TW201030338A - Method for predicting therapeutic effect of combination chemotherapy - Google Patents

Method for predicting therapeutic effect of combination chemotherapy Download PDF

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TW201030338A
TW201030338A TW098145054A TW98145054A TW201030338A TW 201030338 A TW201030338 A TW 201030338A TW 098145054 A TW098145054 A TW 098145054A TW 98145054 A TW98145054 A TW 98145054A TW 201030338 A TW201030338 A TW 201030338A
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therapeutic effect
cisplatin
chemotherapy
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Toshinori Oka
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Taiho Pharmaceutical Co Ltd
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Abstract

Disclosed is an anti-tumor agent which can exhibit a superior life-prolonging effect on progressive gastric cancer patients, on whom conventional therapy methods cannot exhibit a satisfactory life-prolonging effect, compared to those of the conventional therapy methods, when the patients are selected by employing a thymidylate synthase as a measure. The anti-tumor agent comprises a tegafur-gimeracil-(oteracil potassium) combination preparation and cisplatin.

Description

201030338 六、發明說明： 【明所屬技系奸領域】 技術領域 本發明係有關於：一種預測對替吉奥複合劑與順翻之 併用化學療法之治療效果的方法；_種用來對患者投藥之 抗腫瘤劑，其中該患者係被預測為對該併用化學療法顯示 充分治療效果之可能性高者；引子對及套組。201030338 VI. Description of the Invention: [Technical Field] Field of the Invention The present invention relates to a method for predicting the therapeutic effect of a combination of a tigeo complex and a chemotherapeutic remedy; An anti-tumor agent, wherein the patient is predicted to have a high probability of exhibiting a sufficient therapeutic effect in combination with chemotherapy; a primer pair and a set.

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背景技術 作為對進行性胃癌之化學療法，在國内外有下述抗腫 瘤劑以單劑或併用之形式被臨床應用：5-氟尿嘧啶 (5-fluorouracil)、順鉑（cisplatin)、愛萊諾迪肯（irinotecan)、 多西紫杉醇（docetaxel)、替加氟-尿嘧啶複合劑（商品名： UFT®)、替吉奥複合劑（combination preparation of tegafur, gimeracil and oteracil potassium，替加氟·吉美嘴咬_奥替拉 西鉀複合劑)(商品名：TS-1®，以下，將替加氟、吉美嘧啶、 奥替拉西奸以莫耳比1 : 0.4 : 1所調配之製劑稱為TS-1。） 等。在歐美雖是以5-FU與順鉑之併用化學療法為標準療 法，然而其延命效果尚非可令人滿意者，而TS-1與順翻之 併用化學療法係作為顯示較強延命效果之併用化學療法而 倍受期待(非專利文獻1)。 習知技術文獻 非專利文獻 [非專利文獻 1] Cancer 2007; 109 : 33-40. 201030338 【發明内容】 發明揭示 發明欲解決之課題 本發明係以提供-種併用化學療法為目的，該併用化 學療法雜麟性胃癌患者可產线纽命效果者。 用以解決課題之手段 本發明人等，反覆進行對進行性胃癌之化學療法之研 究的結果，發現-種預測方法，係以胸腺核苦酸合成酵素 基因之表現量(mRNA量或酵素量）為指標，藉以預測對替吉 @ 奥複合劑與順始之併用化學療法顯示充分治療效果之可能 性南的患者，而完成了本發明。再者，雖然胸腺核普酸合 成酵素迄今係作為TS-1之治療效果限制因子而為公知（例 如，Int. J. Cancer: 119,1927-1933 (2006))，但卻完全不知道 在該併用化學療法之選擇中，可以胸腺核苷酸合成酵素基 因之表現產物為指標。 亦即’本發明係提供一種預測對於以下之替吉奥複合 劑與順鉑之併用化學療法之治療效果的方法、抗腫瘤劑、 ® 引子對及套組。 第1項 一種治療效果預測方法，其係預測對胃癌患者的替吉奥 複合劑（combination preparation of tegafur, gimeracil and oteracil potassium，替力σ氟-吉美0定-奥替拉西卸複合劑） 與順鉑（cisplatin)之併用化學療法的治療效果者，且包含下 述步驟（1)〜(2): 4 201030338 (1) 測定步驟，係測定採取自患者之可能含有癌細胞的生物 試樣中所含之胸腺核苷酸合成酵素基因之表現量者； (2) 預測㈣’係與預先設定之對應喊觀較，當以上述 步驟⑴所得狀表現量較低時，即制該併用化學療法對 患者顯不充分治療效果的可能性高。 第2項 如第1項之方法’其中替吉奥複合劑之衫效成分的莫BACKGROUND ART As a chemotherapy for progressive gastric cancer, the following antitumor agents are clinically applied in a single dose or in combination at home and abroad: 5-fluorouracil, cisplatin, Eleno di Irnotecan, docetaxel, tegafur-uracil complex (trade name: UFT®), combination preparation of tegafur, gimeracil and oteracil potassium, tegafur·jimei mouth Bite_Oturacil Potassium Complex) (trade name: TS-1®, below, the formulation of Teflon, Gemexy, Otto, and Mortide 1: 0.4: 1 is called TS -1.) Etc. In Europe and the United States, although the combination of 5-FU and cisplatin is the standard therapy, the prolongation effect is not satisfactory, and the combination of TS-1 and sputum is used to show the effect of strong prolongation. It is expected to be treated with chemotherapy (Non-Patent Document 1). CITATION TECHNOLOGIES Non-patent literature [Non-Patent Document 1] Cancer 2007; 109: 33-40. 201030338 SUMMARY OF THE INVENTION The present invention is directed to providing a combination of chemical treatments for the purpose of chemical chemistry. The treatment of patients with heterozygous gastric cancer can produce a line effect. Means for Solving the Problem The present inventors have repeatedly conducted research on the chemotherapy of progressive gastric cancer, and found that the prediction method is based on the expression amount of the thymidine nucleotide synthesis enzyme gene (the amount of mRNA or the amount of enzyme). As an indicator, the present invention has been completed by predicting a patient who is likely to have a sufficient therapeutic effect with the combination of the genomics and the chemotherapeutic. Furthermore, although thymidine synthase has heretofore been known as a therapeutic effect limiting factor for TS-1 (for example, Int. J. Cancer: 119, 1927-1933 (2006)), it is completely unknown. In the choice of chemotherapy, the expression product of the thymidine nucleotide synthetase gene can be used as an indicator. That is, the present invention provides a method, antitumor agent, ® primer pair and kit for predicting the therapeutic effect of the