(Translated by https://www.hiragana.jp/)
胸苷激酶 - 维基百科，自由的百科全书 跳とべ转到内容ないよう

胸むね苷激酶

维基百科ひゃっか，自由じゆう的てき百科ひゃっか全ぜん书
胸むね苷激酶
Crystal structure of a tetramer of thymidine kinase from U. urealyticum (where the monomers are color cyan, green, red, and magenta respectively) in complex with thymidine (space-filling model, carbon = white, oxygen = red, nitrogen = blue).[1]
识别码
EC編へん號ごう 2.7.1.21
CAS号ごう 9002-06-6
数かず据すえ库
IntEnz IntEnz浏览
BRENDA（英えい语：BRENDA） BRENDA入口いりくち
ExPASy（英えい语：ExPASy） NiceZyme浏览
KEGG KEGG入口いりくち
MetaCyc（英えい语：MetaCyc） 代だい谢路径みち
PRIAM（英えい语：PRIAM_enzyme-specific_profiles） 概がい述じゅつ
PDB RCSB PDB PDBj PDBe PDBsum
基もと因いん本体ほんたい AmiGO / EGO
胸むね苷激酶
鑑定かんてい
標しるべ誌しTK
PfamPF00265（旧版きゅうばん）
Pfam宗むね系けいCL0023（旧版きゅうばん）
InterPro（英えい语：InterPro）IPR001267
PROSITE（英えい语：PROSITE）PDOC00524
胸むね苷激酶1，可か溶
識別しきべつ
符號ふごう TK1
Entrez 7083
HUGO 11830
OMIM 188300
RefSeq NM_003258
UniProt P04183
其他資料しりょう
EC編へん號ごう 2.7.1.21
基もと因いん座ざ 17 q23.2-25.3
胸むね苷激酶2，线粒体たい
識別しきべつ
符號ふごう TK2
Entrez 7084
HUGO 11831
OMIM 188250
RefSeq NM_004614
UniProt O00142
其他資料しりょう
EC編へん號ごう 2.7.1.21
基もと因いん座ざ 16 [1]

胸むね苷激酶（英語えいご：thymidine kinase）是ぜ一种磷酸转移酶（激げき酶）：2’-脱だつ氧胸苷激酶，三さん磷酸腺せん苷-胸むね苷 5’-磷酸转移酶，EC 2.7.1.21[2][3]存在そんざい于大部分ぶぶん活かつ体たい细胞中ちゅう。它以两种同工どうこう酶的形式けいしき存在そんざい于哺乳ほにゅう动物细胞中ちゅう，TK1和わTK2。某ぼう些病毒びょうどく同どう样含有がんゆう病びょう毒性どくせい胸むね苷激酶表达的遗传信しん息いき。

胸むね苷激酶催化か以下いか反はん应：

•Thd + ATP → TMP + ADP

Thd是ぜ脱だつ氧胸苷，ATP是ぜ5’-三さん磷酸-腺せん苷，TMP是ぜ5’-一いち磷酸-脱だつ氧胸苷，ADP是ぜ5’-二に磷酸-腺せん苷。

胸むね苷激酶的主要しゅよう作用さよう体たい现在细胞分裂ぶんれつ过程中ちゅう的てきDNA合成ごうせい期き，是ぜ介かい导脱氧胸苷进入にゅうDNA合成ごうせい的てき旁つくり路ろ途と经的一いち部分ぶぶん。脱だつ氧胸苷存在そんざい于体液えき中ちゅう，是ぜ食物しょくもつ细胞或ある机つくえ体たい细胞死亡しぼう后きさき，DNA凋亡退化たいか的てき产物。很多抗こう病毒びょうどく药物的てき反はん应都需要じゅよう胸むね苷激酶的参与さんよ。

胸むね苷激酶可用よう于在生せい产单克かつ隆たかし抗体こうたい过程中ちゅう，筛选杂交瘤こぶ细胞。临床医学いがく中ちゅう，胸むね苷激酶作为一种细胞增殖标志物，用よう于恶性せい肿瘤的てき辅助诊断，治ち疗监控ひかえ和わ跟踪随ずい访。最近さいきん也有やゆう研究けんきゅう报道提出ていしゅつ，胸むね苷激酶在早期そうき癌がん症しょう预防中ちゅう的てき应用价值。

历史

[编辑]

胸むね苷参与さんよDNA合成ごうせい的てき途と经是在ざい1950年ねん前まえ后きさき发现的てき[4]，后きさき来らい进一いち步ほ明あきら确，这一途经始于胸苷的磷酸化[5]；在ざい1960年ねん左右さゆう，参与さんよ此过程ほど的てき激げき酶（胸むね苷激酶）被ひ首くび次じ纯化出来でき并进行ぎょう了りょう鉴定[6][7]。


分ぶん类

[编辑]

目前もくぜん已やめ得え到いた鉴别的てき胸むね苷激酶可分ぶん为两大だい类[8][9]：

一いち类存在そんざい于疱疹病毒びょうどく与あずか细胞胸むね苷激酶类似；

一类广泛存在于脊椎动物，细菌，T4噬菌体たい，痘病毒びょうどく，非ひ洲しゅう猪いのしし瘟病毒びょうどく（ASFV）和かず鱼淋巴りんぱ囊肿病毒びょうどく（FLDV）。昆虫こんちゅう虹彩こうさい病毒びょうどく衣ころも壳蛋白也はくや属ぞく于此类。

目前もくぜん只ただ确认了りょう细胞胸むね苷激酶的蛋白たんぱく位い点てん模型もけい。

生なま化か特とく点てん

[编辑]

高等こうとう生物せいぶつ胸むね苷激酶以两种同工どうこう酶形式しき存在そんざい，TK1和わTK2，具有ぐゆう很大的てき化学かがく差さ异性。

前ぜん一种最初在胎儿组织中发现，后きさき一种大量存在于成人组织，所以ゆえん最初さいしょ，被ひ分ぶん别命名めいめい为胎儿胸苷激酶和成人せいじん胸むね苷激酶。不ふ久之ひさゆき后きさき发现，TK1仅于细胞分裂ぶんれつ初期しょき（与あずか细胞周期しゅうき相しょう关）存在そんざい于细胞质中ちゅう[10][11]，而TK2定位ていい于线粒つぶ体たい中ちゅう，与あずか细胞周期しゅうき无关[12][13]。

1970年代ねんだい中期ちゅうき定位ていい了りょう两种酶的基もと因いん[14][15]，TK1基き因いん的てき克かつ隆和たかかず测序完成かんせい[16]，其所对应蛋白たんぱく的てき分子ぶんし量りょう为25kD；通常つうじょう以二聚体的形式出现在组织中，能のう够被ATP激げき活かつ；激げき活かつ后きさき，转化为四聚体。重じゅう组后的てきTK1无法被ひ激げき活かつ也无法ほう转化为四聚体，表明ひょうめい这种存在そんざい于细胞中的てき激げき酶在合成ごうせい后きさき性状せいじょう已やめ经发生せい了りょう改あらため变[17][18][19]。

细胞中ちゅうTK1的てき合成ごうせい发生在ざい细胞分裂ぶんれつ周期しゅうき的てきS期き。细胞分裂ぶんれつ完成かんせい后きさき，TK1在ざい细胞内部ないぶ降くだ解かい，因いん此在正常せいじょう细胞分裂ぶんれつ中ちゅう，TK1一般不会进入体液[20]。细胞中ちゅう胸むね苷激酶的反はん馈调节作用よう机つくえ理り：三さん磷酸胸むね苷（TTP：胸むね苷磷酸化さんか后きさき的てき终产物ぶつ）扮ふん演えんじ着ぎ胸むね苷激酶抑制よくせい剂的角かく色しょく[21][22][23][24]。这一机制确保了核酸合成所需的TTP量りょう维持在ざい平衡へいこう状じょう态，而不会かい出で现过饱和。5'-氨基胸むね苷是一种无毒性的胸苷类似物，能のう够干扰这一いち调控机つくえ理り，因いん此，胸むね苷类似に物ぶつ作さく为一种细胞毒性物质被应用于很多抗肿瘤药物[25][26][27][28][29][30][31]。

一些病毒的特殊胸苷激酶基因也已经得到了鉴别，如单纯疱疹病毒びょうどく，水痘すいとう带状疱疹病毒びょうどく和わEB病毒びょうどく（一种疱疹病毒）[32][33][34][35][36][37][38]。

生理学せいりがく背景はいけい

[编辑]

胸むね苷激酶催化か反はん应的产物——一磷酸脱氧胸苷，会かい继续被ひ胸むね苷酸激げき酶催化か生成せいせい二磷酸脱氧胸苷，之これ后きさき再さい被ひ二磷酸核苷激酶催化生成三磷酸脱氧胸苷。在ざい互补DNA和わDNA聚合酶的催化作用さよう下か（或ある是ぜ逆ぎゃく转录过程中ちゅう，在ざいRNA和わ逆ぎゃく转录酶的作用さよう下か），三磷酸脱氧胸苷进入了DNA分子ぶんし。

一磷酸脱氧胸苷可由两种不同的反应得到——一种是前文所述的脱氧胸苷磷酸化反应得到；还有一种是在不动用胸苷的情况下，通つう过胸苷酸磷酸酶催化か其他代だい谢途径みち产生的てき脱だつ氧尿苷甲基もと化か反はん应得到いた。细胞在ざい正常せいじょう情じょう况下（非ひ细胞分裂ぶんれつ状じょう态）采さい用よう第だい二种途径为DNA修おさむ复提供ていきょう充足じゅうそく的てき一磷酸脱氧胸苷。但ただし当とう细胞准じゅん备分裂ぶんれつ时，需要じゅよう构建一いち组全新しん的てきDNA，对组成なりDNA的てき材料ざいりょう，如三磷酸脱氧胸苷的需求也增加了。在ざい准じゅん备细胞分裂ぶんれつ的てき过程中ちゅう，一些细胞分裂所必需的酶开始产生。

这些酶平时不存在そんざい于细胞中，当とう细胞分裂ぶんれつ完成かんせい后きさき，在ざい调控下か浓度降くだ低てい，最さい终降解かい。这一类酶被称为补救酶。胸むね苷激酶1（TK1）就是一いち种补救すくい酶，但ただし胸むね苷激酶2（TK2）却与细胞周期しゅうき不ふ相あい关[39][40][41][42][43][44][45][46][47]。

用途ようと

[编辑]

鉴别处于分裂ぶんれつ期き的てき细胞

[编辑]

胸むね苷激酶在生せい化か研究けんきゅう中ちゅう的てき第だい一种直接应用是联合放射ほうしゃ性せい标记的てき胸むね苷和后きさき继用来らい测定放射ほうしゃ活性かっせい的てき放射ほうしゃ自じ显影技わざ术来鉴别处于分裂ぶんれつ期き的てき细胞。为了达到此目的もくてき，氚化的てき胸むね苷需保存ほぞん在ざい培つちかえ养基中ちゅう。[48] 尽つき管かん技わざ术上存在そんざい缺陷けっかん，该技术仍被ひ用もちい来らい测定恶性肿瘤细胞的てき增殖ぞうしょく比例ひれい和わ研究けんきゅう免疫めんえき过程中ちゅう淋巴りんぱ细胞的てき活性かっせい。

PET 扫描活かつ体たい肿瘤

[编辑]

3’-脱だつ氧-3’-[氟18]氟化胸むね苷是一种胸苷类似物。它由胸むね苷激酶1调控，被ひ迅速じんそく增殖ぞうしょく的てき肿瘤组织优先摄取。同位どうい素もと氟18是ぜ一种在正电子发射型断层显像技术（PET）中ちゅう常用じょうよう的てき正せい电子发射体たい。这种标记物ぶつ和わ另一常用じょうよう的てき标记物ぶつ2-[氟18]氟基-2-脱だつ氧-D-葡萄糖ぶどうとう相しょう比ひ，在ざい对增殖ぞうしょく状じょう态的活かつ体たい肿瘤的てきPET成なり像ぞう方面ほうめん更さら有ゆう优势[49][50][51][52][53]。

筛选杂交瘤こぶ细胞

[编辑]

