆ‫ވ‬ѝጙᅄ੾ǫ٣ப౿ጌᡆϚѝጙτ໋‫ݹވ‬፝பЧកз‫ڀ‬ಉऔ፝ྴτǭ. 2. PTP (permeability transition pore) ѓԍ΂ᅶᇜ‫ݛ‬ᇘࢸǫ౿ጌᡆጙΙѓԍ΂ॸԍը‫ܤ‬VDAC ‫ވ‬೦ၧǫӓࢸ PTP(permeability transition pore)ǫΟӌኣ‫ٷ‬ԍፊ࿦౿ጌᡆ೦೯‫ވۻ‬лિǭPTP ‫ ވ‬Ѽ ያ ಋ Ԃ Ԃ Ϡ ҕ ߲ ‫ ۏ‬ѹ ְ һ ያ Ҝ ǭ ՗ ι ያ ‫ ތ‬Զ ϶ ԍ ANT (adenylate translocator)ǬVDAC ЧϮcyclophilin D ೤ΖᅶԂϠǭ޺‫׸‬ᇘࢸPTP шᙍҎ೤ ٛಋԂ᐀ၗ౿ጌᡆ‫ވ‬Ϛѝጙ໋ǫٗӞ౿ጌᡆ‫ވ‬Ϛѝጙ໋‫ׅ‬Ԃ΂ॸ೦ၧ83-85ǭ Ҏ‫ܤ‬PTP ࡹ΂ॸჰ‫ີܤ‬з‫ݹ‬፝σ‫ٷ‬ԍᒞᏮ‫ވۻ‬೦ၧǫәԓ΂՗ѱ້ǫ೑ӤϠή ຽβ‫ܤ‬1.5 kDa ‫ݹވ‬፝ߘшෙΌ౿ጌᡆ୮፝ϚǫᏛग౿ጌᡆጙ႔Ն৘ॕ՜ǫϮ H2O ϠήӚࢣ‫ڀ‬୮፝τǫີԭᏛग౿ጌᡆ‫ވ‬୮፝ᅄάٗߝີ౿ጌᡆ‫ވ‬Ϛጙೆ ኍ້ǫϮѝጙೆᅄ੾ǫԭកз౿ጌᡆϚѝጙχ໋‫ݹވ‬፝ǭ 33.

(36) D. ࢩ‫ۻ‬ਲ਼Ϧ‫) ݹ‬Reactive oxygen species* ࣴᏙ৅Ӟ்૯ԫϦ‫ڠ‬Ӻពχ໋‫ވ‬᜙ߦǫ‫ࡹܤ‬ԍΊඓзЭᖫ‫܃‬ౙҊ΂ᅶࢩ‫ۻ‬ ά‫ୂވ‬ౙ‫ݹ‬ᅷȟࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬Ƞ(ROSǫreactive oxygen species)ǫᇘࢸROS ཥ ໵ ৄ ಉ औ ǫ ೮ Ԃ DNA ໵ ৄ ǫ ٗ ш િ ཥ Ꮫ ग ԫ Ϧ ǭ ROS Ӭ ຣ ਲ਼ ਜ ഄ ᙽ ή ȇsuperoxide anionȈǬ΂ਲ਼Ϧෑȇnitric oxideȈǫࣚᆭҊ‫౓ވڥ‬ດԍ᜙ǭ٦Ӭ NOȇnitric oxideȈǫཥᆭፊொԿᓯԍ᜙ǫࡱ᜛Ч࣑‫ۊ‬ROS ࡹӪ‫ࡹۿ‬σӪǫࡌ ٧ พ ౓ ‫ ܤ ؃ ڎ‬ROS ჰ ‫ ܤ‬Ί ᡆ ౙ Ҋ ϯ ᓿ ‫ ވ‬Ӫ ᚦ Ӟ ‫ ܤ‬ਲ਼ Ϧ ᓯ Α )oxidative stress*ǫԭժҋၯਲ਼Ϧ‫݋‬ౝ䁐)superoxide dismutase*ǫ‫ڠ‬໴Ϧ䁐)catalase*ш Чჰ‫ד‬ਲ਼ϦᓯΑԭ‫߆ۦ‬Ҋ‫ڥ‬ǭԭ෻ીළ୆‫ވݹ‬୮әࣸᠹ஛Ҏ‫္ܤ‬ა‫߆ۦ‬Ҋ‫ڥ‬ຳ න‫ڠ‬к஥‫דܙ‬ᕀდτ‫ވ‬ਲ਼ϦᓯΑႴࡹultraviolet light ‫ࡹۿ‬reactive oxygen species ԭพҊ‫ވ‬ǭჰ‫ܤ‬জٙ୆‫ݹ‬ԭ‫ع‬ǫፊ࿦ᓯΑϯᓿ‫ވ‬Έဵᗂσ୳೯ჾٗС ෻ι‫ވތ‬୮әિ‫߆ۦ‬Ҋ‫ڥ‬ຳනǭԭԍࣴᏙ৅พ౓ԫႬ‫ވ‬p66shc ୮әિՙࢸከ ‫ࣸވ‬ᠹ୮әٗᇟพ‫דܙ‬ᓯΑٗ‫߆ۦ‬Ҋ‫ڥ‬ǭp66shc ࡹ΂ᅶp52shc/p46shc ៻௎ ᠹౝ(splice variant)ǫಉऔ፝ట‫૲ވ‬ဝ໱ᇷм࡫٧Ե‫ࢩܤ‬Ϧ‫ڐ‬ᏋԶRas ‫ވ‬ಉऔ Ϡຂߕဝ‫ވ‬໱ᒘǫྴၭ‫ڀ‬hydrogen peroxide (H2O2) ‫ܢࡹۿ‬োጌultraviolet light ਋ǫp66shc ‫ވ‬serine ᕎᇿϦཥΙϩǭԭp66shc ࢸߕဝ໱ᒘၘৠ‫΂ވ‬೴ Ϡшિཥፊ࿦ಉऔউ΢‫ވ‬ᓯΑٗિ‫߆ۦ‬জٙ୆‫ވݹ‬Ҋ‫ڥ‬ǭԭਲ਼ཥ௎‫ٸڐ‬ЫϠή ‫ވ‬႔ήԭ‫ׅ‬Ԃਲ਼ϦԵҎ୮ǫࡇӤಉऔϚ‫ވ‬ϯᓿм࡫‫ڜ‬օϯᓿǫመवᗂ঑ਲ਼ᠹԂ superoxide (O.-) ࡹၯਲ਼Ϧచǫ೤ٛϠήཥፊ࿦Ҋ‫ݹ‬ᡆϚϠή໋‫ވ‬ϯᓿǭྴЫ ॱԍଦࡂ‫ވ‬ϯᓿ਋ཥ‫ׅ‬ԂROS ԭ೮Ԃਲ਼Ϧ‫ۻ‬໵ৄ(oxidative damage)ǭ‫ة‬഍ಉ औউ΢‫ވ‬ౙҊࡹոመवࢩ‫ۻ‬ਲ਼Ϧ‫(ݹ‬ROS) ‫ࣴ?ڢ‬Ꮩ৅଱ΈΖᗱ௙෪Ǳ(1) ྴROS ‫ࡹۿ‬Ϛ྄‫דۻ‬ਲ਼Ϧᐉ‫ڂ‬઩џ਋ཥᇟพಉऔউ΢‫ވ‬ౙҊǭ(2) ಉऔউ΢шિԍ਋ ॹཥч‫ڂפ‬Ϛ྄‫ࡹۿۻ‬ѝ྄‫דވۻ‬ਲ਼Ϧᐉ‫ڂ‬ǭ(3) ಉऔউ΢ԍ਋ॹཥᓼծಉऔ ϚROS ‫ވ‬ቑкǭԭάᆸᆉԂҴ‫ވ‬diallyl disulfide(DADS) ཥᇟพಉऔউ΢ǫٗ ཥ٣ᕅಉऔ‫דވ‬ਲ਼Ϧᐉ‫ڂ‬઩џ௕ǫີԭ‫דܙ‬ਲ਼ϦᓯΑǫࡱшિՙࢸᕅ੨‫ݦ‬ᕄ‫ވ‬ 34.