combination of the following tiggio complex with cisplatin. Item 1 is a method for predicting therapeutic effect, which predicts a combination preparation of tegafur, gimeracil and oteracil potassium, and a combination of sigma fluoro-jimei 0-otalazide unloading compound The combination of cisplatin and chemotherapeutic effect, and including the following steps (1) to (2): 4 201030338 (1) The measurement step is determined from a biological sample of a patient that may contain cancer cells. The expression of the thymidine synthase gene contained in the test; (2) predicting (4) 'the system is compared with the pre-set corresponding call, when the amount of expression obtained by the above step (1) is low, the combined use of chemotherapy There is a high probability that the patient will have insufficient therapeutic effects. Item 2 The method of item 1

耳比為：替吉奥：吉美做：錢拉西㈣：04 :卜 第3項 :種由替吉奥複合劑及顧所構成之抗腫瘤劑 ，其特 ;22癌症患者實施❹化學療法，且《症患者係 一曰第⑷項之方法，被賴為選擇該制化學療法會顯 7Γ充刀冶療效果之可能性高者。 第4項 :對癌症患者實施 1或2項之方法，被 治療效果之可能性 —種胃癌的治療方法，其特徵在於 併用化學療法’且該癌症患者係藉由第 預測為選擇該併用化學療法會顯示充分 高者。 第5項 ^㈣吉奥複合劑及仙所構成之抗腫瘤劑 途係用以對癌症患者實施併用化學 :::藉由第1或一，被預測為選擇該Si:; 法會顯示充分轉效果之可祕冑者。 干療 第6項 201030338 一種引子對，係用、、 量者，Μ含相，合鱗素之表現 子。 列編號2之逆向引 第7項 如第6項之引子對， 劑之化學療法的㈣料㈣預卿Μ含替吉奥複合 第8項 如第7項之引子對，其係用於 複合劑及順鉑的併用 j對月癌患者之替吉奥 第9項 ；/、法之治療效果者。 一種用於預剛對於勺A 士 療效果之套組，其包合匕3吉奥複合劑之化學療法的治 號2之逆向引子所構成由序列編號1之順向引子及序列編 量之引子對。㈣腺核㈣合成酵素表現 第10項 a劍月第#之套組，其仙於預測對胃癌患者之替吉奥複 口劑及順鉑的併用化學療法之治 第11項 第10項之套組’其進—步含有序列編號3之探針。 發明效果 本發明之預測方法，係可選擇具有對胃癌患者之強大 L p效果的有效化學療法者。亦即，對被預麟胃癌之延 P效果间之患者’可確實地提供—軸示較強延命效果之 併用化學療法，而由於可省去不必要的化學療法，在醫療 201030338 經濟上是有利的。 根據非專利文獻1，雖然TS-1與順鉑之併用化學療法一 向被認為是優異的，然而本發明卻首度揭示了該併用化學 療法之有效性係與胸腺核苷酸合成酵素基因（TS)之表現量 息息相關，且認為其只有在TS基因表現量在一定量以下時 是有效的。 C實施方式3 用以實施發明之最佳形態 本發明之預測方法係基於患者之胸腺核苷酸合成酵素 基因之表現量，來預測對藉由替吉奥複合劑與順鉑之併用 化學療法的治療，顯示較強延命效果之可能性高的患者。 本發明中，「於替吉奥複合劑進一步併用順鉑之化學療 法」係意味著：併用替吉奥複合劑及順鉑兩種抗腫瘤劑， 而進行投藥之化學療法。又，將前述複合劑與順鉑併用投 藥時，可將複合劑與順鉑同時投藥，亦可以一定間隔投藥。 本發明中，「對選擇於替吉奥複合劑進一步併用順鉑之 化學療法（以下亦稱為併用化學療法）具充分治療效果」，係 意味著：其顯示較歐美等地所使用之標準療法(例如，5_FU 與順鉑之併用化學療法)優異之延命效果。至於是否顯示了 該種延命效果，可由TSM之表現量是否錢點以下來判 斷，若TS基因之表現量在截點以下’則判斷選擇併用化學 療法具有充分的治療效果。 本發明之有效成分替加氟(一般名，化學名：5_氟_1_(2_ 四氫呋喃）-2,4-(ih，3H)-嘧啶二酮）為公知化合物，且為在生 201030338 物體内受到活化而釋出抗腫瘤活性的本體5-氟尿嘧啶之藥 劑。替加氟係可依照公知方法，例如日本專利公開昭 49-10510號之方法製造。 本發明之有效成分吉美嘧啶（一般名，化學名：2,4-二 羥-5-氣吡啶）亦為公知化合物，雖然其本身係完全不具抗腫 瘤活性者，但由於可抑制5_氟尿嘧啶在生物體内被代謝而 失活’因此可使抗腫瘤效果增強。 本發明之有效成分奥替拉西鉀（一般名，化學名： 1，2,3,4-四羥-2,4-二氧-ΐ，3,5·三嗪_6_羧酸_)亦為公知化合 物，雖然其本身不具抗腫瘤活性，然其為主要分布於消化 管’並藉由抑制在該部位的5_氟尿嘧啶之活化來抑制消化 管障礙者。 本發明之有效成分順鉑（一般名，化學名：（sp_4_2)二 胺二氣鉑）為公知白金錯合物，一般知道其係藉由DNA合成 阻害作用而達成抗腫瘤效果。又，順鉑可藉由公知方法製 ，且亦且使用Briplatin®(Bristol-Myers社製）等的市售醫藥 品0 本發明之治療效果，可用生存期間等來作判定，生存 /月門了藉由.生存期間中間值(期間越長則治療效果越高）、 1年生存率及2年生存率（比例越大則治療效果越高）等來表 示。 本發明中所投藥之替加敗、吉美做及奥替拉西卸的 比U若在達成各個複合目的之範圍内就無特別限制，例 如可為與日本專利第加偏號公報之公知複合劑相同的 201030338 範圍：相對於1莫耳替加氟，吉美嘧啶可為01〜5莫耳左右， 而以0.2〜1.5莫耳左右為佳；奥替拉西鉀可為可為〇 ι〜5莫耳 左右，而以0.2〜2莫耳左右為佳。其莫耳比特宜為，替吉奥： 吉美嘧咬：奥替拉西鉀=1 : 0.4 : 1。 本發明中所投藥之賴的比例，若在達成抗腫瘤效果 之條件下則無特別限制，例如，以la量而言，相對於1莫 耳替加氟，順在白可為0.01〜5.0莫耳左右，而以〇卜2 〇莫耳左 右為佳’以0.2〜1.5莫耳左右為特佳。 本發明之各有效成分的投藥量，可由用法、患者年齡、 性別、病期、有無轉移、治療史、有無其他抗腫瘤劑等的 條件作適宜選擇，而宜以下述範圍的量為建議量：替加氟 的量為0.1~100mg/kg/日左右，而以〇.2〜40mg/kg/日左右為 佳、以0.5〜20mg/kg/日左右為更佳；吉美嘧啶的量為 〇_〇2〜30mg/kg/日左右，而以〇.05〜12mg/kg/日左右為佳，以 〇·1〜6mg/kg/日左右為更佳；奥替拉西鉀的量為 〇.1〜100mg/kg/日左右，而以〇·2〜4〇mg/kg/日左右為佳，以 〇·5〜20mg/kg/日左右為更佳；順鉑的量為0.08〜2〇〇mg/kg/日 左右’而以〇.15~8〇111§/1^/日左右為佳，以0.4〜4〇111§/1(；§/日 左右為更佳。又，各有效成分係以1日1次，或分成複數次 投藥。再者’各有效成分係同時或有間隔地進行投藥，其 投藥順序並無特別限制。 本發明所提供之替加氟、吉美嘧啶、奥替拉西鉀係業 經製劑化為一劑型之複合劑。又，本發明中，順鉑係可為 僅將其製劑化而成之單劑，亦可為與替加氟、吉美嘧啶、 201030338 奥替拉西卸合併而製劑化為一劑型之複合劑。而以各 劑化為一劑型之單劑為佳。 本發明之製劑在將各有效成分併用投藥之條件下，可 為使上述各製劑被獨立個別地製造、包敦、流通者，或者 亦可作為適於將上述製劑之全部或一部份併用投藥之單— 包裝（套組製劑）而被製造、包裝、流通者。 作為本發明之製劑的投藥形態並無特別限制，具體而 言可例示如：口服劑(錠劑、膜衣錠、散劑、顆粒劑、膠囊、 液劑等）、注射劑、坐劑、貼布、軟膏等。在將本發明之各 參 有效成分製劑化為複數的劑型時，該等製劑可各為不同的 投藥形態，亦可為相同的投藥形態。例如，替吉奥複合劑 宜為口服劑，而含有順鉑之製劑宜為注射劑。 本發明之製劑係使用藥理學上容許之載劑，且在各投 藥形態中以一般公知的製劑化方法來製造。其載劑為廣泛 使用於一般藥劑之各種載劑，可例示如：赋形劑、黏合劑、 破碎劑、潤滑劑、稀釋劑、助溶劑、懸浮劑、等張劑、pH 調整劑、緩衝劑、安定劑、著色劑、調咮劑、氣味改善劑 (odor improving agent)等。 就賦形劑而言，可舉例如：乳糖、蔗糖、氣化鈉、葡 萄糖、乳糖、麥芽糖、甘露糖醇、赤藻糠醇、木糖醇、麥 芽糖醇、肌醇、聚葡萄糖、山梨糖醇、蛋白素、尿素、澱 粉、碳酸鈣、高嶺土、結晶纖維素、矽酿、甲基纖維素、 甘油、海藻酸鈉、***膠及該等之混合物等。 就潤滑劑而言，可舉例如：精製滑石、硬脂酸鹽、硼 10 201030338 砂、聚乙二醇及該等之混合物等。 就黏合劑而言，可舉例如：單糖漿、葡萄糖液、澱粉 液、明膠溶液、聚乙烯醇、聚乙烯醚、聚乙烯氫吡咯酮、 羧曱基纖維素、蟲膠、甲基纖維素、乙基纖維素、水、乙 醇、磷酸鉀及該等之混合物等。 就破碎劑而言，可舉例如：乾燥澱粉、海藻酸鈉、洋 菜粉、昆布糖粉、碳酸氫鈉、碳酸鈣、聚氧乙烯山梨醇酐 脂肪酸酯類、月桂硫酸鈉、硬脂酸單甘油酯、澱粉、乳糖 及該等之混合物等。 就稀釋劑而言，可舉例如：水、乙基醇、聚乙烯二醇、 乙氧基化異硬脂醇、聚氧化異硬脂醇、聚氧乙烯山梨醇酐 脂肪酸酯類及其等之混合物等。 就安定劑而言，可舉例如：焦亞硫酸鈉、乙二胺四乙 酸、硫代乙醇酸、硫代乳酸及該等之混合物等。 就等張劑而言，可舉例如：氯化鈉、硼酸、葡萄糖、 甘油及該等之混合物等。 就pH調整劑及緩衝劑而言，可舉例如：檸檬酸鈉、擰 檬酸、乙酸鈉、磷酸鈉及該等之混合物等。 就舒緩劑（soothing agent)而言，可舉例如：鹽酸普羅卡 因、鹽酸木卡因及該等之混合物等。 就著色劑而言，可列舉如：氧化鈦、氧化鐵等。 就調味、氣味改善劑而言，可列舉如：白糖、橙皮、 檸檬酸、酒石酸等。 就助溶劑而言，可列舉如：聚乙二醇、D-甘露糖醇等。 201030338 就懸浮劑而言’可列舉如：硬脂酸三乙醇胺、月桂硫 酸鈉、羥基氯苯胺。 本發明之投藥法(dosing schedule)係可依患者的年齡、 性別、病期、有無轉移、治療史等條件作適當選擇，例如， 本發明之併用化學療法，宜在4個星期内，以將替加氟、吉 美嘧啶及奥替拉西鉀連續投藥21天，並在其最初之投藥曰 (第1天）將順鉑投藥為一循環，進行丨次或複數次。 成為本發明預測方法之對象的患者，係患有胃癌之患 者，亦可為患有原病灶為胃癌，且已轉移到胃以外之臟器、 @ 組織之胃癌的患者。 作為可用於測定本發明之胸腺核苷酸合成酵素基因表 現量之生物試樣，若為可能含有癌細胞之試樣則無特別限 疋，可例示如體液(血液、尿等）、組織、其抽出物及所採取 之組織的培養物等。又，生物試樣的採取方法，可依因應 生物試樣的種類或癌種之方法作適當選擇。來自生物試樣 之DNA、RNA、蛋白質之調製’可藉由—般公知的方法來 進行。就組織而言，雖可特別舉如胃，然而在已從胃轉移 _ 到其他臟器或腹膜等時’即以所轉移之部位為對象組織。 胸腺核普酸合成酵素，係具有以葉酸為輔酶而從dUMp 合成dTMP之活性的酵素，其以作為DNA合成_必要之酵 素而廣為人知。又’亦以作為5_氟尿射之目標酵素而為 人所知。再者，人的胸腺核苷酸合成酵素之基因的鹼基序 列及胺基酸序列為公知（Nuleic Acids心13 2035-2043(1985))。 