杂交瘤こぶ细胞是ぜ肿瘤细胞（具有ぐゆう无限分裂ぶんれつ能力のうりょく）和わB淋巴りんぱ细胞融合ゆうごう后きさき获得的てき。杂交瘤こぶ细胞能のう够持续、大量たいりょう地ち产生具有ぐゆう专属特とく异性的てき免疫めんえき球だま蛋白たんぱく（单克隆たかし抗体こうたい）。但ただし问题是ぜ如何いか在ざい细胞融合ゆうごう后きさき，从大量的りょうてき多た余あまり的てき未み融合ゆうごう细胞中ちゅう，挑选出で杂交瘤こぶ细胞。

一种解决该问题的方法就是使用胸苷激酶阴性（TK-）的てき肿瘤细胞系けい进行融合ゆうごう。在ざい增殖ぞうしょく的てき肿瘤细胞系けい中ちゅう加入かにゅう胸むね苷类似に物ぶつ，将はた杀死胸むね苷激酶阳性せい（TK+）细胞，如此就得到いた了りょう胸むね苷激酶阴性せい细胞。然しか后きさき，这些阴性细胞用よう来らい与あずか胸むね苷激酶阳性せい的てき（TK+）B淋巴りんぱ细胞进行融合ゆうごう。融合ゆうごう之の后きさき，细胞需在添加てんか了りょう氨甲蝶ちょう呤[54]或ある氨基蝶ちょう呤[55]的てき培つちかえ养基中ちゅう培つちかえ养，以防止ぼうし二氢叶酸还原酶阻碍一磷酸胸苷的重新合成。培つちかえ养基一般いっぱん选用HAT培つちかえ养基（含有がんゆう次じ黄き嘌呤，氨基蝶ちょう呤，胸腺きょうせん嘧啶脱だつ氧核苷）。 胸むね苷激酶阴性せい细胞系けい中ちゅう的てき未み融合ゆうごう细胞将はた由ゆかり于一磷酸胸苷的断供而死亡。而未融合ゆうごう淋巴りんぱ细胞的てき死亡しぼう则是由よし于它们不是ぜ“不朽ふきゅう”的てき（不具ふぐ备肿瘤こぶ细胞的てき无限分裂ぶんれつ能力のうりょく）。只ただ有ゆう杂交瘤こぶ细胞由よし于同时继承了りょう肿瘤细胞系けい的てき“不朽ふきゅう”和わB淋巴りんぱ细胞的てき胸むね苷激酶得以幸存そん。这样，可か以用于生产所需抗体こうたい的てき杂交瘤こぶ细胞就筛选出来でき了りょう，在ざい培つちかえ养后用よう于生产单克かつ隆たかし抗体こうたい。[56][57][58][59][60]

不ふ过，采さい用よう相しょう同どう原理げんり，也可以通过筛选另一种次黄嘌呤-鸟嘌呤磷酸さん核かく糖とう转移酶（HGPRT）细胞系けい来らい达到筛选杂交瘤こぶ细胞的てき目的もくてき从而替がえ代だい胸むね苷激酶，该酶在ざい补救合成ごうせい途と经中调控鸟嘌呤核苷酸合成ごうせい所しょ必须的てき次つぎ黄き嘌呤的てき合成ごうせい。

应用案あん例れい

[编辑]

临床应用

[编辑]

胸むね苷激酶是一种补救酶，仅在细胞分裂ぶんれつ前出ぜんしゅつ现。由よし于细胞具有ぐゆう特殊とくしゅ的てき调控机つくえ制せい能のう够降解かい细胞分裂ぶんれつ后きさき不ふ再さい需要じゅよう的てき酶和蛋白たんぱく，所以ゆえん在ざい正常せいじょう的てき细胞分裂ぶんれつ后きさき，胸むね苷激酶不会かい从细胞释放。[61]因いん此一般いっぱん条件下じょうけんか，血清けっせい或ある血ち浆中的てき胸むね苷激酶含量りょう很低。肿瘤细胞释放胸むね苷激酶进入にゅう循环系けい统，可能かのう是ぜ与あずか已やめ经死亡しぼう或ある即そく将はた死亡しぼう的てき肿瘤细胞的てき瓦解がかい有ゆう关。因よし此，血清けっせい胸むね苷激酶水平すいへい能のう够用来らい评估肿瘤的てき增殖ぞうしょく程度ていど，并可以此来らい直接ちょくせつ评估肿瘤的てき攻おさむ击力。有ゆう一个令人关注的情况，存在そんざい于循环系统中的てき胸むね苷激酶与基もと因いん编码的てき酶并不一致ふいっち：基もと因いん编码的てき酶分子ぶんし量りょう为25kD。二聚体分子量为50kD，被ひATP激げき活かつ转化为四聚体后きさき，分子ぶんし量りょう为100kD。[62]而循环系统中具有ぐゆう活性かっせい的てき酶的分子ぶんし量りょう为730kD，很有可能かのう是ぜ与あずか其他蛋白たんぱく绑定形成けいせい了りょう复合物ぶつ[63] 。

目前もくぜん胸むね苷激酶检测在临床应用中ちゅう的てき价值主要しゅよう体たい现在以下いか几点：

1、评估放化か疗效果こうか：由よし于胸苷激酶水平すいへい与あずか肿瘤细胞恶性增殖ぞうしょく程度ていど具有ぐゆう相しょう关性，治ち疗前后きさき的てき胸むね苷激酶水平すいへい变化情じょう况能为治疗评估提供ていきょう辅助参考さんこう；

2、评估手しゅ术效果こうか：通つう过比较肿瘤こぶ患者かんじゃ手しゅ术前后きさき肿瘤细胞的てき增殖ぞうしょく情じょう况，为手术效果こうか评价提供ていきょう参考さんこう；

3、评估肿瘤复发风险：对肿瘤こぶ患者かんじゃ手しゅ术及治ち疗恢复期的てき残留ざんりゅう肿瘤细胞的てき增殖ぞうしょく状じょう态进行ぎょう动态评估，较影像ぞう学がく更さら早はや发现复发转移风险。[64]

不同ふどう肿瘤类别的てき胸むね苷激酶应用よう案あん例れい：

1、血液けつえき学がく恶性肿瘤中ちゅう胸むね苷激酶的增ぞう长具有ぐゆう规律性せい。例れい如，胸むね苷激酶1（TK1）用よう于监控ひかえ非ひ霍奇金きん淋巴りんぱ瘤こぶ。这种肿瘤的てき攻おさむ击性差さ别很大だい，有ゆう些属于慢速そく增殖ぞうしょく，很难觉察难以及时治ち疗；还有一些属于快速增殖，具有ぐゆう高だか攻おさむ击性需要じゅよう紧急治ち疗。这些差さ异可以在血清けっせい胸むね苷激酶的水平すいへい高低こうてい上じょう得とく以体现，与あずか正常せいじょう水平すいへい相近すけちか的てき对应慢速增殖ぞうしょく肿瘤，具有ぐゆう很高水平すいへい的てき对应快速かいそく增殖ぞうしょく肿瘤。[65][66][67][68][69][70][71][72] 淋巴りんぱ瘤こぶ患者かんじゃ血清けっせいTK1水平すいへい升ます高だか，可能かのう预示着ぎ肿瘤具有ぐゆう高だか活性かっせい和わ高だか攻おさむ击性，因いん此通过监测血清けっせいTK1水平すいへい的てき变化，适合于肿瘤こぶ的てき治ち疗评估。[73]

该模型がた也使用しよう于其他た类型血液けつえき恶性肿瘤中ちゅう（白血病はっけつびょう[74][75][76]，浆细胞骨髓こつづい瘤こぶ[77][78]，骨髓こつづい增ぞう生せい异常综合症しょう）。需要じゅよう关注的てき是ぜ在ざい骨髓こつづい增ぞう生せい异常综合症しょう中ちゅう：有ゆう一部分病例会迅速转变为进行白血病，但ただし是ぜ还有一些在很长一段时间内进展缓慢。那な如果能のう够鉴别出是ぜ否いや有ゆう进展为白血病はっけつびょう的てき趋势将はた对治疗非常ひじょう重要じゅうよう。

2、实体肿瘤中ちゅう胸むね苷激酶的升ます高だか往往おうおう也与肿瘤恶性增殖ぞうしょく程度ていど，治ち疗效果こうか，复发情じょう况具有ぐゆう相しょう关性[79][80][81][82]。有ゆう报告指出さしで在ざい前列ぜんれつ腺せん癌がん症しょう中ちゅう，胸むね苷激酶能够如同どうPSA（前列ぜんれつ腺せん特とく异抗原こうげん，目前もくぜん前列ぜんれつ腺せん癌がん中ちゅう使用しよう最さい频繁的てき肿瘤标志物ぶつ）一样提供辅助参考。PSA提示ていじ肿瘤大小だいしょう，而TK提示ていじ肿瘤增殖ぞうしょく速度そくど[83][84][85][86]。对于其他实体肿瘤，如小しょう细胞肺癌はいがん[87][88][89]，乳腺にゅうせん癌がん[90][91][92]，胃癌いがん[93]，肾癌[94]，膀胱ぼうこう癌がん[95]等とう都と有ゆう应用价值。

非ひ恶性肿瘤而造成ぞうせい血清けっせい胸むね苷激酶升高だか的てき原因げんいん有ゆう维生素もとB12缺乏けつぼう引起的てき恶性贫血，[96][97]病毒びょうどく感染かんせん（部分ぶぶん由よし于疱疹病毒びょうどく）[97][98][99] 或ある正せい处于创伤、手て术恢复期[100]。

恶性增殖ぞうしょく风险评估

[编辑]

由よし于胸苷激酶1与あずか细胞增殖ぞうしょく的てき相しょう关性，近きん些年来らい，有ゆう关于胸むね苷激酶1对于进展期き癌がん前まえ病びょう变的检测意い义，及在癌がん症しょう预防体たい检中的てき应用价值的てき探さがせ讨。

有ゆう研究けんきゅう指出さしで胸むね苷激酶1水平すいへい高低こうてい与あずか不ふ同年どうねん龄结构，及所处不同どう生活せいかつ、工作こうさく环境的てき肿瘤发生风险具有ぐゆう相しょう关性，在ざい进行长期跟踪后きさき，TK1水平すいへい的てき持もち续升高だか与あずか所ところ患癌前まえ病びょう变的恶性进程具有ぐゆう相しょう关性，在ざい早期そうき恶性肿瘤病びょう变预防ぼう中ちゅう能のう够发挥一定いってい作用さよう。[101][102]

治ち疗

[编辑]

有ゆう些药物ぶつ专门针对分裂ぶんれつ期き细胞有效ゆうこう。一般被用来治疗肿瘤和病毒性疾病（同どう时作用よう于逆转录病毒びょうどく和わ其他病毒びょうどく），这是由よし于病变细胞比正常せいじょう细胞复制更さら快かい更さら频繁，同どう时也会かい杀死一些复制迅速地非恶性肿瘤细胞。

有ゆう不同ふどう种类的てき药物可か以控制せい细胞分裂ぶんれつ过快，能のう够直接ちょくせつ作用さよう于胸苷代谢也因いん此与胸むね苷激酶有关联[103][104][105][106]：

胸むね苷类似に物ぶつ作さく为DNA链终止とめ物ぶつ进入DNA链复制せい，但ただし是ぜ由よし于结构已经改变所以ゆえん抑制よくせい了りょうDNA链的延のべ长。作さく为胸苷类似に物ぶつ，更さら容易ようい磷酸化か生成せいせい5’-一いち磷酸复合物ぶつ。一磷酸复合物进一步磷酸化生成三磷酸复合物参与到DNA链的复制。但ただし类似物ぶつ结构有ゆう所しょ变化，一般いっぱん不ふ具有ぐゆうDNA链复制せい所しょ必须的てき3’端はし羟基。如：叠氮胸むね苷（AZT；ATC：J05AF01）的てき3’端はし羟基被ひ叠氮基もと替がえ代だい；[107][108] 双そう脱だつ氧胸苷（ATC：J05AF04）能のう够竞争そう性せい抑制よくせい胸むね苷。[109][110] AZT在ざい一种检测血清胸苷激酶的方法中被用做底物。[111] 这意味いみ着ぎAZT会かい干ひ扰这一步骤或是作为一种抑制剂： AZT是ぜ针对HIV（艾あい滋しげる病びょう病毒びょうどく）感染かんせん的てきHAART（Highly Active Antiretroviral Therapy 高だか活性かっせい抗こう逆ぎゃく转录病毒びょうどく疗法）疗法的てき组分之の一いち。AIDS的てき最さい终结果はて一般いっぱん是ぜ淋巴りんぱ癌がん，而胸苷激酶检测的一项最重要的诊断应用就是监控淋巴癌。