(37) ‫ד‬ငዝቑҊ‫္ވ‬Ꮑǭԭࢩ‫ۻ‬ਲ਼Ϧ‫(ݹ‬reactive oxygen species) ཥፊ࿦Ӥᅶಉऔ ‫ވ‬Ԕ΢ǫԭଦᐑࡂ‫ۻࢩވ‬ਲ਼Ϧ‫ݹ‬ཥᏛगશ፝ၯਲ਼ϦǬಉऔጙཕ໵Ǭcaspase ᇾ ટ‫ވ‬ѹࢩϦ‫ڠ‬ಉऔᚦԔǭࣣϯ‫ވ‬ǫ՜ᐑࡂ‫ۻࢩވ‬ਲ਼Ϧ‫ݹ‬ཥࢩϦಿҒ፝ᐖ䁐‫ڠ‬ᕎ ᇿ䁐ǬເᙽήᓦӯǬࢩϦ‫ۿ‬ѹࢩϦᙦᒬәή‫ڠ‬Ꮫगಉऔউ΢‫౓ވ‬ດǭଦᐑࡂ‫ވ‬ ࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬ཥ‫ދ‬௎ཕ໵ಉऔٗగԔಉऔǫࣣϯӝǫ՜ᐑࡂ‫ۻࢩވ‬ਲ਼Ϧ‫ݹ‬ཥ໋௎ ‫ވ‬࿭ҎಿҒ፝ᐖ䁐‫ڠ‬ᕎᇿ䁐Ǭᙦᒬәή‫ڠ‬Ϡήτ୮ә޻౓ԭᇟพಉऔউ΢ǭԭ ࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬Ӟಉऔτᇟพ‫ވ‬ಉऔউ΢‫ވ‬୮ә޻౓Ѽೆ࣫‫ة‬τǫӬBcl-2 ၯࡂ޻ ౓ᙍҎࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬ཥᇟพಉऔউ΢ԭߜឿಉऔǫ෼ԭǫᙍҎBcl-2 ْЎࢩ‫ۻ‬ਲ਼ Ϧ ‫ ݹ‬ᇟ พ ಉ औ উ ΢ ‫ ވ‬ᐉ ‫ ڂ‬ϔ ࡹ ѹ ‫ ވ ތ‬ǫ መ ີ ΂ ‫ ் ׸‬૯ ǫ ԭ ࡌ พ ౓ Bcl-2 down-regulation ٣ࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬чࢩϦTಉऔǫԭС መव‫ٶ‬ᅶߕဝኪӻπિࢩϦT ಉऔ‫ވ‬ಉऔউ΢౓ດǭ౺΂ॸߕဝࡹࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬ ٣Bcl-2 down-regulationǫԭ౺Ήॸ૲ဝࡹBim ‫౓޻ވ‬ǭ Һ߲ඓ‫ڀ‬೮Ԃಉऔউ΢‫ၘॸٶވ‬ৠǫѝӞၘৠࡹ࿭Ҏಉऔ޻ॖ‫ڐ‬ᏋᏛगࢩ Ϧ૽‫(ޚڿ‬Ӭcaspase-8) ‫ڠ‬ϯᓿ‫(ޚ‬Ӭcaspase-3) ಿҒДဵᇾટǫԭϚӞၘৠУ वࡹࡧ౿ጌᡆǫ‫ٸ‬ཥកзcytochrome c ‫ࢩڠ‬Ϧ૽‫ޚڿ‬caspaseǫӬcaspase-9ǫ ᒶࡌࢩϦϯᓿ‫(ޚ‬caspase-3)ǫԭϚӞၘৠУवࡹ౿ጌᡆ‫ވ‬ከ‫ދވ‬௎ࢩϦǫ‫ࡹۿ‬ ໋௎࿭ҎѝӞၘৠcaspase-8 ϠဵѹࢩϦ‫ވ‬ಿҒBIDǭྴࢩϦBID ࡌǫBIDཥᙦ ౴‫ڀ‬౿ጌᡆٗ‫ٿ‬ᐖcytochrome c ‫ވ‬ក‫ܢ‬ǭԭBcl-2ࢸ΂ᅶ‫ד‬ಉऔউ΢‫ވ‬ಿҒǫ ѣӞ౿ጌᡆΙ‫ס‬ᄴْЎcytochrome c ក‫ظވܢ‬Լǭࢩ‫ۻ‬ਲ਼Ϧ‫ࢸݹ‬ਲ਼‫ވ‬ϦᏙϯ .-. ᓿχळҊ‫ݹ‬ǫѣм࡫ԵҎ୮(free radicals) Ⴔࡹຣਲ਼ᙽή(O2 )Ǭచਲ਼ԵҎ୮ .. ( OH)Ǭၯਲ਼Ϧచ(H2O2)ǭѣॱ‫ވ‬ଦϦᏙϯᓿཥ٣பDNAǬಿҒ፝ǬᅰДϦӔ ‫ڠݹ‬શ፝፸‫੾ڐ‬ᚦǭಉऔժҋ‫ד‬ਲ਼Ϧْᐾ‫ت‬಄чჰ‫ۻࢩד‬ਲ਼Ϧ‫ݹ‬ǫ࿭Ҏ‫ދ‬௎‫ۿ‬ ࡹ໋௎чჰ‫ד‬ਲ਼Ϧ‫ۻ‬໵ৄǭྴࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬чգܱ೤ْٛᐾ‫ت‬಄ǫ฿ܷౙҊਲ਼Ϧ ᓯΑ(oxidative stress)ǭਲ਼ϦᓯΑм࡫੧౒Ͼ૽‫ވ‬੦੧ӬAIDS, ܳ҂ႜГᆯᖹ ੨(Huntington’s disease)Ǭ‫߅۝‬රГ੨(Parkinson’s disease)Ǭߊ෮ਾᓟ੨ 35.