12 201030338 本發明之預測方法是以胸腺核苷酸合成酵素基因的表 現量為指標，而其表現量可為mRNA的表現量’亦可為蛋 白質的表現量。在此，mRNA的表現量可使用與胸腺核苷 酸合成酵素基因特異性雜交之探針或引子，而以北方點墨 法、定量或半定量的PCR法(例如：RT-PCR法、real-time PCR 法）、原位雜交(in situ hybridization)法等公知的基因表現量 測定法進行測定。前述表現量係可以經常表現一定範圍的 量之蛋白質/基因（例如：p肌動蛋白等的家務基因 (housekeeping gene)，或其之表現蛋白質）為基準，以比例 來進行評價。 又，蛋白質表現量係可使用特異辨識胸線核苷酸合成 酵素之抗體，藉由施行酵素免疫測定法、放射性免疫測定 法、螢光免疫測定法、ELISA法、西方點墨法、免疫組織 化學染色法等公知的免疫學上測定法來進行測定。 用於北方點墨法、原位雜交法等的基因表現量測定法 之探針，係為了與胸腺核苷酸合成酵素基因之鹼基序列内 的至少15鹼基長至全鹼基長，且宜為20鹼基長至全鹼基 長’更宜為30鹼基長至全鹼基長之連續的鹼基序列進行特 異性雜交’而遵照一般公知的探針設計方法，設計成具有 上述各驗基長度之多核苦酸(polynucleotide)。 用於RT-PCR法、reai_time PCR法等的定量或半定量 pCR法之引子、探針的設計，例如可如下述來進行。 本發明之引子及探針，係為了與胸腺核苷酸合成酵素 (TS)基因的鹼基序列内之至少10鹼基長至全鹼基長，且宜 13 201030338 為10至100鹼基長，較宜為ίο至50鹼基長，更宜為ίο至35鹼 基長之連續的鹼基序列特異性雜交，而遵照一般公知的引 子及探針設計方法’設計成具有上述各鹼基長度之多核苷 酸。例如，TS基因表現產物檢出用引子，即pCR之順向引 子及逆向引子’係可由TS基因中的外顯子區來設計及合 成。順向引子及逆向引子係在TS基因之各外顯子區中，一 邊根據於上游側之外顯子區的鹼基序列來設計（順向引 子），而另一邊根據其下游侧之外顯子區的鹼基序列來設計 (逆向引子）。例如，在根據外顯子1〜3來設計TS基因之引子 © 時’在根據外顯子1區的序列來設計順向引子的情況下，逆 向引子就是根據其下游側的外顯子2或外顯子3區之序列來 設計。逆向引子係設計成與TS之mRNA序列互補。又，作 為該引子，係可使用含各外顯子區之TS2mRNA的鹼基序 列之全部及其中一部分的序列，但期望是考慮到自各外顯 子區因PCR之擴增效率，而進行引子的設計。更具體來說， 作為TS基因表現產物檢出用的順向引子，以序列編號丨所表 示之引子為佳，而作為逆向引子，以序列編號2所表示之引 ® 子為佳。 作為TS基因表現產物檢出用探針，若為可與藉使用上 述引子進行PCR反應所擴增之TS基因之各一條鏈DNA雜交 者，則無特別限制。只要是具有可與TS基因之全外顯子的 鹼基序列或其一部份互補之序列者，或可在嚴格條件下雜 交者即可。較具體而言，作為TS基因表現產物檢出用之探 針，以序列編號3所表示之探針為佳。 14 201030338 互補==若為與TS基因特異性雜交者，則無完全 酵素_ 核㈣，宜為與由胸腺《酸合成 之同—性^ 酸比較下’驗基排列具有70%以上 更宜為95%以^酸^宜為嶋以上’較宜為慨以上， 而特宜為具有98%以上同_性者。 件下再Li發明中:特異性雜交」係指在嚴格的雜交條 格的雜、备杜異性雜父，而不會形成非特異性雜交者。嚴 核賤的融解温度(Tm)等來決二雜交之 ::::Γ，-般…二=二態 件件’更嚴格為「〇+吻c,議-，吹」左 公知:故由=腺核*酸合成酵素基因之驗基序列為 〜基序列作為模板，:二= 成酵素基因探=::::τ能容易地檢*胸腺核*酸合 化學發光物質'或酵素::::放射性物質、鸯光物質、 :即可，而無特別限制。可為單 ：。成酵素 者，亦可為-片段及啊’)2片段等的抗體;段=中^ 5亥抗 15 201030338 體可依一般公知的方法製造（例如：Current protocols in Molecular Biology edit. Ausubel et al. (1987), Publish. John Wiley and S.ons. Section 11. 12-11, 13)。 在預測是否應實施藉替吉奥複合劑與順鉑之併用化學 療法之治療的步驟中’在與預先設定的各截點比較下，胸 腺核苷酸合成酵素的表現量較低時，預測患者對選擇該併 用化學療法顯示充分治療效果之可能性高。 本發明之截點，由於係依測定對象及測定方法的種類 等諸條件而變動者，因此有因應條件而預先設定的必要。 ® 截點會因測定對象（患者人數、年齡、性別、體重、健康狀 態、疾患的狀態）、測定方法（是否以基因與蛋白質之中任一 者的表現產物為測定對象）、測定條件（例如基因表現產物 (mRNA)測定之引子、探針的序列、標記的種類、表現產物 為蛋白質時抗體的種類及敏感性等）及統計的手法等而變 動，因此本發明廣泛包含使用了可因該等諸條件而變動之 任意截點的發明，而非限定於特定值。在此，截點可藉各 種統計解析手法，自預先測定好的胸腺核苷酸合成酵素基 © 因表現量求得。可例示如：接受了替吉奥複合劑與順鉑之 併用化學療法的患者之胸腺核苷酸合成酵素基因表現量之 平均值或中央值；從接受了替吉奥複合劑與順鉑之併用化 學療法的患者之胸腺核苷酸合成酵素基因表現量，與對替 吉奥複合劑與順始之併用化學療法有無一定以上的治療效 果（延命效果）間的關係，依據R〇c(Receiver 〇perating Characteristic)分析，使敏感性及特異性的和達到最大所求 16 .201030338 值，以及，使用已接受使用了替吉奥複合劑與順鉑之 旦用化予療法的患者之胸腺核苷酸合成酵素基因之表現 量’從與對替吉奥複合劑與棚之併用化學療法的治療效 d P效果）間的關係’以對數等級檢定(㈣僅k㈣使p 值為最小的值(根據卡方檢定所求得的值）。 、、-果’本併用化學療法之胸腺核*酸合成酵素基因 的截點(3相對於β肌動蛋白的比），例如在⑽_ PCR法中The ear ratio is: Tiggio: Jigme: Chelsea (4): 04: Bu 3: an anti-tumor agent composed of Teggio compound and Gu, special; 22 cancer patients undergo sputum chemotherapy, And the "patients of the disease" is the method of item (4), which is considered to be the most likely to choose the chemical therapy. Item 4: A method of performing 1 or 2 on cancer patients, the possibility of being treated - a method of treating gastric cancer, characterized in that a combination of chemotherapy is used, and the cancer patient is selected by the first prediction to use the combination chemotherapy Will show the full height. Item 5 (4) The anti-tumor agent pathway formed by Gio Complex and Xian is used to administer chemistry for cancer patients::: By the first or the first, it is predicted to select the Si:; The secret of the effect. Dry therapy Item 6 201030338 A pair of primers, which are used, measured, sputum-containing, and squamous. Column number 2 is reversed to refer to item 7 as in item 6 of the primer pair, and the agent of the chemotherapeutic (four) material (four) pre-clearing Μ containing the tiggio compound item 8 as in item 7 of the primer pair, which is used in the compounding agent And cisplatin combined with j for the month of cancer patients, the second item; /, the therapeutic effect of the method. A set for pre-rigid effect of scoop A treatment, which consists of a reverse primer of the chemistry of the 匕3 Gio complex, which constitutes the forward primer of sequence number 1 and the primer of the sequence number Correct. (4) Glandular nucleus (4) Synthetic enzymes show the 10th item of a Jianyue No. #1, which is the set of Item 11 of Item 10 for the treatment of combined chemotherapy with thiophene and cisplatin for gastric cancer patients. The group 'steps' contains the probe of SEQ ID NO: 3. EFFECTS OF THE INVENTION The predictive method of the present invention is to select an effective chemotherapist having a potent L p effect on a gastric cancer patient. That is to say, patients who are prolonged in the effect of pre-lind gastric cancer can be surely provided - the combination of strong fatal effects and chemotherapy, and because it can save unnecessary chemotherapy, it is economically beneficial in medical 201030338 of. According to Non-Patent Document 1, although the combination of TS-1 and cisplatin has always been considered to be excellent, the present invention reveals for the first time the effectiveness of the combined chemotherapy and the thymidine synthase gene (TS). The amount of