酶底物ぶつ类似物的ぶってき化学かがく结构

[编辑]

其他胸むね苷类似に物ぶつ，如碘苷（ATC：J05AB02）能のう够在随ずい后きさき的てき复制循环中ちゅう阻碍そがい基もと础配对，最さい终导致DNA合成ごうせい链缺陷けっかん。[112]此物质结合ごう化か疗能够达到促使恶性肿瘤细胞凋亡的てき目的もくてき。[113]

一些抗病毒药物，如阿昔むかし洛らく韦（ATC：J05AB01）和わ更さら昔むかし洛らく韦（ATC：J05AB06）与あずか其他一些研究成功的核酸类似物一样，[114]则是利用りよう了りょう对病毒びょうどく胸むね苷激酶而非ひ对人胸むね苷激酶的专属特とく异性。[115]这些药物机つくえ理り如同前ぜん体からだ药物，本身ほんみ不具ふぐ有毒ゆうどく性せい，但ただし是ぜ被ひ病毒びょうどく胸むね苷激酶磷酸化さんか后きさき，会かい转变为细胞毒性せい药物。感染かんせん了りょう病毒びょうどく的てき细胞由よし于产生出おいで高だか细胞毒性どくせい的てき三磷酸核苷最终导致细胞的凋亡。而相反あいはん的てき，人にん胸むね苷激酶由于其专属特とく异性，不ふ会かい磷酸化か而激活かつ前ぜん体からだ药物。因よし此，只ただ有ゆう感染かんせん了りょう病毒びょうどく的てき细胞对药物ぶつ敏感びんかん。这些药物仅对具有ぐゆう特とく异的疱疹病毒びょうどく类胸苷激酶的病毒びょうどく有效ゆうこう。[116]

自じ1979年ねん12月，WHO宣布せんぷ天花てんげ病毒びょうどく已やめ经根除じょ之の后きさき，牛痘ぎゅうとう接せっ种项目め也已经终止とめ了りょう。该病毒びょうどく如果由よし于意外がい事故じこ或ある被ひ作さく为生化か武器ぶき重じゅう新出しんで现，将しょう会かい在ざい毫无防ぼう备的人じん群ぐん中ちゅう爆ばく发性传播而难以控制せい。接せっ种牛痘似乎是不道德ふどうとく的てき，因いん为唯一いち对天花はな有效ゆうこう的てき疫苗本身ほんみ就含有用ゆうよう于刺激しげき机つくえ体たい产生免疫めんえき效果こうか反はん应的活性かっせい牛痘ぎゅうとう病毒びょうどく。但ただし出で于安全ぜん问题考こう虑，有ゆう大量たいりょう的てき疫苗需要じゅよう长期储备，其中以高效こう的てき抗こう天花てんげ药物最さい为优先さき。一いち种可能かのう的てき方式ほうしき是ぜ利用りよう痘病毒びょうどく胸むね苷激酶的特とく异性来らい达到目的もくてき，作用さよう机つくえ理り与あずか抗こう疱疹病毒びょうどく类药物ぶつ类似。有ゆう一いち个难点てん是ぜ痘病毒びょうどく胸むね苷激酶与人じん胸むね苷激酶属于同一いち家族かぞく谱系，化学かがく结构相似そうじ。目前もくぜん痘病毒びょうどく的てき结构已やめ经探明あきら并正在ざい寻找潜在せんざい的てき抗こう病毒びょうどく药物。[117]但ただし有效ゆうこう的てき抗こう痘病毒びょうどく药物研究けんきゅう尚なお无结果はて。

疱疹病毒びょうどく胸むね苷激酶基因いん也当做“自じ杀基因いん”作さく为基因いん治ち疗实验中的てき安全あんぜん系けい统，诱导细胞表ひょう达该基もと因いん后きさき被ひ更さら昔むかし洛らく韦杀死し。此种方法ほうほう适用于通过重组基因いん诱发突变而最终导致的细胞增殖ぞうしょく失しつ控ひかえ（诱导突变）。这些突变细胞产生的てき胸むね苷激酶扩散ち入にゅう周しゅう围细胞中，会かい导致周しゅう围细胞同样对更さら昔むかし洛らく韦敏感かん，该现象ぞう称しょう为“旁つくり观者效こう应”。此方こちら法ほう已やめ用よう于动物体ぶったい的てき肿瘤治ち疗，有ゆう10%的てき恶性肿瘤细胞表ひょう达该基もと因いん并会被ひ有效ゆうこう杀死。[118][119]利用りよう一些肿瘤所特有的物质（肿瘤标志物ぶつ）也能实现类似的てき胸むね苷激酶应用よう。这些肿瘤标志物ぶつ，如CEA（癌がん胚はい抗原こうげん）和かずAFP（甲きのえ胎蛋白しろ）。将はた这些肿瘤标志物的ぶってき基もと因いん作さく为胸苷激酶的启动基もと因いん。胸むね苷激酶将在ざい表ひょう达肿瘤こぶ标志物ぶつ基もと因いん的てき细胞中ちゅう被ひ激げき活かつ，在ざい正常せいじょう细胞中ちゅう则不会かい，因いん此使用よう更さら昔むかし洛らく韦治疗只会かい杀死肿瘤细胞。[120][121][122][123][124][125]尽つき管かん如此，这些基もと因いん治ち疗方法ほう仍在实验阶段，一些与基因转移相关的问题，还未完全かんぜん解かい决。

一种含硼元素的胸苷类似物已经被建议并用于BNCT法ほう（硼-中子なかご交互こうご放射ほうしゃ疗法）治ち疗脑部ぶ肿瘤的てき动物实验。[126][127][128][129][130][131][132][133][134][135][136]

检测方法ほうほう

[编辑]

血清けっせい学がく

[编辑]

血清けっせい胸むね苷激酶检测主要よう是ぜ检测胸むね苷激酶1（TK1），检测方法ほうほう目前もくぜん主要しゅよう有ゆう两类，一种是酶活性测定法；一种是酶浓度测定法。

使用しよう酶活性せい测定法ほう，一般通过将血清样本和底物类似物共同培养来实现。最初さいしょ的てき商しょう业可行ぎょう性せい技わざ术是使用しよう碘代脱だつ氧尿苷，即そく使用しよう放射ほうしゃ性せい碘替代だい了りょう胸むね苷的一いち个甲基もと。[137][138][139]该底物ぶつ能のう够被酶很好このみ的てき识别。一いち磷酸化か的てき碘代脱だつ氧尿苷被添加てんか在ざい培つちかえ养基中ちゅう的てき氧化铝所吸附。在ざい倾倒和わ洗あらい脱だつ后きさき，氧化铝的放射ほうしゃ性せい可か换算出さんしゅつ样本中ちゅう胸むね苷激酶的量りょう。应用此原理げんり的てき商しょう业试剂盒由よし贝克曼公司こうし和わ索さく灵公司こうし提供ていきょう。

此外索さく灵公司こうし还研究けんきゅう出で一いち种非放射ほうしゃ性せい分析ぶんせき方法ほうほう。在ざい该技术中3’-叠氮-2’，3’-脱だつ氧胸苷（AZT：叠氮胸むね苷）首くび先さき被ひ样本中ちゅう的てきTK1磷酸化か生成せいせい5’-一いち磷酸-AZT（AZTMP：叠氮胸むね苷一磷酸）。AZTMP通どおり过免疫学えきがく方法ほうほう测定，使用しよう抗こう-AZTMP抗体こうたい为AZTMP标记上じょう过氧化物ばけもの。测定需在索さく灵公司こうし提供ていきょう的てき封ふう闭式实验工作こうさく系けい统内进行。[140][111]

另一种新研发的技术是使用胸苷类似物——溴化尿にょう苷，作さく为酶底そこ物ぶつ。反はん应产物ぶつ（在ざい微量びりょう滴しずく定てい板いた中ちゅう）吸附在ざい滴しずく定てい板いた各かく孔あな的てき底部ていぶ。再さい通つう过ELISA方法ほうほう测定：在ざい各かく孔あな中ちゅう加入かにゅう抗こう溴化尿にょう苷的单克隆たかし抗体こうたい溶液ようえき。单克隆たかし抗体こうたい上じょう结合有ゆう碱性磷酸酶。洗あらい脱だつ掉过量的りょうてき结合有ゆう碱性磷酸酶的抗体こうたい，加入かにゅう含有がんゆう碱性磷酸酶底物ぶつ——4-硝基苯酚的てき溶液ようえき。反はん应产物ぶつ4-硝基酚在磷酸pH环境中ちゅう是ぜ黄色おうしょく能のう够通过光度こうど法ほう测定。[141]此种分析ぶんせき方法ほうほう能のう够进行ぎょう更さら加か灵敏的てき检测。商しょう业试剂盒由よしBiovica公司こうし提供ていきょう。

使用しよう酶浓度ど测定法ほう，一般いっぱん对抗TK1抗体こうたい的てき灵敏度ど要求ようきゅう很高，之これ前ぜん很长一段时间内没有突破。20世せい纪末至いたり21世せい纪初，瑞みず典てんkarolinska医学いがく院いん利用りよう鸟类特とく异性IgY抗体こうたい，开发出で一种新型多克隆抗体——抗こう人じんTK1-IgY抗体こうたい，并申请了国こく际专利り，此抗体こうたい具有ぐゆう很高的てき灵敏度ど和わ特とく异性，能のう够识别人血清けっせい中ちゅう低てい浓度TK1。[142]此抗体こうたい在ざい结合化学かがく发光检测技わざ术后，进一步提高了检测灵敏度。商用しょうよう试剂盒由SSTK公司こうし（中国ちゅうごく，深ふか圳）提供ていきょう。

组织学がく

[编辑]

从组织提取と物もの样本中ちゅう能のう够检测到胸むね苷激酶。但ただし尚なお没ぼっ有ゆう标准的てき组织提ひっさげ取ど或ある分析ぶんせき方法ほうほう，组织和わ细胞提ひっさげ取ど物もの中ちゅう的てきTK检测与实际临床问题的てき相しょう关性也未得え到いた证实。见Romain等とう[143]和かずArnér等とう[144]。有ゆう一いち种方法ほう使用しよう5’-溴-2’-脱だつ氧尿苷作为底物ぶつ类似物ぶつ特とく异性检测细胞提ひっさげ取ど物もの中ちゅう的てきTK2。[145]但ただし在ざい使用しよう此方こちら法的ほうてき其他研究けんきゅう中ちゅう，报告的てき结果差さ异很大だい方法ほうほう可か行ぎょう性せい不ふ佳けい。

处于发展阶段的てき胎儿组织的てきTK1水平すいへい比ひ之の后きさき要よう高だか。[146][147][148]

某ぼう些非恶性肿瘤细胞和わ组织中ちゅう的てきTK1水平すいへい也会出で现明显升高だか：如存在そんざい单核细胞增ぞう多た症しょう时的周しゅう围淋巴りんぱ细胞，[149]和わ存在そんざい恶性贫血是ぜ的てき骨髓こつづい细胞。[150][151]

由よし于TK1存在そんざい于处于分裂ぶんれつ期き的てき细胞中ちゅう，因いん此有理由りゆう认为恶性肿瘤组织中ちゅう的てきTK活性かっせい应比正常せいじょう组织中ちゅう的てき要よう高だか。这已在ざい大だい部分ぶぶん的てき研究けんきゅう中ちゅう得え到いた证实。肿瘤组织中ちゅうTK活性かっせい比ひ一いち般组织要高だか[146][152][153][154]，如脑瘤こぶ[155]，血液けつえき系けい统恶性せい肿瘤[156]，结肠癌がん和わ结肠息いき肉にく[157][158][159][160][161][162]，乳腺にゅうせん癌がん[163][164][165][166][167][168]，肺癌はいがん[169][170][171]，胃癌いがん[172]，卵巢らんそう癌がん[173]，间皮瘤こぶ[174]，黑くろ色素しきそ瘤こぶ[175]，和かず甲状腺こうじょうせん肿瘤[176][177]。