(38) (Alzheimer’s disease)‫΂ڠ‬ٛଆϦ‫ۻ‬ઊ࿭‫ۻ‬੦੧ǭਲ਼ϦᓯΑУव‫ވ‬٧྄ࢸࢩ‫ۻ‬ਲ਼ Ϧ‫ݹ‬ǫࡱፊ࿦ࢩ‫ۻ‬ਲ਼Ϧ‫ݹ‬ჰ‫ܤ‬ፊொਲ਼ϦᓯΑ‫ס‬ᄴ๨ॐव‫ظވ‬ԼǫҤшЧ٣ҋ‫ו‬ ೃчፊொಉऔউ΢ԍ᜙‫ވ‬ਲ਼ϦᓯΑǭ. E. Ca2+ᙽήក‫ܢ‬ ΂૊ເᙽήཥᓦӯӞϚ፝ᆒȇendoplasmic reticulumǰERȈτǫྴԔ΢૲ ৩‫ۿ‬ᛧ‫ٿݹ‬ᐖΗǫཥߝ٣ເᙽή஬Ϛ፝ᆒក‫ܢ‬з٧ǫᏛगಉऔϚເᙽήࡘ‫ۊ‬ ȇintracellularcalcium homostasisȈ‫צ‬ᠹȇBeyersmann et al., 1997; Shen et al., 2001Ȉǫ޿٧࣫‫ࡧة‬зǫເᙽήཥተ៓౿ጌᡆጙ႔Ն‫਺ވ‬ජǫग٣cytochrome. c កзЧϮάຽROSౙҊǫԭᏛगಉऔউ΢ȇLemairié et al., 2004ǰBae et al., 2003Ȉǭເᙽή(Ca2+ )ჰಉऔӯࢩ౎‫ވ‬ፊ࿦‫ס‬ᄴ΂ॐव‫ظ‬ԼǫԭເᙽήҤᆭᇟ พಉऔউ΢ϯᓿԍ᜙ǭԭЧάᆸτ‫ވ‬ԂҴDially disulfideчಷ౒Կᕅಉऔٗ࿭Ҏ caspase-3٠ᒏࠗၘৠԭᇟพಉऔউ΢ǭԭDially disulfideӞԿᕅಉऔτཥౙҊ ເᙽή‫ڠ‬caspase-3‫ࢩވ‬Ϧǭࡱଷ෪ເᙽή(Ca2+ )шЧີ΂‫்׸‬૯ಉऔউ΢‫ވ‬ ᐉ‫ڂ‬ǭ ೮ԂDNAཕ໵(DNA damage) ‫ވ‬঑әм࡫โѝጌǬᙽήϦ൦ো(ionizing radiation) Ϯ DNA ጻ ᇐ ‫ ݹ ڂ פ‬చ ਲ਼ ୮ ֶ ટ (hydroxyurea) า ୮ ә ࢜ ‫ ۻ‬ᓯΑ (genotoxic stress)ǭԭྴDNA ཕ໵‫ވ‬ಉऔࢸΈҽᝠឲDNAጻᇐϮಉऔϠຂาၯ สǫԓ਋ൠመवDNA ॼိ‫ވ‬୆ՙ٧ᆙࡤಉऔጻᇐ਋‫ވ‬Ѽያ‫ۻ‬ǫْٗዻಉऔᕅ Ϧ‫ވ‬஺‫ׅ‬ǭᆭВಉԿᅼᘀத‫ۻ‬џፊԍ᜙χATM (ataxia telangiectasia mutated) ಿҒ፝ӞDNA ཕ໵ϯᓿτ‫ס‬ᄴཬࢸॐव‫ظވ‬ԼǭATR ϮATM ᆭᕎᇿԳ፾ᐖ䁐 ৅௳(phospho-inositide kinase family)‫ވ‬฿ᄣၟࢸࣣՖǫᆭp53ǬBRCA1 าಿ Ғ፝‫ވ‬ᕎᇿϦϯᓿԍ᜙ǭࣴᏙ৅พ౓ྴΊᜡ‫ވ‬Rad17 ಿҒ፝ѯ໡ೆATR/ATM ᐖ䁐ᕎᇿϦࡌǫπཥϾพ୮ә࢜ ‫ۻ‬ᓯΑϯᓿǭࡱәԓǫᙍҎ૲৩໱ᇷೳৠ‫ވ‬ፊொǫDNA ཕ໵ᆭ૲৩໱ᇷၘৠ ፊொԍࣣ᜙‫ۻ‬ǫᆭಉऔຳනଭЎ(cell-cycle arrest)Ǭಉऔউ΢Ǭ੔‫ۊ‬୮әχᙦ 36.