performance is closely related and is considered to be effective only when the TS gene expression is below a certain amount. C Embodiment 3 The best mode for carrying out the invention The prediction method of the present invention is based on the amount of expression of the patient's thymidine synthase gene to predict the combination of chemotherapy with tiline and cisplatin. Treatment, patients who show a high probability of prolonged life effects. In the present invention, the "chemotherapy in which thiophene complex is further used in combination with cisplatin" means that chemotherapy is administered by using a combination of a tiggio complex and a cisplatin antitumor agent. Further, when the complexing agent is administered in combination with cisplatin, the complexing agent can be administered simultaneously with cisplatin, or can be administered at regular intervals. In the present invention, "therapeutic effect of thiophene (hereinafter also referred to as "combination chemotherapy") which is selected for further use of the tigeol complexing agent means that it exhibits standard therapy used in Europe and the United States. (For example, 5_FU combined with cisplatin for chemotherapy) excellent prolongation effect. As to whether or not the fate effect is shown, it can be judged by whether or not the TSM expression is below the cut point. If the expression of the TS gene is below the cut-off point, it is judged that the selection and the use of chemotherapy have sufficient therapeutic effects. The active ingredient of the present invention, tegafur (general name, chemical name: 5-fluoro-1-(2-tetrahydrofuran)-2,4-(ih,3H)-pyrimidinedione) is a known compound, and is in the object of 201030338. An agent that releases a bulk 5-fluorouracil that is activated to release antitumor activity. The tegafur type can be produced by a known method, for example, the method of Japanese Patent Laid-Open Publication No. SHO 49-10510. The active ingredient of the present invention, gemcitabine (general name, chemical name: 2,4-dihydroxy-5-pyridine), is also a well-known compound, although it is completely free of antitumor activity, but it can inhibit 5-fluorouracil in The organism is metabolized and inactivated', thus enhancing the anti-tumor effect. The active ingredient of the present invention is oxybutacil potassium (general name, chemical name: 1,2,3,4-tetrahydroxy-2,4-dioxo-oxime, 3,5-triazine_6-carboxylic acid_) Also known as a compound, although it does not have antitumor activity by itself, it is mainly distributed in the digestive tract' and inhibits gastrointestinal disorders by inhibiting the activation of 5-fluorouracil at this site. The active ingredient of the present invention, cisplatin (general name, chemical name: (sp_4_2) diamine, di-p-platinum), is a well-known platinum complex, which is generally known to achieve an antitumor effect by DNA synthesis inhibition. Further, cisplatin can be produced by a known method, and a commercially available pharmaceutical product such as Briplatin® (manufactured by Bristol-Myers Co., Ltd.) can be used. The therapeutic effect of the present invention can be determined by the survival period or the like, and the survival/monthly door is used. It is expressed by the median value of the survival period (the longer the period, the higher the therapeutic effect), the 1-year survival rate, and the 2-year survival rate (the higher the ratio, the higher the therapeutic effect). In the present invention, there is no particular limitation on the ratio of the substitution of the drug to the drug, the yummi, and the oxicilin. For example, it may be a known compounding agent with the Japanese Patent No. The same 201030338 range: relative to 1 molars plus fluoride, gemcitabine can be about 01~5 moles, and about 0.2~1.5 moles is better; oltipraz potassium can be 〇ι~5 The ear is about to be around, and it is preferably about 0.2 to 2 m. The Molot should be, Tiggio: Jimei's bite: Otticept potassium = 1 : 0.4 : 1. The ratio of the drug to be administered in the present invention is not particularly limited as long as the antitumor effect is achieved. For example, in terms of the amount of la, the amount of the drug may be 0.01 to 5.0 in terms of 1 molar. The ear is around, and it is better to use around 2 〇 〇. The dosage of each active ingredient of the present invention can be appropriately selected from the conditions of usage, patient age, sex, stage of disease, presence or absence of metastasis, history of treatment, presence or absence of other anti-tumor agents, and the like, and the recommended amount is as follows: The amount of tegafur is about 0.1 to 100 mg/kg/day, and preferably about 2 to 40 mg/kg/day, more preferably about 0.5 to 20 mg/kg/day; the amount of tiramime is 〇_ 〇 2~30mg/kg/day, and about 05.05~12mg/kg/day is better, 〇·1~6mg/kg/day is better; the amount of oltipraz potassium is 〇. 1~100mg/kg/day, and preferably 〇·2~4〇mg/kg/day, preferably 〇·5~20mg/kg/day; the amount of cisplatin is 0.08~2〇 〇mg/kg/day or so 'and 〇.15~8〇111§/1^/day is better, with 0.4~4〇111§/1 (; §/day is better. Also, each