对于白血病はっけつびょう[178][179]和かず乳腺にゅうせん癌がん[180]，治ち疗对细胞增殖ぞうしょく速そく率りつ的てき影かげ响与对TK值的影かげ响是由よし相しょう关性的てき。

免疫めんえき组织化学かがく染色せんしょく

[编辑]

抗こう胸むね苷激酶抗体こうたい可か以用于免疫组化か检测。[181]胸むね苷激酶染色しょく就是一种可靠的用于鉴别2期き乳腺にゅうせん癌がん患者かんじゃ的てき技わざ术。胸むね苷激酶和Ki-67染色せんしょく技わざ术的联合使用しよう已やめ经使相当そうとう多おお的てき患者かんじゃ得え到いた了りょう诊断。[182][183]

该技术对肺癌はいがん[182][184]，结直肠癌[185]，非ひ小しょう细胞肺癌はいがん[186]和かず肾癌[187]具有ぐゆう同どう样价值。

标签

[编辑]

胸むね苷激酶1；疱疹病毒びょうどく胸むね苷激酶；胸むね苷酸激げき酶；二磷酸核苷激酶；胸むね苷酸合成ごうせい酶

参考さんこう文献ぶんけん

[编辑]
  1. ^ PDB 2B8T; Kosinska U, Carnrot C, Eriksson S, Wang L, Eklund H. Structure of the substrate complex of thymidine kinase from Ureaplasma urealyticum and investigations of possible drug targets for the enzyme. FEBS J. December 2005, 272 (24): 6365–72. PMID 16336273. doi:10.1111/j.1742-4658.2005.05030.x. 
  2. ^ Kit S (December 1985). "Thymidine kinase". Microbiol. Sci. 2 (12): 369–75.
  3. ^ Wintersberger E (February 1997). "Regulation and biological function of thymidine kinase". Biochem. Soc. Trans. 25 (1): 303–8.
  4. ^ Reichard P, Estborn B (February 1951). "Utilization of desoxyribosides in the synthesis of polynucleotides". J. Biol. Chem. 188 (2): 839–46.
  5. ^ Kornberg A, Lehman IR, Simms ES (1956). "Polydeoxyribonucleotide synthesis by enzymes from Eschrichia coli". Fed. Proc. 15: 291–2.
  6. ^ Bollum FJ, Van Potter R (August 1958). "Incorporation of thymidine into deoxyribonucleic acid by enzymes from rat tissues". J. Biol. Chem. 233 (2): 478–82.
  7. ^ Weissman SM, Smellie RMS, Paul J (December 1960). "Studies on the biosynthesis of deoxyribonucleic acid by extracts of mammalian cells. IV. The phosphorylation of thymidine". Biochim. Biophys. Acta 45: 101–10.
  8. ^ Boyle DB, Gibbs AJ, Seigman LJ, Both GW, Coupar BE (1987). "Fowlpox virus thymidine kinase: nucleotide sequence and relationships to other thymidine kinases". Virology 156 (2): 355–365.
  9. ^ Lopez-Otin C, Blasco R, Vinuela E, Munoz M, Simon-Mateo C, Bockamp EO (1990). "Sequence and evolutionary relationships of African swine fever virus thymidine kinase". Virology 178 (1): 301–304.
  10. ^ Littlefield JW (February 1966). "The periodic synthesis of thymidine kinase in mouse fibroblasts". Biochim. Biophys. Acta 114 (2): 398–403
  11. ^ Bello LJ (December 1974). "Regulation of thymidine kinase synthesis in human cells". Exp. Cell Res. 89 (2): 263–74.
  12. ^ Berk AJ, Clayton DA (April 1973). "A genetically distinct thymidine kinase in mammalian mitochondria. Exclusive labeling of mitochondrial deoxyribonucleic acid". J. Biol. Chem. 248 (8): 2722–9.
  13. ^ Berk AJ, Meyer BJ, Clayton DA (February 1973). "Mitochondrial-specific thymidine kinase". Arch. Biochem. Biophys. 154 (2): 563–5.
  14. ^ Elsevier SM, Kucherlapati RS, Nichols EA, Creagan RP, Giles RE, Ruddle FH, Willecke K, McDougall JK (October 1974). "Assignment of the gene for galactokinase to human chromosome 17 and its regional localisation to band q21-22". Nature 251 (5476): 633–6.
  15. ^ Willecke K, Teber T, Kucherlapati RS, Ruddle FH (May 1977). "Human mitochondrial thymidine kinase is coded for by a gene on chromosome 16 of the nucleus". Somatic Cell Genet. 3 (3): 237–45
  16. ^ Flemington E, Bradshaw HD, Traina-Dorge V, Slagel V, Deininger PL (1987). "Sequence, structure and promoter characterization of the human thymidine kinase gene". Gene 52 (2–3): 267–77.
  17. ^ Welin M, Kosinska U, Mikkelsen NE, et al. (December 2004). "Structures of thymidine kinase 1 of human and mycoplasmic origin". Proc. Natl. Acad. Sci. U.S.A. 101 (52): 17970–5.
  18. ^ Munch-Petersen B, Cloos L, Jensen HK, Tyrsted G (1995). "Human thymidine kinase 1. Regulation in normal and malignant cells". Adv. Enzyme Regul. 35: 69–89.
  19. ^ Li CL, Lu CY, Ke PY, Chang ZF (January 2004). "Perturbation of ATP-induced tetramerization of human cytosolic thymidine kinase by substitution of serine-13 with aspartic acid at the mitotic phosphorylation site". Biochem. Biophys. Res. Commun. 313 (3): 587–93.
  20. ^ Zhu C, Harlow LS, Berenstein D, Munch-Petersen S, Munch-Petersen B (2006). "Effect of C-terminal of human cytosolic thymidine kinase (TK1) on in vitro stability and enzymatic properties". Nucleosides Nucleotides Nucleic Acids 25 (9–11): 1185–8.
  21. ^ 引用いんよう错误：没ぼつ有ゆう为名为pmid7572355的てき参考さんこう文献ぶんけん提供ていきょう内容ないよう
  22. ^ null Van Potter. FEEDBACK INHIBITION OF THYMIDINE KINASE BY THYMIDINE TRIPHOSPHATE. Experimental Cell Research. 1963, 24: SUPPL9:259–262 [2019-05-26]. ISSN 0014-4827. PMID 14046233. 
  23. ^ E. S. Severin, A. V. Itkes, O. N. Kartasheva, V. L. Tunitskaya, K. T. Turpaev, C. A. Kafiani. Regulation of 2-5 A phosphodiesterase activity by cAMP-dependent phosphorylation: mechanism and biological role. Advances in Enzyme Regulation. 1985, 23: 365–376 [2019-05-26]. ISSN 0065-2571. PMID 3000146. 
  24. ^ Nils Egil Mikkelsen, Kenth Johansson, Andreas Karlsson, Wolfgang Knecht, Gorm Andersen, Jure Piskur, Birgitte Munch-Petersen, Hans Eklund. Structural basis for feedback inhibition of the deoxyribonucleoside salvage pathway: studies of the Drosophila deoxyribonucleoside kinase. Biochemistry. 2003-05-20, 42 (19): 5706–5712 [2019-05-26]. ISSN 0006-2960. PMID 12741827. doi:10.1021/bi0340043. 
  25. ^ P. H. Fischer, A. W. Phillips. Antagonism of feedback inhibition. Stimulation of the phosphorylation of thymidine and 5-iodo-2'-deoxyuridine by 5-iodo-5'-amino-2',5'-dideoxyuridine. Molecular Pharmacology. 1984-5, 25 (3): 446–451 [2019-05-26]. ISSN 0026-895X. PMID 6727866. 
  26. ^ P. H. Fischer, M. A. Vazquez-Padua, C. A. Reznikoff. Perturbation of thymidine kinase regulation: a novel chemotherapeutic approach. Advances in Enzyme Regulation. 1986, 25: 21–34 [2019-05-26]. ISSN 0065-2571. PMID 3812083. 
  27. ^ P. H. Fischer, M. A. Vazquez-Padua, C. A. Reznikoff, W. J. Ratschan. Preferential stimulation of iododeoxyuridine phosphorylation by 5'-aminothymidine in human bladder cancer cells in vitro. Cancer Research. 1986-9, 46 (9): 4522–4526 [2019-05-26]. ISSN 0008-5472. PMID 3731105. 
  28. ^ P. H. Fischer, T. T. Fang, T. S. Lin, A. Hampton, J. Bruggink. Structure-activity analysis of antagonism of the feedback inhibition of thymidine kinase. Biochemical Pharmacology. 1988-04-01, 37 (7): 1293–1298 [2019-05-26]. ISSN 0006-2952. PMID 3355601. 
  29. ^ M. A. Vazquez-Padua, K. Kunugi, P. H. Fischer. Enzyme regulatory site-directed drugs: study of the interactions of 5'-amino-2', 5'-dideoxythymidine (5'-AdThd) and thymidine triphosphate with thymidine kinase and the relationship to the stimulation of thymidine uptake by 5'-AdThd in 647V cells. Molecular Pharmacology. 1989-1, 35 (1): 98–104 [2019-05-26]. ISSN 0026-895X. PMID 2536472. 
  30. ^ M. A. Vazquez-Padua, P. H. Fischer, B. J. Christian, C. A. Reznikoff. Basis for the differential modulation of the uptake of 5-iododeoxyuridine by 5'-aminothymidine among various cell types. Cancer Research. 1989-05-01, 49 (9): 2415–2421 [2019-05-26]. ISSN 0008-5472. PMID 2706629. （原始げんし内容ないよう存そん档于2016-10-01）. 
  31. ^ M. A. Vázquez-Padua. Modulation of thymidine kinase activity: a biochemical strategy to enhance the activation of antineoplastic drugs. Puerto Rico Health Sciences Journal. 1994-3, 13 (1): 19–23 [2019-05-26]. ISSN 0738-0658. PMID 8016290. 
  32. ^ McKnight SL. The nucleotide sequence and transcript map of the herpes simplex virus thymidine kinase gene. Nucleic Acids Res. December 1980, 8 (24): 5949–64. PMC 328064 可免费查阅. PMID 6258156. doi:10.1093/nar/8.24.5949. 
  33. ^ Halliburton IW, Morse LS, Roizman B, Quinn KE. Mapping of the thymidine kinase genes of type 1 and type 2 herpes simplex viruses using intertypic recombinants. J. Gen. Virol. August 1980, 49 (2): 235–53. PMID 6255066. doi:10.1099/0022-1317-49-2-235. 
  34. ^ McDougall JK, Masse TH, Galloway DA. Location and cloning of the herpes simplex virus type 2 thymidine kinase gene. J. Virol. March 1980, 33 (3): 1221–4 [2012-03-01]. PMC 288658 可免费查阅. PMID 6245273. （原始げんし内容ないよう存そん档于2011-08-07）. 
  35. ^ Kit S, Kit M, Qavi H, Trkula D, Otsuka H. Nucleotide sequence of the herpes simplex virus type 2 (HSV-2) thymidine kinase gene and predicted amino acid sequence of thymidine kinase polypeptide and its comparison with the HSV-1 thymidine kinase gene. Biochim. Biophys. Acta. November 1983, 741 (2): 158–70. PMID 6317035. doi:10.1016/0167-4781(83)90056-8. 
  36. ^ Sawyer MH, Ostrove JM, Felser JM, Straus SE. Mapping of the varicella zoster virus deoxypyrimidine kinase gene and preliminary identification of its transcript. Virology. February 1986, 149 (1): 1–9. PMID 3004022. doi:10.1016/0042-6822(86)90081-4. 
  37. ^ Littler E, Zeuthen J, McBride AA, Trøst Sørensen E, Powell KL, Walsh-Arrand JE, Arrand JR. Identification of an Epstein-Barr virus-coded thymidine kinase. EMBO J. August 1986, 5 (8): 1959–66. PMC 1167064 可免费查阅. PMID 3019675. 
  38. ^ Kit S, Dubbs DR. Acquisition of thymidine kinase activity by herpes simplex-infected mouse fibroblast cells. Biochem. Biophys. Res. Commun. April 1963, 11: 55–9. PMID 14033128. doi:10.1016/0006-291X(63)90027-5. 
  39. ^ Schlosser CA, Steglich C, deWet JR, Scheffler IE. Cell cycle-dependent regulation of thymidine kinase activity introduced into mouse LMTK- cells by DNA and chromatin-mediated gene transfer. Proc. Natl. Acad. Sci. U.S.A. February 1981, 78 (2): 1119–23. PMC 319958 可免费查阅. PMID 6940130. doi:10.1073/pnas.78.2.1119. 
  40. ^ Coppock DL, Pardee AB. Control of thymidine kinase mRNA during the cell cycle. Mol. Cell. Biol. August 1987, 7 (8): 2925–32 [2012-03-01]. PMC 367911 可免费查阅. PMID 3670299. （原始げんし内容ないよう存そん档于2011-09-27）. 
  41. ^ Stewart CJ, Ito M, Conrad SE. Evidence for transcriptional and post-transcriptional control of the cellular thymidine kinase gene. Mol. Cell. Biol. March 1987, 7 (3): 1156–63 [2012-03-01]. PMC 365188 可免费查阅. PMID 3561412. （原始げんし内容ないよう存そん档于2011-09-27）. 
  42. ^ Piper AA, Tattersall MH, Fox RM. The activities of thymidine metabolising enzymes during the cell cycle of a human lymphocyte cell line LAZ-007 synchronised by centrifugal elutriation. Biochim. Biophys. Acta. December 1980, 633 (3): 400–9. PMID 6260157. 
  43. ^ Pelka-Fleischer R, Ruppelt W, Wilmanns W, Sauer H, Schalhorn A. Relation between cell cycle stage and the activity of DNA-synthesizing enzymes in cultured human lymphoblasts: investigations on cell fractions enriched according to cell cycle stages by way of centrifugal elutriation. Leukemia. March 1987, 1 (3): 182–7. PMID 3669741. 
  44. ^ Sherley JL, Kelly TJ. Regulation of human thymidine kinase during the cell cycle. J. Biol. Chem. June 1988, 263 (17): 8350–8 [2012-03-01]. PMID 3372530. （原始げんし内容ないよう存そん档于2005-01-26）. 
  45. ^ Gross MK, Kainz MS, Merrill GF. The chicken thymidine kinase gene is transcriptionally repressed during terminal differentiation: the associated decline in TK mRNA cannot account fully for the disappearance of TK enzyme activity. Dev. Biol. August 1987, 122 (2): 439–51. PMID 3596017. doi:10.1016/0012-1606(87)90308-3. 
  46. ^ Kauffman MG, Kelly TJ. Cell cycle regulation of thymidine kinase: residues near the carboxyl terminus are essential for the specific degradation of the enzyme at mitosis. Mol. Cell. Biol. May 1991, 11 (5): 2538–46 [2012-03-01]. PMC 360023 可免费查阅. PMID 1708095. （原始げんし内容ないよう存そん档于2011-09-27）. 
  47. ^ Sutterluety H, Bartl S, Karlseder J, Wintersberger E, Seiser C. Carboxy-terminal residues of mouse thymidine kinase are essential for rapid degradation in quiescent cells. J. Mol. Biol. June 1996, 259 (3): 383–92. PMID 8676376. doi:10.1006/jmbi.1996.0327. 