(39) ᒬᆭDNA ॼိา୮ә࢜‫ۻ‬ᓯΑϯᓿ(genotoxic stress responses)ࡹԍ᜙‫ވ‬ǫࡱ መवີ΂‫்׸‬૯೮ԂDNAཕ໵χᐉ‫ڂ‬ǭԭ΂ਲ਼Ϧෑ(nitric oxide)ࡹҎ΂ਲ਼Ϧෑ ӔԂ䁐(iNOS)‫ވ‬ѼӒፊ࿦ϯᓿ‫܃‬೮Ԃ‫ވ‬ǫ‫ٸ‬ཥ೮Ԃ઩Կ‫ވۻ‬ᓯΑǫҤཥ೮Ԃಉ औউ΢ǫ೦஛ՋᒶЧΗ‫ၘވ‬ৠǱ. (1) ౿ጌᡆጙ႔Ն(mitochondrial membrane potential)‫ވ‬Ηॕǭ (2) ࿭Ҏ౿ጌᡆកз cytochrome cǭ (3) ࢩϦcaspase-9‫ڠ‬-3٣பౙҊ՜ᐑࡂNO‫ߜވ‬ឿᐉ‫ڂ‬ԭч‫דܙ‬ઊ࿭ಉऔԔ ΢ǭ ࡱ΂ਲ਼Ϧෑ(NO)ᆭ΂ٛଆϦ‫ۻ‬ઊ࿭੦੧ԍ᜙ǫӬܳ҂ႜГᆯᖹ੨(Huntington’s disease)Ǭ‫߅۝‬රГ੨(Parkinson’s disease)Ǭߊ෮ਾ ᓟ੨(Alzheimer’s disease)ǫࡱ७ப‫்׸΂ີॱב‬૯ǭ. F. NF-ǉBȇNuclear factor kappa BȈ‫ވ‬ፊொ NF-ǉB ࢸಉऔਘτॐवᙦᒬәήǫ΂૊Ն‫ܤ‬ಉऔ፝τཥᆭ‫ڂפٸ‬ᏁIǉB ȇ Inhibitor of ǉB Ȉ ฿ Ӕ ǫ ٗ σ ‫ ٷ‬ԍ ࢩ ‫ ވ ۻ‬ǫ ྴ ಉ औ ‫ ڐ‬proinflammatory cytokinesǬgrowth factorǬoxidative stress Ϯultraviolet light ‫ٿ‬ᐖ਋ǫཥࢩ ϦIǉB kinaseȇIKKȈcomplexǫᝠԭஉIǉB ᕎᇿϦǫ௎๨ཥೆE3 ubiquitin ligase ີՀubiquitinationǫٗСIǉB ཥೆproteasome ॕဵǫԭកзNF-ǉBǫ෕ᙽ‫ވ‬ NF-ǉB ղшtranslocate Զಉऔਘτǫተ៓ࣣ᜙୮әᙦᒬՙҋǭಉऔτടУव ‫ވ‬NF-ǉB ࡹҎRel-Aȇp65Ȉ ǬNF-ǉBȇp50Ȉ‫ׅ‬ԂχheterodimerȇSuh and Rabson, 2004Ȉǭ‫ڐ‬NF-ǉB ‫܃‬ፊொ‫ࣣވ‬᜙୮әԍǫᆭ‫ڂפ‬ಉऔউ΢ԍ᜙χBcl-xLǬBcl-2 ȇChiao et al., 2002ǰLemarie et al.,2004ǰLi et al., 1999ȈǫᆭಉऔҊ߆ԍ᜙ χIL-6ȇZerbini et al., 2004ȈϮc-mycȇSuhand Rabson, 2004ȈЧϮcyclin D1 ȇAlbanese et al., 1995Ȉา୮ә೶ࡹ‫ڐ‬NF-ǉB ‫܃‬ፊொǭ. 37.

(40) G. p53 ‫פ‬ᕅ୮ә 1. p53 ୮ә p53୮әǫՆ‫ܤ‬Ίᡆ౺17ჰࢀԼᡆฤᖀI7p13.1‫ވ‬Ն࿳ǫࢸ΂Ҏ΂ ࿛ϛр‫ٶڀ‬࿛ॸᡭ୮ჰȫղ16-20 kilobase (kb)Ȭ‫܃‬ಋԂ‫ވ‬ಉऔчਲ਼ਘᗇਘᇿ (DNA)Ϡήǫࡹፊொಉऔቑ෎‫ވ‬୮әǭΊᜡ‫ވ‬p53୮әǫӞີϦၯสߜӯΗ٧ ‫ވ‬୮әୋ࢛ǫΟࡹӞΊᜡ೑Ӥᕅ੨τǫട஛ೆพ౓พҊࣸᠹ‫ވ‬Ն࿳ǫУवҎ11 ॸ޻౓‫־‬ҿ‫܃‬ಋԂǫ‫ٸ‬౺΂޻౓‫־‬ҿࢸߑஆዯୋǫՆ‫ܤ‬຦౺2-11޻౓‫־‬ҿ 8-10kb‫ވ‬Ն࿳ǫ൵‫ۻ‬ငዝँຣၯ90%‫ވ‬࿳ඛ‫ࣸۻ‬ᠹ(substitution mutations)ǫ Մ໚‫־౓޻ܤ‬ҿ5-8ǭp53ಿҒ፝ԍ5ॸଦᓅ౎(>90%)ߜ੥ୋ࢛ǫϠըՆ‫ܤ‬਴୮ ᇿ13-19, 117-142, 171-181,234-258ЧϮ270-286ǫ‫ٸ‬τ਴୮ᇿ175Ǭ248Ǭ273 Ϯ282าՆ࿳ǫΕࢸࣸᠹพҊᓅ౎ടଦ‫"ވ‬ћॸዎᗱ" (hotspots) ‫ۿ‬਴୮ᇿ248Ǭ 273Ǭ175Ǭ245Ǭ249Ǭ282Ǭ176Ǭ179Ǭ220Ϯ213าՆ࿳ǫࢸࣸᠹพҊᓅ౎ ടଦ‫"ވ‬Γॸዎᗱ" ( IARC, 2002 )ǭพҊ‫ܤ‬೤ٛ"ዎᗱ"ஆዯ‫ࣸވ‬ᠹՕ‫܃‬ԍp53ࣸ ᠹχά೴ҴǭӞάӤኞ‫ވ‬ငዝǫp53‫ވ‬ჰ଴୮әࣚӌ਋พҊࣸᠹǫшિ΂ॸพ Ҋᗱࣸᠹǫѓ΂ॸߵพҊիෞ‫ࣸۻ‬ᠹǭΊᜡάӤኞ‫ވ‬p53ࣸᠹ೴ឝ‫ܤ‬ᇛ༷ࣸᠹ (missense mutation)ǫЧगౙҊ΂ॸ฿ᄣϮ‫ۻ‬፝೶‫צ‬ᠹΈ‫ވ‬ಿҒ፝ǫ p53‫ވ‬೤ Γॸዎᗱχұ΂ୋ࢛΂ѶพҊࣸᠹǫ p53ᗍ฿ୋղളџ‫ٸ‬ᗍ฿િΑǫີԭџч ‫ࢩٸ‬Ϧᙦᒬ୮ә‫ވ‬ҊϦлિǭ. 2. p53ಿҒ፝ p53୮ә‫ވ‬ౙ‫֍΂ࢸݹ‬393ॸ਴୮ᇿ‫ވ‬ਘᕎಿҒ፝ǫϠήຽँύ࿛Ζрၧԯ ႜ[ղ53kilodalton (kd)]ǫᘸᅷp53ಿҒ፝ǫ‫ܤ‬1979Ӻೆያᇘ‫ࢸٸ‬ш‫ڠ‬SV-40‫ވ‬ άT‫ד‬঑‫ׅ‬Ԃᆐஆ‫ވ‬ጻӔ‫ވݹ‬ಉऔಿҒ፝ǫәԓǫшЧ‫ڠ‬ҎSV40ᙦࠗಉऔ‫ׅ‬Ԃ ‫דވ‬T‫ד‬ᡆǫҼӌ‫ׅ‬Ԃդࣔ‫׿‬ᐏ‫ݹ‬ǭp53ಿҒ፝ӞѼ஛ಉऔ‫֍ވ‬ຽߑ஛՜ǫԭӞ ᡆѝ୲᎝‫ۿ‬Ίᜡငዝ‫ވ‬ᠹ‫ׅ‬ಉऔǫp53ಿҒ፝‫֍ވ‬ຽшଦ‫ܤ‬Ѽ஛ၩ5Զ100।χ. 38.

(41) ӤǭЅᝏോւ‫܃‬ҙǫ঑‫ڿ‬p53୮әӞಉऔቑ෎਋ǫУवፊ࿦ಉऔຳනҎG1නၯ ෗‫ڀ‬SනǫС‫ۊ؃‬ಉऔࡹո࿭Ҏಉऔউ΢(apoptosis: programmed cell death) Եగԭ΢ǭҊ‫ݹ‬ᏙΙ‫ވ‬Ϡ݂ᡀҙǫӞፊொѼ஛ಉऔຳන‫ވ‬ၥᙦΙǫp53୮ә‫ס‬ ᄴ๨ٗσϳॐव‫ظވ‬Լǭ՗Ӟፊொ‫ڐ܄‬ᓯΑಉऔ(stressed cells)‫ވ‬Ҋ߆Ιǫ߼ ‫ס‬ᄴ๨ᖇ‫ـ‬ᇯॐ‫ظވ‬ԼǰᅶᅶᛵᏬҤᡀҙǱѼ஛஺‫ݠ‬Ηǫp53୮ә‫ވ‬Уवлિ ӞᅨொDNAࡹո‫ڀڐ‬໵ৄǭәԓǫѼ஛‫ވ‬p53ಿҒ፝ขӬ"Ϡή᝵்"(molecular policeman)ᅨ຅ࢀԼᡆ୮әಋ‫ְވ‬Ᏽ‫ۻ‬ǫӬܷಉऔ࿭ჰDNAિౙҊ໵ৄ‫ވ‬әή ӬโѝጌǬᛧ‫ވݹ‬ಷ౒ǫ‫ۿ‬Ǆ‫ܢ‬োጌา‫ྚވ‬োǫp53ಿҒ፝ཥೆάຽ‫ވ‬ᇟพǫ‫ٸ‬ ᆴᐿຽϮᛐ‫ࣚࡂۊ‬άຽቑкǫٗଭЎࢀԼᡆጻᇐǫЧඓ٥ಉऔॼ൱ᐉᙦၟбဲ ‫ވ‬਋໋ǫѣ‫ވ‬೙ұࡹवያ‫ۊ‬ӞDNAጻᇐ߲ǫ‫܃‬ԍ‫ވ‬DNAॼိηՙ೶ιְ౜ǭә ࢸǫྴಉऔDNA‫ڀڐ‬໵ৄǫԓ਋ӬܷಉऔຳනσଭЎǫDNAᗂཥᝠឲີՀጻᇐǫ َር‫ڐ‬ཕ‫ވ‬ᒡ໱၎૲ൠཥ໱‫ڀ‬ήЭಉऔǭәԓǫP53ಿҒ፝ೆᇟพ‫ވ‬ҕ‫ࡹވ‬व Һொ‫ڂ‬ಉऔຳනີՀǫᡚDNAԍᐉཥॼိְһࡌǫπҽີՀጻᇐǭ΂Ѷॼ൱џ ௪ǫ p53ಿҒ፝ղЮಉऔ࿭Ҏಉऔউ΢ԵగԭԔ΢ǭp53ಿҒ፝шЧ‫΂ڂפ‬ᅶ गᕅ୮ә-MDM-2‫౓޻ވ‬ǫ΂ѶMDM-2พҊ୮әቑ൦ԭ‫ڠ‬p53ಿҒ፝ᗍ฿ཥ٣ p53ಿҒ፝џਆǫMDM-2गᕅ୮әཥάຽ޻౓ǫάँӞ30%ೣଥಋᘺԱዝǫพ ౓MDM-2୮әཥάຽጻᇐǫәԓp53ಿҒ፝ᆭMDM-2໋‫ވ‬ፊொǫшિᆭԱዝ‫ވ‬ ‫ׅ‬Ԃԍ᜙ǭp53ಿҒ፝ҤшЧ‫ٿ‬ᐖ‫ٸ‬ѣ୮ә‫౓޻ވ‬ǫӬWAF1ǭWAF1୮әཥᇐ ೮΂ᅶϠήຽࢸ21 kd‫ވ‬ಿҒ፝ǫ೤ᅶಿҒ፝ཥᆭொ‫ڂ‬ಉऔຳනີՀ‫ވ‬᜙ᗍᇾ ટ฿Ӕǫٗᡚѣॱџчࢩ‫ۻ‬ǭӬԓ΂٧ǫಉऔຳන෻‫ݛ‬௙ີǫDNAσጻᇐǫಉ औҊ߆Ե෼ൠபτᘇǭଟΈொ‫ڂ‬ಉऔҊ߆ѝǫӞࢃٛ੔ਯ‫ވ‬ಉऔǫӬధϺಉऔǫ p53ಿҒ፝Ӭܷάຽ޻౓ǫσ໲ಉऔσཥᝠឲҊ߆ǫ᜻ॐ‫ވ‬ᗂཥᇟพಉऔউ΢ǭ p53ಿҒ፝ᗂཥቑк΂ٛᆭDNAॼိࣣ᜙‫ވ‬୮ә(GADD-45)‫౓޻ވ‬ǭᒡ໱‫ۻ‬В ಉԿᅼᘀதџፊ੨(ataxia telangiectasia: AT)‫ވ‬੔ቲղࢸDNAॼိԍ୙ᚉǫல ‫ࡇޚ‬৉‫ܧ‬ᑘலғጜᕅǫӌ਋೤ٛல‫فޚ‬Ι‫ވ‬ಉऔǫ‫ܢڐ‬োጌྚোࡌǫ‫ٸ‬p53୮ 39.