effective The ingredients are administered once a day, or divided into multiple doses. Further, 'the active ingredients are administered at the same time or at intervals, and the order of administration is not particularly limited. The present invention provides tegafur, gemcitabine, and Tetraxis potassium system preparation In the present invention, the cisplatin system may be a single agent prepared by merely formulating it, or may be formulated by unloading with tegafur, gemcitabine, 201030338 oltipraz. It is preferred to use a single agent in a single dosage form, and it is preferred to use a single agent in a single dosage form. The preparation of the present invention can be separately and individually manufactured under the conditions of administering the active ingredients in combination. The circulator may be manufactured, packaged, or circulated as a single-package (set preparation) suitable for use in combination with all or a part of the above-mentioned preparations. The dosage form of the preparation of the present invention is not particularly Specific examples thereof include an oral preparation (a tablet, a film-coated tablet, a powder, a granule, a capsule, a liquid, etc.), an injection, a sitting agent, a patch, an ointment, etc., and the various parameters of the present invention are effective. When the ingredients are formulated into a plurality of dosage forms, the preparations may each be in a different administration form or may be in the same administration form. For example, the tiggio complex is preferably an oral preparation, and the preparation containing cisplatin is preferably an injection. The invention The preparation is a pharmacologically acceptable carrier, and is produced by a generally known formulation method in each administration form. The carrier is a carrier which is widely used in general pharmaceutical agents, and examples thereof include excipients and adhesion. Agents, breakers, lubricants, diluents, solubilizers, suspending agents, isotonic agents, pH adjusters, buffers, stabilizers, colorants, scenting agents, odor improving agents, etc. Examples of the agent include lactose, sucrose, sodium carbonate, glucose, lactose, maltose, mannitol, erythritol, xylitol, maltitol, inositol, polydextrose, sorbitol, and protein. , urea, starch, calcium carbonate, kaolin, crystalline cellulose, brewing, methyl cellulose, glycerin, sodium alginate, gum arabic, and mixtures thereof. Examples of the lubricant include purified talc, stearate, boron 10 201030338 sand, polyethylene glycol, and the like. The binder may, for example, be a monosaccharide syrup, a glucose solution, a starch solution, a gelatin solution, polyvinyl alcohol, polyvinyl ether, polyvinylpyrrolidone, carboxymethyl cellulose, shellac, methyl cellulose, Ethyl cellulose, water, ethanol, potassium phosphate, and mixtures thereof. As the breaker, for example, dry starch, sodium alginate, acacia powder, laminaria powder, sodium hydrogencarbonate, calcium carbonate, polyoxyethylene sorbitan fatty acid ester, sodium lauryl sulfate, stearic acid single can be mentioned. Glycerides, starch, lactose, mixtures of these, and the like. Examples of the diluent include water, ethyl alcohol, polyethylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, polyoxyethylene sorbitan fatty acid ester, and the like. Mixture, etc. The stabilizer may, for example, be sodium metabisulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid or the like. Examples of the isotonic agent include sodium chloride, boric acid, glucose, glycerin, and the like. The pH adjuster and the buffer may, for example, be sodium citrate, citric acid, sodium acetate, sodium phosphate or the like. The soothing agent may, for example, be procaine hydrochloride, xycaine hydrochloride or a mixture thereof. Examples of the colorant include titanium oxide, iron oxide, and the like. Examples of the seasoning and odor improving agent include white sugar, orange peel, citric acid, tartaric acid, and the like. Examples of the co-solvent include polyethylene glycol, D-mannitol, and the like. 201030338 In the case of a suspending agent, for example, triethanolamine stearate, sodium lauryl sulfate, and hydroxychloroaniline may be mentioned. The dosing schedule of the present invention can be appropriately selected according to the age, sex, disease duration, presence or absence of metastasis, treatment history, and the like of the patient. For example, the combined chemotherapy of the present invention should be carried out within 4 weeks. Tegafur, gemcitabine and oltipraz potassium were administered continuously for 21 days, and cisplatin was administered as a cycle in its initial administration (Day 1) for one or more times. The patient who is the subject of the prediction method of the present invention may be a patient suffering from gastric cancer, or a patient having a gastric cancer whose original lesion is gastric cancer and has metastasized to an organ other than the stomach and a tissue of the @ tissue. The biological sample which can be used for measuring the expression amount of the