  48. ^ Johnson HA, Rubini JR, Cronkite EP, Bond VP. Labeling of human tumor cells in vivo by tritiated thymidine. Lab. Invest. 1960, 9: 460–5. PMID 14407455. 
  49. ^ Barthel H; Cleij MC; Collingridge DR; et al. 3'-deoxy-3'-[18F]fluorothymidine as a new marker for monitoring tumor response to antiproliferative therapy in vivo with positron emission tomography. Cancer Res. July 2003, 63 (13): 3791–8. PMID 12839975. 
  50. ^ Chao KS. Functional imaging for early prediction of response to chemoradiotherapy: 3'-deoxy-3'-18F-fluorothymidine positron emission tomography--a clinical application model of esophageal cancer. Semin. Oncol. December 2006, 33 (6 Suppl 11): S59–63. PMID 17178290. doi:10.1053/j.seminoncol.2006.10.011. 
  51. ^ Salskov A, Tammisetti VS, Grierson J, Vesselle H. FLT: measuring tumor cell proliferation in vivo with positron emission tomography and 3'-deoxy-3'-[18F]fluorothymidine. Semin Nucl Med. November 2007, 37 (6): 429–39. PMID 17920350. doi:10.1053/j.semnuclmed.2007.08.001. 
  52. ^ de Langen AJ; Klabbers B; Lubberink M; et al. Reproducibility of quantitative (18)F-3'-deoxy-3'-fluorothymidine measurements using positron emission tomography. Eur. J. Nucl. Med. Mol. Imaging. October 2008, 36 (3): 389–95. PMID 18931838. doi:10.1007/s00259-008-0960-5. 
  53. ^ Shields AF; Lawhorn-Crews JM; Briston DA; et al. Analysis and reproducibility of 3'-Deoxy-3'-[18F]fluorothymidine positron emission tomography imaging in patients with non-small cell lung cancer. Clin. Cancer Res. July 2008, 14 (14): 4463–8. PMID 18628460. doi:10.1158/1078-0432.CCR-07-5243. 
  54. ^ Methotrexate - Compound Summary. [2012-03-01]. （原始げんし内容ないよう存そん档于2014-03-10）. 
  55. ^ Aminopterin - Compound Summary. [2012-03-01]. （原始げんし内容ないよう存そん档于2014-03-10）. 
  56. ^ Köhler G, Milstein C. Continuous cultures of fused cells secreting antibody of predefined specificity. Nature. August 1975, 256 (5517): 495–7. Bibcode:1975Natur.256..495K. PMID 1172191. doi:10.1038/256495a0. 
  57. ^ Köhler G, Howe SC, Milstein C. Fusion between immunoglobulin-secreting and nonsecreting myeloma cell lines. Eur. J. Immunol. April 1976, 6 (4): 292–5. PMID 825374. doi:10.1002/eji.1830060411. 
  58. ^ Köhler G, Milstein C. Derivation of specific antibody-producing tissue culture and tumor lines by cell fusion. Eur. J. Immunol. July 1976, 6 (7): 511–9. PMID 825377. doi:10.1002/eji.1830060713. 
  59. ^ Köhler G, Pearson T, Milstein C. Fusion of T and B cells. Somatic Cell Genet. May 1977, 3 (3): 303–12. PMID 305123. doi:10.1007/BF01538748. 
  60. ^ Milstein C, Adetugbo K, Cowan NJ, Kohler G, Secher DS. Expression of antibody genes in tissue culture: structural mutants and hybrid cells. Natl Cancer Inst Monogr. May 1978, (48): 321–30. PMID 107455. 
  61. ^ 引用いんよう错误：没ぼつ有ゆう为名为pmid4223355的てき参考さんこう文献ぶんけん提供ていきょう内容ないよう
  62. ^ 引用いんよう错误：没ぼつ有ゆう为名为pmid15611477的てき参考さんこう文献ぶんけん提供ていきょう内容ないよう
  63. ^ Karlström AR, Neumüller M, Gronowitz JS, Källander CF. Molecular forms in human serum of enzymes synthesizing DNA precursors and DNA. Mol. Cell. Biochem. January 1990, 92 (1): 23–35. PMID 2155379. doi:10.1007/BF00220716. 
  64. ^ 劉りゅう秀しげる菊きく，周しゅう際ぎわ，李り遠とお等ひとし。TK1——一種新的腫瘤生長相關標誌物的應用新進展。《中國ちゅうごく藥理やくり學がく與あずか毒どく理學りがく雜誌ざっし》2010年ねん12月。
  65. ^ Ellims PH, Van der Weyden MB, Medley G. Thymidine kinase isoenzymes in human malignant lymphoma. Cancer Res. February 1981, 41 (2): 691–5. PMID 7448815. 
  66. ^ Hagberg H, Glimelius B, Gronowitz JS, Killander A, Källander CFR, Schröder T. Biochemical markers in non-Hodgkin's lymphoma stages III and IV and prognosis: a multivariate analysis. Scand J Haematol. July 1984, 33 (1): 59–67. PMID 6379852. doi:10.1111/j.1600-0609.1984.tb02211.x. 
  67. ^ Gronowitz JS, Hagberg H, Källander CFR, Simonsson B. The use of serum deoxythymidine kinase as a prognostic marker, and in the monitoring of patients with non-Hodgkin's lymphoma. Br. J. Cancer. April 1983, 47 (4): 487–95. PMC 2011337 可免费查阅. PMID 6849793. doi:10.1038/bjc.1983.78. 
  68. ^ Hallek M, Wanders L, Strohmeyer S, Emmerich B. Thymidine kinase: a tumor marker with prognostic value for non-Hodgkin's lymphoma and a broad range of potential clinical applications. Ann. Hematol. July 1992, 65 (1): 1–5. PMID 1643153. doi:10.1007/BF01715117. 
  69. ^ Bogni A, Cortinois A, Grasselli G; et al. Thymidine kinase (TK) activity as a prognostic parameter of survival in lymphoma patients. J. Biol. Regul. Homeost. Agents. 1994, 8 (4): 121–5. PMID 7660854. 
  70. ^ Rehn S, Gronowitz JS, Källander C, Sundström C, Glimelius B. Deoxythymidine kinase in the tumour cells and serum of patients with non-Hodgkin lymphomas. Br. J. Cancer. May 1995, 71 (5): 1099–105. PMC 2033808 可免费查阅. PMID 7734308. doi:10.1038/bjc.1995.213. 
  71. ^ Suki S, Swan F, Tucker S; et al. Risk classification for large cell lymphoma using lactate dehydrogenase, beta-2 microglobulin, and thymidine kinase. Leuk. Lymphoma. June 1995, 18 (1–2): 87–92. PMID 8580834. doi:10.3109/10428199509064927. 
  72. ^ Hallek M, Wanders L, Ostwald M; et al. Serum beta(2)-microglobulin and serum thymidine kinase are independent predictors of progression-free survival in chronic lymphocytic leukemia and immunocytoma. Leuk. Lymphoma. August 1996, 22 (5–6): 439–47. PMID 8882957. doi:10.3109/10428199609054782. 
  73. ^ Zhu-Lin Pan, Xing-Ying Ji, Yan-Min Shi, et al.(2010). " Serum thymidine kinase 1 concentration as a prognostic factor".J Cancer Res Clin Oncol.136:1193-1199.
  74. ^ Källander CFR, Simonsson B, Gronowitz JS, Nilsson K. Serum deoxythymidine kinase correlates with peripheral lymphocyte thymidine uptake in chronic lymphocytic leukemia. Eur. J. Haematol. April 1987, 38 (4): 331–7. PMID 3609253. doi:10.1111/j.1600-0609.1987.tb00007.x. 
  75. ^ Källander CFR, Simonsson B, Hagberg H, Gronowitz JS. Serum deoxythymidine kinase gives prognostic information in chronic lymphocytic leukemia. Cancer. December 1984, 54 (11): 2450–5. PMID 6498737. doi:10.1002/1097-0142(19841201)54:11<2450::AID-CNCR2820541123>3.0.CO;2-R. 
  76. ^ A. Rivkina, G. Vitols, M. Murovska, S. Lejniece. Identifying the stage of new CLL patients using TK, ZAP-70, CD38 levels. Experimental Oncology. 2011-6, 33 (2): 99–103 [2019-05-26]. ISSN 1812-9269. PMID 21716207. （原始げんし内容ないよう存そん档于2019-09-05）. 
  77. ^ Simonsson B, Källander CFR, Brenning G, Killander A, Gronowitz JS, Bergström R. Biochemical markers in multiple myeloma: a multivariate analysis. Br. J. Haematol. May 1988, 69 (1): 47–53. PMID 3289607. doi:10.1111/j.1365-2141.1988.tb07601.x. 
  78. ^ Simonsson B, Källander CFR, Brenning G, Killander A, Ahre A, Gronowitz JS. Evaluation of serum deoxythymidine kinase as a marker in multiple myeloma. Br. J. Haematol. October 1985, 61 (2): 215–24. PMID 4041368. doi:10.1111/j.1365-2141.1985.tb02820.x. 
  79. ^ Yan Chen, MinGang Ying, YanSong Chen, et al. (2010). 「Serum thymidine kinase 1 correlates to clinical stages and clinical reactions and monitors the outcome of therapy of 1,247 cancer patients in routine clinical settings」. Int J Clin Oncol.
  80. ^ Zhishan Li, Yinghong Wang, Jie He, Jie Ma, et al. (March 2010). 「Serological thymidine kinase 1 is a prognostic factor in oesophageal, cardial and lung carcinomas」. European Journal of Cancer Prevention 19:313-318.
  81. ^ Qimin He, PingGN Zhang, Li Zou, et al. (May 2005). 「Concentration of thymidine kinase 1 in serum(S-TK1) is a more sensitive proliferation marker in human solid tumors than its activity". Oncology Reports 14: 1013-1019.
  82. ^ Zhenxin Wang, Bin Zhang, Bin Ni, Jin Zang. (September 2011). 「Value of serum thymidine kinase 1 in evaluating the efficacy of malignant tumor treatment」. Jiangsu Med J, September 2011, Vol37, No.18:2174-2175.
  83. ^ Larson A, Fritjofsson A, Norlén BJ, Gronowitz JS, Ronquist G. Prostate specific acid phosphatase versus five other possible tumour markers: a comparative study in men with prostatic carcinoma. Scand. J. Clin. Lab. Invest. Suppl. 1985, 179: 81–8. PMID 2417306. 
  84. ^ Letocha H, Eklöv S, Gronowitz S, Norlén BJ, Nilsson S. Deoxythymidine kinase in the staging of prostatic adenocarcinoma. Prostate. July 1996, 29 (1): 15–9. PMID 8685050. doi:10.1002/(SICI)1097-0045(199607)29:1<15::AID-PROS2>3.0.CO;2-H. 
  85. ^ Lewenhaupt A, Ekman P, Eneroth P, Nilsson B. Tumour markers as prognostic aids in prostatic carcinoma. Br J Urol. August 1990, 66 (2): 182–7. PMID 1697204. doi:10.1111/j.1464-410X.1990.tb14900.x. 
  86. ^ Ekman P, Lewenhaupt A. Serum tumour markers in human prostatic carcinoma. The value of a marker panel for prognostic information. Acta Oncol. 1991, 30 (2): 173–5. PMID 2029401. doi:10.3109/02841869109092345. 
  87. ^ Gronowitz JS, Bergström R, Nôu E; et al. Clinical and serologic markers of stage and prognosis in small cell lung cancer. A multivariate analysis. Cancer. August 1990, 66 (4): 722–32. PMID 2167141. doi:10.1002/1097-0142(19900815)66:4<722::AID-CNCR2820660421>3.0.CO;2-J. 
  88. ^ Gronowitz JS, Steinholtz L, Källander CF, Hagberg H, Bergh J. Serum deoxythymidine kinase in small cell carcinoma of the lung. Relation to clinical features, prognosis, and other biochemical markers. Cancer. July 1986, 58 (1): 111–8. PMID 3011236. doi:10.1002/1097-0142(19860701)58:1<111::AID-CNCR2820580120>3.0.CO;2-K. 
  89. ^ H.X.Li, S Zhang, D.S Lei, X.Q Wang, et al. (August 2005). 「Serum thymidine kinase 1 is a prognostic and monitoring factor in patients with non-small cell lung cancer」. Oncology Reports 13: 145-149.
  90. ^ Benjamin Nisman, Tanir Allweis, Luna Kaduri, Bella Maly, Simon Gronowitz, Tamar Hamburger, Tamar Peretz. Serum thymidine kinase 1 activity in breast cancer. Cancer Biomarkers: Section A of Disease Markers. 2010, 7 (2): 65–72 [2019-05-26]. ISSN 1875-8592. PMID 21178264. doi:10.3233/CBM-2010-0148. （原始げんし内容ないよう存そん档于2019-09-05）. 
  91. ^ Q. He, L. Zou, P.A Zhang, et al. (2000) 「The clinical significance of thymidine kinase 1 measurement in serum of breast cancer patients using anti-TK1 antibody」. J.Biol.Marker, 15:139-146
  92. ^ Qimin He, Tommy Fornander, Hemming Johansson, et al. (2006) 「Thymidine kinase 1 in serum predicts increased risk of distant or loco-regional recurrence following surgery in patients with early breast cancer」. Anticancer Research 26: 4753-4760.
  93. ^ L. Zou, P.G Zhang, S. Zou, et al.(2002) 「The half-life of thymidine kinase 1 in serum measured by ECL dot blot: a potential marker for monitoring the response to surgery of patients with gastric cancer」. The international Journal of biological Markers, Vol. 17 No. 2:135-140.
  94. ^ Benjamin Nisman, Vladimir Yutkin, Hovav Nechushtan, Ofer N. Gofrit, Tamar Peretz, Simon Gronowitz, Dov Pode. Circulating tumor M2 pyruvate kinase and thymidine kinase 1 are potential predictors for disease recurrence in renal cell carcinoma after nephrectomy. Urology. 2010-8, 76 (2): 513.e1–6 [2019-05-26]. ISSN 1527-9995. PMID 20573390. doi:10.1016/j.urology.2010.04.034. （原始げんし内容ないよう存そん档于2019-09-05）. 
  95. ^ Jie Zhang, Quanan Jia, Shan Zou, et al. (August 2006). 「Thymidine kinase 1: A proliferation marker of determining prognosis and monitoring the surgical outcome of primary bladder carcinoma patients」. Oncology Reports 15:455-461.
  96. ^ P. H. Ellims, R. J. Hayman, M. B. Van der Weyden. Expression of fetal thymidine kinase in human cobalamin or folate deficient lymphocytes. Biochemical and Biophysical Research Communications. 1979-07-12, 89 (1): 103–107 [2019-05-26]. ISSN 0006-291X. PMID 475797. 