(42) әೆᇟพ‫ވ‬ϯᓿࡇ৘ǫGADD45୮ә‫ވ‬ౙҊԵ෼Οൠ‫ڀڐ‬ተ៓ǭp53୮әшә ᗱࣸᠹǬჰ଴୮әളџǬ୮әॐ௟Ǭ୮әիෞา୮ә‫ࣸވ‬ᠹǫҽᆌӔ‫ٸ‬ѣगᕅ ୮әǬ‫פ‬ᕅ୮ә‫ࣸވ‬ᠹǫңᘺԂࣸᠹ୮әᆒၘǫ࿭ӤໟәήӤॐ‫׸‬ᡦ‫ވ‬गᕅᐉ ᙦᏛगΊᜡᕅ੨‫ވ‬พҊǭ Ѽ஛஺‫ݠ‬ΗǫፊொಉऔҊ߆‫ވ‬୮ә‫ٷ‬ԍ΂ॸp53ᗍ฿ୋǫ঑‫ڿ‬p53ಿҒ፝‫ڠ‬ p53ᗍ฿ୋᗍ฿ǫ‫ׅ‬Ԃ΂ॸΖࡂ‫ވ໋ޓ‬ћॖᡆҜᡆ฿ᄣǫٗСࢩϦ௫୆ԓᗍ฿ ୋχࡌ‫ވ‬୮ә޻౓ǫԭԓᗍ฿ୋχࡌ‫ވ‬୮әౙ‫ݹ‬шЧ‫ڂפ‬ಉऔ‫ވ‬ၯࡂ‫ۻ᠄ߖۿ‬ Ҋ߆ǭp53୮әѸ‫ف‬พҊࣸᠹ‫צ‬ᠹተ៓p53ಿҒ፝‫ވ‬ҊϦೳৠǱp53୮әพҊࣸ ᠹǫଟΈҼӌളџᆭp53ಿҒ፝ᗍ฿ୋᗍ฿‫ވ‬િΑǫԍٛࣸᠹ‫ۏ‬С‫צ‬ᠹΈp53 ಿҒ፝‫ݺ౑ވ‬ᡆ฿ᄣϮлિǫ٦ӬԍٛࣸᠹӞ୮әஆዯ213-217‫ވ‬Ն࿳ǫз౓ ΂ॸ੔Ϧ‫޻ވ‬ॖ‫ד‬঑ǫ٣‫ٸ‬шЧ‫ڠ‬ഹਪ‫ד‬ᡆ240ՙҋǭԍٛࣸᠹ‫ۻ‬p53ಿҒ፝ߵ шЧ‫ڠ‬ዎҭգಿҒ፝฿Ӕǭԍٛߵ‫צ‬ᠹΈෑᅻ‫ވ‬ᇿ‫ۻ‬ୋ࢛ǫџчΈ‫ڠ‬GAL4‫ވ‬ DNAᗍ฿‫ވ‬િΑǫີԭџч‫ࢩٸ‬ϦлિǭΕp53ಿҒ፝‫ׅ‬Ԃ‫ވ‬ћॖᡆጻӔ‫ݹ‬ǫ єव‫ٸ‬τ΂ॸp53ჰ଴୮әพҊᇛ༷ࣸᠹǫ࿭ԍไϠຂ‫ވ‬୮әॐಋǫ۪۪೮Ԃ ѓ΂ჰ଴୮әΟพҊիෞ‫ࣸۻ‬ᠹǫԭ‫ٸ‬ᎠѼ஛‫ވ‬঑‫ڿ‬p53ಿҒ፝Οཥၖ๨พҊ ฿ᄣ‫ڠ‬ᙦᒬлિΙ‫צވ‬ᠹǫѣॱ‫ވ‬Ҝᡆ฿ᄣ‫౓޻ڠ‬ཥ‫ࣸڠ‬ᠹ‫ۻ‬p53ಿҒ፝΂ गǭСࣸᠹ‫ۻ‬p53ၟ঑‫ڿ‬p53ᛐ‫ۊ‬ԭ‫ٸ‬ၟ߆‫ވ‬с૧නǫ٣ࣸᠹ‫ۻ‬p53‫ٷ‬ၟᓣ໿‫ވ‬ Ᏸொ‫ࡤݠݺ‬ឲ൵Ϧǭ٦ӬพҊ‫ܤ‬άကǬဇǬ‫ޛ‬Ǭ‫ڠخ‬ᆥࡔ‫ވ‬ငዝǫp53୮әχ ΂‫ۿ‬Ήჰ଴୮әพҊ΂ά࢛઩ཕԂִ೴‫ވ‬իෞǫղॕ՜Έ঑‫ڿ‬p53ಿҒ፝ћॖ ᡆ‫ވ‬ᐑࡂǫग෻‫ְݛ‬һ‫ڂפ‬ಉऔౝ஛‫ވ‬ቑ෎ǭᡆϚϮᡆѝ‫ވ‬ძᡄࣚᛵ‫ܫ‬ǫ঑‫ڿ‬ p53ಿҒ፝‫ࣸڠ‬ᠹ‫ۻ‬p53ಿҒ፝‫ׅ‬Ԃ‫ވ‬ћॖᡆጻӔ‫ݹ‬ǫ‫܃ٸ‬ԍѼ஛‫ࣸۿ‬ᠹ‫ވ‬p53 ಿҒ፝ࣚളџ‫ڠ‬p53ᗍ฿ୋᗍ฿Ϯ௫୆ᙦᒬՙҋ‫ވ‬િΑǭҎࣸᠹ‫ۻ‬p53‫ڠ‬঑‫ڿ‬ p53ᗍ฿ղ‫צ‬ᠹ‫ࢩٸ‬ϦϮᙦᒬ‫ވ‬лિǫ‫ۿ‬ш௙ፌp53‫ࣸވ‬ᠹ୮әшЧ౴ᙦ໱ᇷๆ ঑‫ڿ‬p53ಿҒ፝ǫີԭᏰொǬᙦϦǬ‫ڂפ‬঑‫ڿ‬p53ಿҒ፝‫ވ‬лિǭӬܷࣸᠹ‫ވ‬พ ҊࡹஉີՀჩӔՙҋ‫ވ‬ᅰᅻᄉᘇǫԓᏰொᆭᙦϦ‫ވ‬ՙҋߘσ൱ີՀǭ٦Ӭࢃٛ ငዝǫp53୮әพҊ෻༷࿷(nonsense)ࣸᠹǫ‫ٸ‬ᅰᅻᆭp53ᗍ฿ୋີՀჩӔՙҋ 40.