thymidine synthase gene of the present invention is not particularly limited as long as it is a sample which may contain cancer cells, and examples thereof include body fluids (blood, urine, etc.), tissues, and the like. The extract and the culture of the tissue taken, and the like. Further, the method of taking the biological sample can be appropriately selected depending on the type of the biological sample or the method of the cancer type. The modulation of DNA, RNA, and protein from a biological sample can be carried out by a generally known method. In terms of tissue, although it is particularly useful as a stomach, when it has been transferred from the stomach to other organs or peritoneum, it is the tissue to be transferred. The thymocyte nucleoside synthase is an enzyme having an activity of synthesizing dTMP from dUMp using folic acid as a coenzyme, and is widely known as an enzyme necessary for DNA synthesis. It is also known as the target enzyme for 5-fluorourine. Further, the base sequence and the amino acid sequence of the gene of human thymidine synthase are known (Nuleic Acids, Heart 13 2035-2043 (1985)). 12 201030338 The prediction method of the present invention is based on the expression of the thymidine nucleotide synthetase gene, and the expression amount thereof may be the expression amount of mRNA' or the expression amount of the protein. Here, the expression amount of the mRNA may be a probe or primer which specifically hybridizes with the thymine nucleotide synthetase gene, and the Northern blotting method, quantitative or semi-quantitative PCR method (for example, RT-PCR method, real- It is measured by a known gene expression amount measurement method such as time PCR method or in situ hybridization method. The above expression amount can be evaluated in proportion to a protein/gene (for example, a housekeeping gene such as p-actin or a protein thereof) which is often expressed in a certain range. In addition, protein expression can be used to specifically identify antibodies to the thoracic nucleotide synthetase, by performing enzyme immunoassay, radioimmunoassay, fluorescent immunoassay, ELISA, Western blotting, immunohistochemistry The measurement is carried out by a known immunological measurement method such as a staining method. A probe for measuring the gene expression amount of a northern blotting method, an in situ hybridization method, or the like, for at least 15 bases to a total base length in a base sequence of a thymine nucleotide synthetase gene, and It is preferable to carry out specific hybridization of a base sequence of 20 bases to a total base length, more preferably 30 bases to a total base length, and follow the generally known probe design method, and design The polynucleic acid of the length of the test. The design of primers or probes for quantitative or semi-quantitative pCR methods such as RT-PCR method, reai_time PCR method, etc. can be carried out, for example, as follows. The primer and the probe of the present invention are at least 10 bases long to the total base length in the base sequence of the thymine nucleotide synthase (TS) gene, and preferably 13 201030338 is 10 to 100 bases long. Preferably, it is ίο to 50 bases long, more preferably contiguous base sequence-specific hybridization of ίο to 35 bases in length, and is designed to have the length of each of the above bases according to generally known primer and probe design methods. Polynucleotide. For example, the TS gene expression product detection primer, i.e., the forward and reverse primers of pCR can be designed and synthesized from the exon region of the TS gene. The forward primer and the reverse primer are designed in each exon region of the TS gene, and are designed according to the base sequence of the exon region on the upstream side (the forward primer), while the other side is displayed according to the downstream side. The base sequence of the subregion is designed (reverse primer). For example, when designing the primer gene © of the TS gene according to exons 1 to 3 'in the case of designing a forward primer based on the sequence of the exon 1 region, the reverse primer is based on the exon 2 on the downstream side thereof or The sequence of the exon 3 region is designed. The reverse primer is designed to be complementary to the mRNA sequence of TS. Further, as the primer, a sequence including the entire base sequence of the TS2 mRNA of each exon region and a part thereof may be used, but it is desirable to carry out the primer based on the amplification efficiency of each exon region due to PCR. design. More specifically, as the forward primer for the detection of the TS gene expression product, the primer represented by the sequence number 丨 is preferred, and the reverse primer is preferably the primer represented by SEQ ID NO: 2. The probe for detecting the product of the TS gene is not particularly limited as long as it can hybridize with one strand of the DNA of the TS gene amplified by the PCR reaction using the above primer. Any sequence having a base sequence complementary to the entire exon of the TS gene or a part thereof may be used as a hybrid under stringent conditions. More specifically, as the probe for detecting the product of the TS gene, the probe represented by SEQ ID NO: 3 is preferred. 