  97. ^ 97.0 97.1 M. Neumuller, C. F. Källander, J. S. Gronowitz. Detection and characteristics of DNA polymerase activity in serum from patients with malignant, viral, or B12-deficiency disease. Enzyme. 1989, 41 (1): 6–16 [2019-05-26]. ISSN 0013-9432. PMID 2543552. 
  98. ^ G. Tufveson, T. H. Tötterman, C. F. Källander, A. Hagström, J. S. Gronowitz. Serum thymidine-kinase and cytomegalovirus-specific antibodies after renal transplantation. Transplantation Proceedings. 1988-6, 20 (3): 405–407 [2019-05-26]. ISSN 0041-1345. PMID 2837850. 
  99. ^ C. F. Källander, J. S. Gronowitz, E. Olding-Stenkvist. Rapid diagnosis of varicella-zoster virus infection by detection of viral deoxythymidine kinase in serum and vesicle fluid. Journal of Clinical Microbiology. 1983-2, 17 (2): 280–287 [2019-05-26]. ISSN 0095-1137. PMC 272623 可免费查阅. PMID 6339548. 
  100. ^ Zhishan Li, Yinghong Wang, Jie Ma, et al. (2010). 「Transient increase in serum thymidine kinase 1 within one week after surgery of patients with carcinoma」. Anticancer Research 30: 1295-1300.
  101. ^ ZhiHeng Chen, Hui Zhou, ShengLan Li, et al. (2008). 「Serological Thymidine Kinase 1 (STK1) indicates an elevated risk for the development of malignant tumors」. Anticancer Research 28:3897-3908.
  102. ^ Shouqing Huang, Jianzh Lin, Na Guo, et al. (2011). 「Elevated serum thymidine kinase 1 predicts risk of pre/early cancerous progression」. Asian Pacific J Cancer Prev, 12, 497-505.
  103. ^ Lin TS, Neenan JP, Cheng YC, Prusoff WH. Synthesis and antiviral activity of 5- and 5'-substituted thymidine analogs. J. Med. Chem. April 1976, 19 (4): 495–8. PMID 177781. doi:10.1021/jm00226a009. 
  104. ^ Helgstrand E, Oberg B. Enzymatic targets in virus chemotherapy. Antibiot Chemother. 1980, 27: 22–69. PMID 6996606. 
  105. ^ Shannon WM, Schabel FM. Antiviral agents as adjuncts in cancer chemotherapy. Pharmacol. Ther. 1980, 11 (2): 263–390. PMID 7001501. doi:10.1016/0163-7258(80)90034-0. 
  106. ^ Hirsch MS. Chemotherapy of human immunodeficiency virus infections: current practice and future prospects. J. Infect. Dis. May 1990, 161 (5): 845–57. PMID 1691243. doi:10.1093/infdis/161.5.845. 
  107. ^ Shiau GT, Schinazi RF, Chen MS, Prusoff WH. Synthesis and biological activities of 5-(hydroxymethyl, azidomethyl, or aminomethyl)-2'-deoxyuridine and related 5'-substituted analogues. J. Med. Chem. February 1980, 23 (2): 127–33. PMID 6244411. doi:10.1021/jm00176a005. 
  108. ^ Mitsuya H, Weinhold KJ, Furman PA; et al. 3'-Azido-3'-deoxythymidine (BW A509U): an antiviral agent that inhibits the infectivity and cytopathic effect of human T-lymphotropic virus type III/lymphadenopathy-associated virus in vitro. Proc. Natl. Acad. Sci. U.S.A. October 1985, 82 (20): 7096–100. PMC 391317 可免费查阅. PMID 2413459. doi:10.1073/pnas.82.20.7096. 
  109. ^ Baba M, Pauwels R, Herdewijn P, De Clercq E, Desmyter J, Vandeputte M. Both 2',3'-dideoxythymidine and its 2',3'-unsaturated derivative (2',3'-dideoxythymidinene) are potent and selective inhibitors of human immunodeficiency virus replication in vitro. Biochem. Biophys. Res. Commun. January 1987, 142 (1): 128–34 [2012-03-13]. PMID 3028398. doi:10.1016/0006-291X(87)90460-8. （原始げんし内容ないよう存そん档于2020-05-29）. 
  110. ^ Hamamoto Y, Nakashima H, Matsui T, Matsuda A, Ueda T, Yamamoto N. Inhibitory effect of 2',3'-didehydro-2',3'-dideoxynucleosides on infectivity, cytopathic effects, and replication of human immunodeficiency virus. Antimicrob. Agents Chemother. June 1987, 31 (6): 907–10. PMC 284209 可免费查阅. PMID 3039911. 
  111. ^ 111.0 111.1 Ohrvik A, Lindh M, Einarsson R, Grassi J, Eriksson S. Sensitive nonradiometric method for determining thymidine kinase 1 activity. Clin. Chem. September 2004, 50 (9): 1597–606. PMID 15247154. doi:10.1373/clinchem.2003.030379. 
  112. ^ Prusoff WH. Synthesis and biological activities of iododeoxyuridine, an analog of thymidine. Biochim. Biophys. Acta. March 1959, 32 (1): 295–6. PMID 13628760. doi:10.1016/0006-3002(59)90597-9. 
  113. ^ Morgenroth A, Deisenhofer S, Glatting G; et al. Preferential Tumor Targeting and Selective Tumor Cell Cytotoxicity of 5-[131/125I]Iodo-4'-Thio-2'-Deoxyuridine. Clin. Cancer Res. November 2008, 14 (22): 7311–9. PMID 19010846. doi:10.1158/1078-0432.CCR-08-0907. 
  114. ^ Graciela Andrei, Robert Snoeck. Emerging drugs for varicella-zoster virus infections. Expert Opinion on Emerging Drugs. 2011-9, 16 (3): 507–535 [2019-05-26]. ISSN 1744-7623. PMID 21699441. doi:10.1517/14728214.2011.591786. （原始げんし内容ないよう存そん档于2011-07-03）. 
  115. ^ Johnson VA, Hirsch MS. New developments in antiretroviral drug therapy for human immunodeficiency virus infections. Ganciclover is a 5' monophosphate that does not require thymidine kinase activation and thus expresses higher toxicity to host enzymes due to a decrease in selectivity. AIDS Clin Rev. 1990: 235–72. PMID 1707295. 
  116. ^ Mar EC, Chiou JF, Cheng YC, Huang ES. Inhibition of cellular DNA polymerase alpha and human cytomegalovirus-induced DNA polymerase by the triphosphates of 9-(2-hydroxyethoxymethyl)guanine and 9-(1,3-dihydroxy-2-propoxymethyl)guanine. J. Virol. March 1985, 53 (3): 776–80. PMC 254706 可免费查阅. PMID 2983088. 
  117. ^ Black ME, Hruby DE. Quaternary structure of vaccinia virus thymidine kinase. Biochem. Biophys. Res. Commun. June 1990, 169 (3): 1080–6 [2012-03-13]. PMID 2114104. doi:10.1016/0006-291X(90)92005-K. （原始げんし内容ないよう存そん档于2015-09-24）. 
  118. ^ Nicholas TW, Read SB, Burrows FJ, Kruse CA. Suicide gene therapy with Herpes simplex virus thymidine kinase and ganciclovir is enhanced with connexins to improve gap junctions and bystander effects. Histol. Histopathol. April 2003, 18 (2): 495–507 [2012-03-13]. PMID 12647801. （原始げんし内容ないよう存そん档于2020-07-23）. 
  119. ^ Ellen Preuss, Alexander Muik, Kristoffer Weber, Jürgen Otte, Dorothee von Laer, Boris Fehse. Cancer suicide gene therapy with TK.007: superior killing efficiency and bystander effect. Journal of Molecular Medicine (Berlin, Germany). 2011-11, 89 (11): 1113–1124 [2019-05-26]. ISSN 1432-1440. PMID 21698427. doi:10.1007/s00109-011-0777-8. （原始げんし内容ないよう存そん档于2019-01-06）. 
  120. ^ Hart IR. Tissue specific promoters in targeting systemically delivered gene therapy. Semin. Oncol. February 1996, 23 (1): 154–8. PMID 8607025. 
  121. ^ Wills KN, Huang WM, Harris MP, Machemer T, Maneval DC, Gregory RJ. Gene therapy for hepatocellular carcinoma: chemosensitivity conferred by adenovirus-mediated transfer of the HSV-1 thymidine kinase gene. Cancer Gene Ther. September 1995, 2 (3): 191–7. PMID 8528962. 
  122. ^ Ido A, Nakata K, Kato Y; et al. Gene therapy for hepatoma cells using a retrovirus vector carrying herpes simplex virus thymidine kinase gene under the control of human alpha-fetoprotein gene promoter. Cancer Res. July 1995, 55 (14): 3105–9. PMID 7541712. 
  123. ^ Kanai F, Shiratori Y, Yoshida Y; et al. Gene therapy for alpha-fetoprotein-producing human hepatoma cells by adenovirus-mediated transfer of the herpes simplex virus thymidine kinase gene. Hepatology. June 1996, 23 (6): 1359–68. PMID 8675152. doi:10.1002/hep.510230611. 
  124. ^ Garver RI, Goldsmith KT, Rodu B, Hu PC, Sorscher EJ, Curiel DT. Strategy for achieving selective killing of carcinomas. Gene Ther. January 1994, 1 (1): 46–50. PMID 7584059. 
  125. ^ Hart IR. Transcriptionally targeted gene therapy. Curr. Top. Microbiol. Immunol. 1996, 213 (3): 19–25. PMID 8815006. 
  126. ^ {{cite journal |author=Byun Y, Thirumamagal BT, Yang W, Eriksson S, Barth RF, Tjarks W |title=Preparation and biological evaluation of 10B-enriched 3-[5-{2-(2,3-dihydroxyprop-1-yl)-o-carboran-1-yl}pentan-1-yl]thymidine (N5-2OH), a new boron delivery agent for boron neutron capture therapy of brain tumors |journal=J. Med. Chem. |volume=49 |issue=18 |pages=5513–23 |pmid=16942024 |doi=10.1021/jm060413w |url=|date=September 2006}}
  127. ^ Thirumamagal BT, Johnsamuel J, Cosquer GY; et al. Boronated thymidine analogues for boron neutron capture therapy. Nucleosides Nucleotides Nucleic Acids. 2006, 25 (8): 861–6. PMID 16901817. doi:10.1080/15257770600793844. 
  128. ^ Narayanasamy S, Thirumamagal BT, Johnsamuel J; et al. Hydrophilically enhanced 3-carboranyl thymidine analogues (3CTAs) for boron neutron capture therapy (BNCT) of cancer. Bioorg. Med. Chem. October 2006, 14 (20): 6886–99. PMID 16831554. doi:10.1016/j.bmc.2006.06.039. 
  129. ^ Byun Y, Narayanasamy S, Johnsamuel J; et al. 3-Carboranyl thymidine analogues (3CTAs) and other boronated nucleosides for boron neutron capture therapy. Anticancer Agents Med Chem. March 2006, 6 (2): 127–44. PMID 16529536. doi:10.2174/187152006776119171. [永久えいきゅう失效しっこう連結れんけつ]
  130. ^ Byun Y, Yan J, Al-Madhoun AS; et al. Synthesis and biological evaluation of neutral and zwitterionic 3-carboranyl thymidine analogues for boron neutron capture therapy. J. Med. Chem. February 2005, 48 (4): 1188–98. PMID 15715485. doi:10.1021/jm0491896. 
  131. ^ Barth RF, Yang W, Al-Madhoun AS; et al. Boron-containing nucleosides as potential delivery agents for neutron capture therapy of brain tumors. Cancer Res. September 2004, 64 (17): 6287–95. PMID 15342417. doi:10.1158/0008-5472.CAN-04-0437. 
  132. ^ Al-Madhoun AS, Johnsamuel J, Barth RF, Tjarks W, Eriksson S. Evaluation of human thymidine kinase 1 substrates as new candidates for boron neutron capture therapy. Cancer Res. September 2004, 64 (17): 6280–6. PMID 15342416. doi:10.1158/0008-5472.CAN-04-0197. 
  133. ^ Johnsamuel J, Lakhi N, Al-Madhoun AS; et al. Synthesis of ethyleneoxide modified 3-carboranyl thymidine analogues and evaluation of their biochemical, physicochemical, and structural properties. Bioorg. Med. Chem. September 2004, 12 (18): 4769–81. PMID 15336255. doi:10.1016/j.bmc.2004.07.032. 
  134. ^ Byun Y, Yan J, Al-Madhoun AS; et al. The synthesis and biochemical evaluation of thymidine analogues substituted with nido carborane at the N-3 position. Appl Radiat Isot. November 2004, 61 (5): 1125–30. PMID 15308203. doi:10.1016/j.apradiso.2004.05.023. 
  135. ^ Yan J, Naeslund C, Al-Madhoun AS; et al. Synthesis and biological evaluation of 3'-carboranyl thymidine analogues. Bioorg. Med. Chem. Lett. August 2002, 12 (16): 2209–12 [2012-03-13]. PMID 12127539. doi:10.1016/S0960-894X(02)00357-8. （原始げんし内容ないよう存そん档于2018-07-02）. 
  136. ^ Barth RF, Yang W, Wu G; et al. Thymidine kinase 1 as a molecular target for boron neutron capture therapy of brain tumors. Proc. Natl. Acad. Sci. U.S.A. November 2008, 105 (45): 17493–7. PMC 2582264 可免费查阅. PMID 18981415. doi:10.1073/pnas.0809569105. 
  137. ^ Gronowitz JS, Källander CF. Optimized assay for thymidine kinase and its application to the detection of antibodies against herpes simplex virus type 1- and 2-induced thymidine kinase. Infect. Immun. August 1980, 29 (2): 425–34. PMC 551136 可免费查阅. PMID 6260651. 
  138. ^ Gronowitz JS, Källander FR, Diderholm H, Hagberg H, Pettersson U. Application of an in vitro assay for serum thymidine kinase: results on viral disease and malignancies in humans. Int. J. Cancer. January 1984, 33 (1): 5–12. PMID 6693195. doi:10.1002/ijc.2910330103. 
  139. ^ Gronowitz JS, Källander CF. A sensitive assay for detection of deoxythymidine kinase and its application to herpesvirus diagnosis. Curr. Top. Microbiol. Immunol. 1983, 104: 235–45. PMID 6307593. 