(43) ‫ވ‬฿Ӕ೴Նೆᄉ௲ǫ٣ࣸᠹp53ಿҒ፝෻‫ׅݛ‬Ԃћॖᡆ‫ވ‬฿ᄣǭ !!!!!!!!!!!!!!!. 41.

(44) ౺Ή࿦ ࣫‫ة‬ҕ‫ވ‬. ‫ޛ‬ᕅ‫ݦވ‬ᕄǫӞϕЉϔ෼ࡹॸබЂ‫ވ‬୙ᚉǫәࢸԍԤϠχ΅ΓЧΙ‫ވ‬ல ‫ޚ‬ǫ۪۪ຑᘇз‫ޛ‬ᕅ਋ιࡹ੦੧ၟѺනǫԭ෻‫ݛ‬٣ҋЂೃ‫ܢۿ‬ো‫ݦ‬ᕄาִ೴ᕄ ‫ݛ‬кЧਜ‫ݦ‬ǭЧ cisplatin ࢸУ‫ވ‬ϦᏙ‫ݦ‬ᕄӞၯчΉΓӺ٧Чቭ‫ݨ‬٣ҋӞβಉऔ Ϯߑβಉऔ‫ޛވ‬ᕅல‫ޚ‬ǫ෼ԭ‫ٸ‬Ԃਆєࡹ΂૊ǭࢸ‫๊צ‬ϦᏙ‫ݦ‬ᕄ‫ވ‬Ԃਆǫ೑Ӥ ཛྷ‫ވ‬ϦᏙ‫ݦ‬ᕄᛧ‫(ݹ‬Ӭ: gemcitabine, decetaxel)ೆ࣫พз٧ǫСᆭ cisplatin Ӕ ٪٣ҋǫพ౓‫ݦٸ‬ᕄ‫ޛ‬ᕅ‫ވ‬ਆܷБഹҋ cisplatine ‫ࢸת‬ᡀ๨ǫСિ‫ޛ߆ۦ‬ᕅல ‫ވޚ‬Ҋ‫ڥ‬ǭ෼ԭǫҎ‫ܤ‬೤ٛϦᏙ‫ݦ‬ᕄᛧ‫ۻ࢜ވݹ‬஥ǬୂՙҋάǫᏁຽΙσિၯ ຽǫᖆ‫׀‬٣ҋѯ໡ᒜྚᙫ৚ࡧҙǫәԭ೑Ӥல‫ڐ܄ޚ‬σΈୂՙҋ‫ވ‬ተ៓ԭσப σ‫ܢ‬ఌϦᏙ‫ݦ‬ᕄǭәԓǫ‫כ‬з‫࣫ۿ‬พз΂ᅶિ୳‫ޛڂפ‬ᕅಉऔٗ٣‫ٸ‬ԵՀಉऔ উ΢ȇapoptosisȈǫСσཥౙҊၯӤୂՙҋ‫ވ‬ᛧ‫ݹ‬ǫࡹѯ෼‫ވ‬ᖶ໿ǫΟࡹ‫ټ‬σ ৉ጎ‫΂ވ‬ໟηสǫ౜഍΂Ѷ‫ޛ‬ᕅ൵ϦԶѺන਋ǫӯࢩ਋໋۪۪໲തฤฤኞॸ Ћǭͺ૊ᇘࢸ໱಄τᛧพ඗ՙҋ‫ވ‬ਆܷၟᄃǫ՗ୂՙҋ϶Сਆܷᡀ๨ǫәԓ೑ Ӥ໱಄‫ވ‬τᛧ‫ވ‬ԂҴೆкЧࣴᏙϦϠ݂ٗСೆᓿҋӞ‫ד‬ᕅਆܷ‫࣫ވ‬พᆭᓿҋ Ιǭ٦ӬǱ໪ኤટᗟ‫ٷ‬ԍ‫ڠۻ࢜خ‬गᕅ‫ۻ‬ǫ՗ࡹǫ΂ॸ໪ኤટ‫ވ‬ळҊ‫ݹ‬ᅷࢸਲ਼ Ϧ໪ኤટȇsafrole oxideȈιᛵძ‫ٷ‬ԍ‫ܫ‬ᡀ‫דވ‬ᕅࢩ‫ۻ‬ǫჰ‫ߑܤ‬βಉऔ‫ޛ‬ဆᕅ ಉऔਪ A549 ਲ਼Ϧ໪ኤટшᇟ٣ಉऔάຽ޻ၩ Fas ‫ ڠ‬FasLǫີ΂‫ࢩ׸‬ϦΗ෕‫ވ‬ caspase-3Ǭ8 Ϯ 9ǫടࡌ٣‫ވ‬ಉऔ‫ؿ‬Ӓউ΢ȇapoptosisȈǫҽ‫ޚ‬ǫਲ਼Ϧ໪ኤટ Ҥ‫ٷ‬ԍ‫ܫ‬ᡀ‫ڂפ‬ԿᅼཛྷҊȇangiogenesisȈχՙҋǫ‫ٸ‬ᐉᙦߵшિࡹ೯ၯᇟᏛ ಉऔ‫ވ‬উ΢ǫӞਲ਼Ϧ໪ኤટಷ౒‫ވ‬୆ાϚғಉऔȇvascular endothelial cellsȈǫ ‫ٸ‬шቑк FasǬp53 ᆭ intergrinǃ4 ‫౓޻ވ‬ຽǭҎࣣ᜙࣫‫ة‬พ౓ǫ໪ኤટട޿ι ೆҎ΂ॸ‫ٷ‬ԍगᕅ‫ވۻ‬ϦӔ‫ݹ‬ǫᙦԭԂࢸ΂ॸшિԍ኿Α‫דވ‬ᕅᛧ‫ݹ‬ǭ ύ।