  140. ^ 引用いんよう错误：没ぼつ有ゆう为名为pmid16140350的てき参考さんこう文献ぶんけん提供ていきょう内容ないよう
  141. ^ Gronowitz, JS (24.2.2006) A method and kit for determination of thymidine kinase activity and use thereof. International patent application PCT/SE2006/000246
  142. ^ Chuanjing Wu, Rong-jiang Yang, Ji Zhou, et al. (February 2003). 「Production and characterization of a novel chicken IgY antibody raised against C-terminal peptide from human thymidine kinase 1」. Journal of Immunological Methods 277:157-169.
  143. ^ Romain S, Spyratos F, Guirou O, Deytieux S, Chinot O, Martin PM. Technical evaluation of thymidine kinase assay in cytosols from breast cancers. EORTC Receptor Study Group Report. Eur. J. Cancer. 1994, 30A (14): 2163–5. PMID 7857717. doi:10.1016/0959-8049(94)00376-G. 
  144. ^ Arnér ES, Spasokoukotskaja T, Eriksson S. Selective assays for thymidine kinase 1 and 2 and deoxycytidine kinase and their activities in extracts from human cells and tissues. Biochem. Biophys. Res. Commun. October 1992, 188 (2): 712–8. PMID 1359886. doi:10.1016/0006-291X(92)91114-6. 
  145. ^ Wang L, Eriksson S. 5-Bromovinyl 2'-deoxyuridine phosphorylation by mitochondrial and cytosolic thymidine kinase (TK2 and TK1) and its use in selective measurement of TK2 activity in crude extracts. Nucleosides Nucleotides Nucleic Acids. June 2008, 27 (6): 858–62. PMID 18600552. doi:10.1080/15257770802146510. 
  146. ^ 146.0 146.1 Herzfeld A, Greengard O. Enzyme activities in human fetal and neoplastic tissues. Cancer. November 1980, 46 (9): 2047–54. PMID 6253048. doi:10.1002/1097-0142(19801101)46:9<2047::AID-CNCR2820460924>3.0.CO;2-Q. 
  147. ^ Machovich R, Greengard O. Thymidine kinase in rat tissues during growth and differentiation. Biochim. Biophys. Acta. December 1972, 286 (2): 375–81. PMID 4660462. doi:10.1016/0304-4165(72)90273-5. 
  148. ^ Herzfeld A, Raper SM, Gore I. The ontogeny of thymidine kinase in tissues of man and rat. Pediatr. Res. December 1980, 14 (12): 1304–10. PMID 7208144. doi:10.1203/00006450-198012000-00006. 
  149. ^ Schollenberger S, Taureck D, Wilmanns W. [Enzymes of thymidine and thymidylate metabolism in normal and pathological blood and bone marrow cells] [Enzymes of thymidine and thymidylate metabolism in normal and pathological blood and bone marrow cells]. Blut. November 1972, 25 (5): 318–34. PMID 4508724. doi:10.1007/BF01631814 （德とく语）. 
  150. ^ Nakao K, Fujioka S. Thymidine kinase activity in the human bone marrow from various blood diseases. Life Sci. April 1968, 7 (8): 395–9. PMID 5649653. doi:10.1016/0024-3205(68)90039-8. 
  151. ^ Wickramasinghe SN, Olsen I, Saunders JE. Thymidine kinase activity in human bone marrow cells. Scand J Haematol. September 1975, 15 (2): 139–44. PMID 1059244. doi:10.1111/j.1600-0609.1975.tb01065.x. 
  152. ^ Gordon HL, Bardos TJ, Chmielewicz ZF, Ambrus JL. Comparative study of the thymidine kinase and thymidylate kinase activities and of the feedbach inhibition of thymidine kinase in normal and neoplastic human tissue. Cancer Res. October 1968, 28 (10): 2068–77. PMID 5696936. 
  153. ^ Stafford MA, Jones OW. The presence of "fetal" thymidine kinase in human tumors. Biochim. Biophys. Acta. August 1972, 277 (2): 439–42. PMID 4672678. 
  154. ^ Maehara Y, Nakamura H, Nakane Y; et al. Activities of various enzymes of pyrimidine nucleotide and DNA syntheses in normal and neoplastic human tissues. Gann. April 1982, 73 (2): 289–98. PMID 6288502. 
  155. ^ Persson L, Gronowitz SJ, Källander CF. Thymidine kinase in extracts of human brain tumours. Acta Neurochir (Wien). 1986, 80 (3–4): 123–7. PMID 3012969. doi:10.1007/BF01812286. 
  156. ^ Filanovskaia LI, Togo AV, Shcherbakova EG, Blinov MN. [Thymidine kinase activity in leukocytes from patients with chronic myeloid leukemia at various periods in the disease] [Thymidine kinase activity in leukocytes from patients with chronic myeloid leukemia at various periods in the disease]. Vopr. Med. Khim. 1994, 40 (1): 29–32. PMID 8122406 （俄にわか语）. 
  157. ^ Lipkin M. Proliferation and differentiation of normal and neoplastic cells in the colon of man. Cancer. July 1971, 28 (1): 38–40. PMID 5110642. doi:10.1002/1097-0142(197107)28:1<38::AID-CNCR2820280108>3.0.CO;2-W. 
  158. ^ Lipkin M, Deschner E, Troncale F. Cell differentiation and the development of colonic neoplasms. CA Cancer J Clin. 1970, 20 (6): 386–90 [2012-03-13]. PMID 4992499. doi:10.3322/canjclin.20.6.386. （原始げんし内容ないよう存そん档于2016-03-04）. 
  159. ^ Weber G, Lui MS, Takeda E, Denton JE. Enzymology of human colon tumors. Life Sci. September 1980, 27 (9): 793–9. PMID 7412505. doi:10.1016/0024-3205(80)90333-1. 
  160. ^ Sagara T, Tsukada K, Iwama T, Mishima Y, Sakamoto S, Okamoto R. [Thymidine kinase isozymes in human colon polyps] [Thymidine kinase isozymes in human colon polyps]. Nippon Gan Chiryo Gakkai Shi. August 1985, 20 (7): 1312–6. PMID 4078430 （日にち语）. 
  161. ^ Sakamoto S, Sagara T, Iwama T, Kawasaki T, Okamoto R. Increased activities of thymidine kinase isozymes in human colon polyp and carcinoma. Carcinogenesis. June 1985, 6 (6): 917–9. PMID 4006080. doi:10.1093/carcin/6.6.917. 
  162. ^ Sakamoto S, Okamoto R. Thymidine kinase activity in familial adenomatous polyposis. Tohoku J. Exp. Med. October 1992, 168 (2): 291–301. PMID 1339104. doi:10.1620/tjem.168.291. （原始げんし内容ないよう存そん档于2012-12-19）. 
  163. ^ Galloux H, Javre JL, Guerin D, Sampérez S, Jouan P. [Prognostic value of fetal thymidine kinase measurements in breast cancer] [Prognostic value of fetal thymidine kinase measurements in breast cancer]. C. R. Acad. Sci. III, Sci. Vie. 1988, 306 (3): 89–92. PMID 3126994 （法ほう语）. 
  164. ^ O'Neill KL, Hoper M, Odling-Smee GW. Can thymidine kinase levels in breast tumors predict disease recurrence?. J. Natl. Cancer Inst. December 1992, 84 (23): 1825–8. PMID 1433372. doi:10.1093/jnci/84.23.1825. 
  165. ^ O'Neill KL, McKelvey VJ, Hoper M; et al. Breast tumour thymidine kinase levels and disease recurrence. Med Lab Sci. December 1992, 49 (4): 244–7. PMID 1339926. 
  166. ^ Romain S, Javre JL, Samperez S; et al. [Prognostic value of thymidine kinase in cancer of the breast] [Prognostic value of thymidine kinase in cancer of the breast]. Bull Cancer. 1990, 77 (10): 973–83. PMID 2249017 （法ほう语）. 
  167. ^ Romain S, Chinot O, Guirou O, Soullière M, Martin PM. Biological heterogeneity of ER-positive breast cancers in the post-menopausal population. Int. J. Cancer. October 1994, 59 (1): 17–9. PMID 7927897. doi:10.1002/ijc.2910590105. 
  168. ^ Sakamoto S, Iwama T, Ebuchi M; et al. Increased activities of thymidine kinase isozymes in human mammary tumours. Br J Surg. April 1986, 73 (4): 272–3. PMID 3697655. doi:10.1002/bjs.1800730409. 
  169. ^ Greengard O, Head JF, Goldberg SL, Kirschner PA. Enzyme pathology and the histologic categorization of human lung tumors: the continuum of quantitative biochemical indices of neoplasticity. Cancer. February 1982, 49 (3): 460–7. PMID 6277448. doi:10.1002/1097-0142(19820201)49:3<460::AID-CNCR2820490312>3.0.CO;2-Y. 
  170. ^ Greengard O, Head JF, Goldberg SL, Kirschner PA. Biochemical measure of the volume doubling time of human pulmonary neoplasms. Cancer. April 1985, 55 (7): 1530–5. PMID 2983858. doi:10.1002/1097-0142(19850401)55:7<1530::AID-CNCR2820550720>3.0.CO;2-V. 
  171. ^ Yusa T, Tamiya N, Yamaguchi Y; et al. [A study of thymidine kinase activity in lung cancer tissue] [A study of thymidine kinase activity in lung cancer tissue]. Nihon Kyobu Shikkan Gakkai Zasshi. March 1994, 32 (3): 211–5. PMID 8189640 （日にち语）. 
  172. ^ Konishi T, Miyama T, Sakamoto S; et al. Activities of thymidylate synthetase and thymidine kinase in gastric cancer. Surg Oncol. June 1992, 1 (3): 215–21. PMID 1341254. doi:10.1016/0960-7404(92)90067-U. 
  173. ^ Look KY, Moore DH, Sutton GP, Prajda N, Abonyi M, Weber G. Increased thymidine kinase and thymidylate synthase activities in human epithelial ovarian carcinoma. Anticancer Res. 1997, 17 (4A): 2353–6. PMID 9252646. 
  174. ^ Greengard O, Head JF, Chahinian AP, Goldberg SL. Enzyme pathology of human mesotheliomas. J. Natl. Cancer Inst. April 1987, 78 (4): 617–22. PMID 2882044. 
  175. ^ Borovanský J, Stríbrná J, Elleder M, Netíková I. Thymidine kinase in malignant melanoma. Melanoma Res. October 1994, 4 (5): 275–9. PMID 7858409. doi:10.1097/00008390-199410000-00001. 
  176. ^ Sakamoto S, Murakami S, Sugawara M, Mishima Y, Okamoto R. Increased activities of thymidylate synthetase and thymidine kinase in human thyroid tumors. Thyroid. 1991, 1 (4): 347–51. PMID 1841732. doi:10.1089/thy.1991.1.347. 
  177. ^ Pikner R, Ludvíkova M, Ryska A; et al. TPS, thymidine kinase, VEGF and endostatin in cytosol of thyroid tissue samples. Anticancer Res. 2005, 25 (3A): 1517–21. PMID 16033053. 
  178. ^ Wilms K, Wilmanns W. [Effects of dauno-rubidomycin and adriamycin on enzymes of DNA synthesis in leukocytes in vivo and in culture] [Effects of dauno-rubidomycin and adriamycin on enzymes of DNA synthesis in leukocytes in vivo and in culture]. Klin. Wochenschr. September 1972, 50 (18): 866–70. PMID 4507472. doi:10.1007/BF01488943 （德とく语）. 
  179. ^ Wilmanns W, Wilms K. DNA synthesis in normal and leucemic cells as related to therapy with cytotoxic drugs. Enzyme. 1972, 13 (1): 90–109. PMID 4507104. 
  180. ^ Zhang HJ, Kennedy BJ, Kiang DT. Thymidine kinase as a predictor of response to chemotherapy in advanced breast cancer. Breast Cancer Res. Treat. 1984, 4 (3): 221–5. PMID 6487823. doi:10.1007/BF01806488. 
  181. ^ Kuroiwa N, Nakayama M, Fukuda T; et al. Specific recognition of cytosolic thymidine kinase in the human lung tumor by monoclonal antibodies raised against recombinant human thymidine kinase. J. Immunol. Methods. July 2001, 253 (1–2): 1–11 [2012-03-13]. PMID 11384664. doi:10.1016/S0022-1759(01)00368-4. （原始げんし内容ないよう存そん档于2018-06-14）. 
  182. ^ 182.0 182.1 He Q, Mao Y, Wu J; et al. Cytosolic thymidine kinase is a specific histopathologic tumour marker for breast carcinomas. Int. J. Oncol. October 2004, 25 (4): 945–53. PMID 15375544. 
  183. ^ Mao Y, Wu J, Wang N; et al. A comparative study: immunohistochemical detection of cytosolic thymidine kinase and proliferating cell nuclear antigen in breast cancer. Cancer Invest. 2002, 20 (7–8): 922–31. PMID 12449723. doi:10.1081/CNV-120005905. 
  184. ^ Mao Y, Wu J, Skog S; et al. Expression of cell proliferating genes in patients with non-small cell lung cancer by immunohistochemistry and cDNA profiling. Oncol. Rep. May 2005, 13 (5): 837–46. PMID 15809747. 
  185. ^ Wu J, Mao Y, He L; et al. A new cell proliferating marker: cytosolic thymidine kinase as compared to proliferating cell nuclear antigen in patients with colorectal carcinoma. Anticancer Res. 2000, 20 (6C): 4815–20. PMID 11205225. 
  186. ^ Li HX, Lei DS, Wang XQ, Skog S, He Q. Serum thymidine kinase 1 is a prognostic and monitoring factor in patients with non-small cell lung cancer. Oncol. Rep. January 2005, 13 (1): 145–9. PMID 15583816. 
  187. ^ Stephan Kruck, Joerg Hennenlotter, Ulrich Vogel, David Schilling, Georgios Gakis, Joachim Hevler, Ursula Kuehs, Arnulf Stenzl, Christian Schwentner. Exposed proliferation antigen 210 (XPA-210) in renal cell carcinoma (RCC) and oncocytoma: clinical utility and biological implications. BJU international. 2012-2, 109 (4): 634–638 [2019-05-26]. ISSN 1464-410X. PMID 21711439. doi:10.1111/j.1464-410X.2011.10392.x. （原始げんし内容ないよう存そん档于2016-06-07）. 