ήᇿ(gallic acid; 3,4,5-trihydroxybenzoic acid)ǫ΂ᅶҎഹშᇿτᆇ‫ڎ‬ з‫ވ‬ϱ෼ස‫⇃ݹ‬ǫҒ‫ض‬าτᛧ֍ԍύ।ήᇿǫ‫ف‬ᡆшЧ࿭फ़ҋԭᔾபύ।ή ᇿǫәԓᆭԍ࢜‫ވۻ‬ϦᏙ‫ݦ‬ᕄᛧ‫ࣣݹ‬Бǫᆀࡹࣣྴ‫ވ‬ӳһǭҺ߲‫ة࣫ވ‬พ౓‫ٸ‬ 42.

(45) િ୳‫ڂפ‬ٙᕅϮឡឿဆᕅಉऔ‫ވ‬ቑ߆Ϯٗߝ٣ᕅಉऔ‫ؿ‬Ӓউ΢ǭ՗ࡹҕ߲‫ٸ‬ᓿ ҋ‫ޛܤ‬ᕅ‫ݦ‬ᕄ‫ة࣫ވ‬ϔࣣྴฬ϶ǫ໲϶ኞ࣫‫ة‬ԍพ޻‫ٸ‬ჰ‫ܤ‬Ίᜡβಉऔ‫ޛ‬ᕅᆭ ‫ޛ‬ဆᕅಉऔǫ‫ٷ‬ԍ٣ಉऔ‫ؿ‬Ӓউ΢‫ވ‬ਆܷǫԶ‫ٸܤ‬ჰ‫ܤ‬ჰ‫ٸܤ‬ѣᜡࠗ‫ޛވ‬ᕅಉ औǫӬǱάಉऔ‫ޛ‬ᕅǬᜡᕅ(carcinoid)Ϯ൵‫໋ۻ‬ғዝ‫ވ‬ተ៓ǫԶϕϔѹԍΊ࣫ ‫்ة‬૯ၯǭәԓǫӞѸ࣫‫ة‬τ‫༺ॱב‬व෪္ύ।ήᇿჰ‫ܤ‬άಉऔ‫ޛ‬ᕅಉऔਪ ȇNCI-H460Ȉ‫דވ‬ᕅࢩ‫ۻ‬ǫ‫ޛ‬ᕅಉऔәࢸ୮ә‫ވ‬σᛐ‫ۊ‬ཥ΂‫ދ‬σᘇ‫ࣸވ‬ᠹǫ೤ ኣ‫ࣸވ‬ᠹ‫܃‬Ꮫग‫ד‬ᛧ‫דࡹދ΂ۻ‬ᕅᛧ‫܃ݹ‬वॖᖆ‫ވ‬ട᜻ॐፇᚉǫ‫܃‬Чǫ࣫‫້ة‬ พཛྷ‫ވ‬ՙҋЈӻᆭᐉᙦ‫דވ‬ᕅᛧ‫ݹ‬ያძࡹ‫ټ‬σ৉ጎ‫ވ‬ǭ‫ࡹܤ‬ǫ‫ॱב‬ఖஉύ।ή ᇿᓿҋӞάಉऔ‫ޛ‬ᕅಉऔ‫דވ‬ᕅ࣫‫ة‬Ιǫҽ‫ޚ‬ǫύ।ήᇿχ‫ד‬ᕅՙҋᐉᙦٗѹ ೆְᏵ‫ة࣫ވ‬ၯǫ‫ֽॱב‬௿Έဵύ।ήᇿࡹ࿭Ҏಉऔউ΢‫ވ‬ೳৠ‫ࡹۿ‬ಉऔᚦԔ ȇNecrosisȈ‫ވ‬ЈӻчᏛगಉऔ‫ވ‬Ԕ΢ǫҤ‫ࡹޚۿ‬೯ၯ‫ٸ‬Ы‫ވ‬ЈӻӬ autophage ‫ ڠ‬cell cycle arrest าၘৠ٧ၩ‫דٸڀ‬ᕅࢩ‫ۻ‬ǫྴ෼ǫύ।ήᇿΟԍшિႴࡹ Herceptin ‫ ࡹۿ‬STI-571 ΂ኣࡹՙҋӞࢃ΂ॸ੔ਯ‫ވ‬ಉऔከ‫ވ‬Ιǫ೤ኣ‫ވ‬ከ‫ވ‬ шિࡹ΂ॸगᕅ୮әǬငዝ‫ڂפ‬әήȇtumor suppressorsȈǬҊ߆‫ڐ‬ᡆȇgrowth receptorsȈ‫ࡹۿ‬ᙦ౴әήาǫ٣ЫॱσࢩϦ‫ࡹۿ‬િୱՀѼ஛‫ވ‬лિǫԭ೯ၯ‫ב‬ ॱ೤ኣ‫ة࣫ވ‬ǫшЧ٣‫ॱב‬ᇘ‫ڀތ‬ύ।ήᇿᓿҋ‫ڀ‬ᕅ੨‫ݦ‬ᕄ‫ވ‬шՀ‫ۻ‬ǭ. 43.