外部がいぶ連結れんけつ

[编辑]
转移酶：含磷基もと团的激げき酶类（EC 2.7）
2.7.1-2.7.4：磷酸转移酶类（英えい语：phosphotransferase）/激げき酶
（PO4）
2.7.1：以羟基为受体たい
2.7.2（英えい语：List_of_EC_numbers_(EC_2)#EC_2.7.2:_Phosphotransferases_with_a_carboxy_group_as_acceptor）：以羧基为受体たい
2.7.3：以含氮基团为受体
2.7.4：以磷酸基もと团为受体たい
2.7.6（英えい语：List of EC numbers (EC 2)#EC_2.7.6:_Diphosphotransferases）：二磷酸转移酶类（英えい语：Diphosphotransferase）
(P2O7)
2.7.7：核かく苷酸基もと转移酶
聚合酶
DNA聚合酶
RNA核かく苷酸转移酶
DNA指ゆび导的RNA聚合酶RNA聚合酶
RNA聚合酶Ⅰ（英えい语：RNA polymerase I）
RNA聚合酶Ⅱ
RNA聚合酶III
RNA聚合酶Ⅳ（英えい语：RNA polymerase IV）
RNA聚合酶V
引發酶
RNA指ゆび导的RNA聚合酶RNA複製ふくせい酶
磷酸解かい作用さよう
由よし3'端はし至いたり5'端はし的てき核かく糖とう核酸かくさん外切がいせつ酶
尿にょう苷酰转移酶
鸟苷酰转移うつり酶
其它
2.7.8：杂项
磷脂酰基转移酶类
糖とう基もと-1-磷酸转移酶类
2.7.10-2.7.13：蛋白たんぱく激げき酶类
（PO4；蛋白たんぱく质受体たい）
2.7.10：蛋白たんぱく酪氨酸さん
2.7.11：蛋白たんぱく丝氨酸さん/苏氨酸さん
2.7.12：蛋白たんぱく双そう特とく异性
2.7.13：蛋白たんぱく组氨酸さん
EC 1.1/2/3/4/5/6/7/8/9/10/11/12/13/14/15/16/17/18/19/20/21/22 · 2.1/2/3/4/5/6/7(2.7.10/11-12)/8/9 · 3.1/2/3/4(3.4.21/22/23/24)/5/6/7/8/9/10/11/12/13 · 4.1/2/3/4/5/6 · 5.1/2/3/4/5/99 · 6.1-3（英えい语：Template:Ligases CO CS and CN）/4/5-6
检索自じ“https://zh.wikipedia.org/w/index.php?title=胸むね苷激酶&oldid=79726525”