14 201030338 Complementation == If it is specifically hybridized with the TS gene, there is no complete enzyme _ nucleus (4), which is better than the thymus "comparative acid-synthesis". 95% of the acid is preferably more than ', more preferably more than 98%, and particularly suitable for 98% or more. In the Li invention, "specific hybridization" refers to a heterozygous heterozygous heterozygous parent in a strict hybridization pattern without forming a non-specific hybrid. The melting temperature (Tm) of the nuclear nucleus is determined by the second hybrid::::Γ,-like...two=two-state pieces' is more strict as "〇+ kiss c, discussion-, blowing" left-known: = The nucleotide sequence of the glandular acid-acid synthase gene is a template based on the ~-based sequence: two = enzyme-producing gene detection =::::τ can be easily detected *thymidine n-acid chemiluminescent substance' or enzyme:: :: Radioactive materials, fluorescent substances, : can be, without any particular restrictions. Can be single :. In the case of an enzyme, it can also be an antibody such as a fragment and a fragment of the 2 fragment; paragraph = medium ^ 5 hai anti 15 201030338 The body can be produced according to a generally known method (for example: Current protocols in Molecular Biology edit. Ausubel et al. (1987), Publish. John Wiley and S.ons. Section 11. 12-11, 13). In predicting whether or not to perform the treatment of thiophene complex with cisplatin in combination with chemotherapy, 'predicting patients when the amount of thymidine synthase is low compared with the preset cut-off points There is a high probability of selecting this and using chemotherapy to show adequate therapeutic effects. Since the cut-off point of the present invention varies depending on conditions such as the type of measurement object and the measurement method, it is necessary to set it in advance according to the conditions. ® The cut point is determined by the measurement target (number of patients, age, sex, weight, state of health, condition of the disease), measurement method (whether or not the expression product of any of the gene and protein is measured), and measurement conditions (for example) The gene expression product (mRNA) measurement primer, the sequence of the probe, the type of the label, the type and sensitivity of the antibody when the protein is a protein, and the like, and statistical methods vary, and thus the present invention widely includes The invention of any intercept point that varies depending on conditions, and is not limited to a specific value. Here, the cut point can be obtained by various statistical analysis methods, from the pre-determined thymidine nucleotide synthase base © due to the amount of expression. For example, the mean or central value of the thymidine nucleotide synthetase gene expression of a patient who has received chemotherapy with a combination of a tigeo complex and cisplatin; from the acceptance of the combination of the tigeol complex and cisplatin The relationship between the thymidine nucleotide synthetase gene expression in patients with chemotherapy and the therapeutic effect (deferred effect) of the combination of the tigeol complex and the chemotherapeutic chemist, according to R〇c (Receiver 〇 Perient Characteristic) analysis, the maximum sensitivity and specificity of the 16 .201030338 value, and the use of thymus nucleotides in patients who have received the use of tegafur complex and cisplatin The relationship between the amount of expression of the synthetic enzyme gene 'from the effect of the therapeutic effect of the combination of the tigeo complex and the chemotherapeutic effect' is determined by logarithmic scale ((4) only k (four) makes the p value the smallest value (according to the card) The value obtained by the square test), , and - the 'cut point of the thymus nuclear acid synthase gene of chemotherapy (3 vs. β actin ratio), for example, in (10)_PCR method

〇10為佳’而以5.31><1〇-3〜8〇2><1〇-3為較佳，以 5·96χΐ〇·3〜6 8〇χ1〇_3為特佳。 本發k胸腺核絲合成酵素表現量敎用的引子 十者係含有序顺㈣子，與序列職2的逆向引 ^本發明之胸隸純合成料表現量測定用套 一ίΐ有上述引子對者’而以進—步含有序列編號3之探 卷\之胸腺核*酸合成酵素表現量測定用之引子對 可用於?s、t可正確地測定胸腺核㈣合成酵素表現量，而 :為含^對含柳系抗腫瘤劑之化學療法的治療效果。 $抗腫瘤劑之化學療法’若為含有5-FU戍盆衍 生物者則無特別_，可例示如含有咖^ j = 複合劑、替吉奥複合劑之化 帛⑽尿較 合劑之化學療法為佳桂ιί其中以含有替吉奥複 療法為特佳。作複合劑與彰自之併用化學 限定，彳絲·録雖無特別 胰臟癌膽…結腸-直腸癌、頭頸部癌、肺癌、乳癌、 臟、膽道癌，而特宜為胃癌。 17 201030338 [實施例] 以下根據實施例詳細說明本發明，然而本發明非受該 等實施例所限定者。 [實施例1 ]胸腺核苷酸合成酵素基因表現量測定 實施了以高加索人之未治療進行性胃癌患者為對象的 TS-1/順鉑併用療法，與5-FU/順鉑併用療法之第III相試驗中 生物標記(biomarker)研究。 TS-1/順始併用療法，係將替加氟換算量25nig/m2之 Ts_l ’在連續21天絕食期間經口投藥，並在其後七天期間 @ 休藥。順鉑係在TS-1投藥開始日（第1天）之TS-1最初的投藥 後’花1〜3小時將75mg/m2的順鉑投藥至靜脈内。以該每四 週期間（28日期間）的投藥法為丨循環，最大重覆6循環進行了 投藥。 · 5_FU/順始併用療法，係將5-FU以1000mg/m2/24小時在 5天期間内持續地進行靜脈内投藥，並於其後的2 3天期間休 藥。順鉑係在5-FU投藥開始日（第丨天），在^以；投藥前，花 1〜3小時將1 〇〇mg/m2的順鉑進行靜脈内投藥。以該每四週期 ❹ (日』間）的投藥法為1循環，最大重覆6循環進行了投 藥。 生存期間係以隨機化之日為起算日，至死亡日為止的 』門關於在解析時點無法取得死亡確認或仍生存之患 者，以最新的觀察日為終止。 _胸腺核普酸合成酵素基因之表現量，係自於藥劑投藥 以月’J所付到的手術檢體或生物檢體之腫瘤組織的福馬林固 18 201030338 定石蠟包埋切片，抽出全部mRNA (total mRNA)，並以Preferably, 〇10 is better than 5.31><1〇-3~8〇2><1〇-3, and 5·96χΐ〇·3~6 8〇χ1〇_3 is particularly preferable. The primers for the expression of k-thymidine synthase are used to contain the sequence of the four (s) sub-sequences, and the reverse sequence of the sequence 2 is used to determine the amount of the pure synthetic material of the invention. And the step-by-step method for the determination of the expression of the thymocyte-acid synthase with the sequence number 3 can be used for ?s, t to correctly measure the expression of the thymocyte (4) synthetase, and: Contains the therapeutic effect of chemotherapeutic treatment of the anti-tumor agent containing the willow. $Anti-tumor chemotherapeutic 'If it is a 5-FU sputum-containing derivative, there is no special _, and chemistries such as chlorpyrifos (10) urinary mixture containing coffee compound and compounding agent can be exemplified. For Jiagui ιί, it is especially good for the treatment of Teggio. As a compounding agent and a combination of chemistry and chemistry, there is no special pancreatic cancer gallbladder... colon-rectal cancer, head and neck cancer, lung cancer, breast cancer, dirty, biliary tract cancer, and especially for gastric cancer. 17 201030338 [Examples] Hereinafter, the present invention will be described in detail based on examples, but the present invention is not limited by the examples. [Example 1] Measurement of thymidine nucleotide synthetase gene expression The TS-1/cisplatin combination therapy for patients with untreated progressive gastric cancer in Caucasians was performed, and the combination of 5-FU/cisplatin therapy was performed. Biomarker study in phase III assays. The TS-1/sequential combination therapy was administered orally with Ts_l ' at a dose of 25 nig/m 2 for a continuous 21-day fasting period, and was taken during the next seven days. Cisplatin was administered intravenously to 75 mg/m2 of cisplatin to the vein 1 to 3 hours after the initial administration of TS-1 on the TS-1 administration start day (Day 1). The administration method was repeated for every four weeks (during the 28th period), and the maximum cycle was repeated for 6 cycles. • 5_FU/sequential combination therapy, 5-FU was continuously administered intravenously at 1000 mg/m2/24 hours over a 5-day period, and the drug was administered for a period of 23 days thereafter. Cisplatin is administered intravenously at a dose of 1 3mg/m2 of cisplatin for 1 to 3 hours before the start of 5-FU administration (day )). The administration method was repeated for one cycle every four cycles (days), and the drug was administered for a maximum of six cycles. The period of survival is based on the date of randomization, and the door until the date of death is terminated by the latest observation date regarding the patient who is unable to obtain death confirmation or survives at the time of analysis. _ The expression level of the thymocyte nucleoside synthase gene is obtained from the surgical specimen or the tumor tissue of the biological specimen administered by the drug, and the paraffin-embedded slice is taken out, and all the mRNA is extracted. (total mRNA), and

Taqman® real-time PCR法定量其相對於β肌動蛋白之比。再 者’作為胸腺核苷酸合成酵素基因表現量測定用的引子及 探針’係使用以下之序列編號卜3所示之引子及探針。更進 一步’在β肌動蛋白基因表現量的測定中，係使用了以下的 序列編號4〜6所表示之引子及探針。 [表1] 基因名 順向引4 逆向引子 Taqman MGB 探針 胸腺核苷酸合 成酵素 GAATCACATCG AGCCACTGAAA (序列編號1) GAAGAATCCTGA GCTTTGGGAAA( 序列編號2) CAGCTTCAGCG AGAAC(序列編號 3) β肌動蛋白 AAGGCCAACCG CGAGAAG(序列 編號4) ATAGCAACGTACA TGGCTGGG(序列編 號5) ACCCAGATCAT GTTT(序列編號6) 除上述表1所記載之引子及探針以外，可以公知的TS 基因序列之開啟讀碼框為基礎，來設計各種順向引子、逆 向引子及探針。若變更引子、探針的序列、標記之種類等， 雖可使截點略微變化，但對可以預測是否能顯示對選擇替 吉奥複合劑與順鉑併用化學療法之充分治療效果之本發明 的效果，並無實質上的影響。 [實施例2]截點的算出 截點係將在實施例1測定之各患者的胸腺核苷酸合成 酵素基因表現量，藉由下述的統計解析手法而求得。 (1) 在TS-1/順始併用群中，為了預測受到疾病控制 (disease control)(PR+SD)之病例，利用R0C分析而算出敏感 性與特異性之和為最大之最適截點，為6.8〇xl〇-3。 (2) 在TS-1/順鉑併用群中’將受到疾病控制（disease control)(PR+SD)之比例，以有效水準1 %與5%算出，各為 19 201030338 5·96χ1〇-3〜6·8〇χ1〇->5.31χΐ〇-3〜8〇2χ1〇-3。 [實施例3]以胸腺核苷酸合成酵素為指標所選擇之患者之併 用療法的治療效果 使用以實施例2所算出之戴點值，分成胸腺核苷酸合成 酵素之低表現群與高表現群2群，實施生存期間解析。將結 果表示於表2〜表5。 再者，5-FU/順鉑併用群，TS低值與TS高值中任一者之 2年生存率皆為〇%，為治療效果低者。又，由於TS低值之 5-FU/順鉑併用群之效果係較TS低值之TS-1/順鉑併用群之 參 生存期間低，故沒有顯示5-FU/順鉑併用群(TS高值)之結果。 [表2] 截點值：6.80xl0-3 —__對象 病例數 生存期間之中央值（月） TS-1/順鉑併用群TS低值 39 9.9 TS-1/順鉑併用群TS高值 15 3.6 順鉑併用群TS低值 33 --—-- __ 7.0 [表3] 截點值：5.96χ1(Γ3 -sj十象 病例數 期間之中央值（月） 用群TS低值 37 ______ 9.8 并用群ts高值 17 ___ 34.4 并用群TS低值 31 _____ 7.0 [表4] 截點值： ----------- -^對象 病例數 生存期間之中央值（月） 并用群ts低值 33 9.8 20 201030338 TS-1/順鉑併用群TS高值 21 5.3 5-FU/順鉑併用群TS低值 29 6.9 [表5] 截點值：8.02χ10_3 對象 病例數 生存期間之中央值（月） TS-1/順鉑併用群TS低值 43 8.4 TS-1/順鉑併用群TS高值 11 3.6 5-FU/順鉑併用群TS低值 36 7.0 TS-1/順鉑併用療法中，腫瘤組織中胸腺核苷酸合成酵 素之基因表現量低的患者中，與表現量高的患者比較，生 存期間的中央值有顯著的差異，顯示了較高的延命效果。 即使在與5-FU/順鉑併用療法中之胸腺核苷酸合成酵素之 基因表現量低之患者比較下，TS-1/順鉑併用療法之生存期 間的中央值亦較長，同樣顯示了較高的延命效果。 如上所述，藉由以胸腺核苷酸合成酵素(TS)基因的表 現量為指標來選擇胃癌患者，TS-1/順鉑併用療法與迄今被 視為標準之治療法相較之下，其可期待較高之延命效果是 顯而易見的。 【圖式簡單說明3 (無） 【主要元件符號說明】 (無） 21 201030338 序列表 <110> 大鵬藥品工業股份有限公司 <120> 併用化學療法之治療效果預測方法 <130〉 2009ACTW • <150〉 JP2008-333267 <151> 2008-12-26 <160> V 6 <170> Patemln 版本 3.4 <210> 1 <211> 22 <212> DNA <213> 人工的 <220> <223> 順向引子 <400> 1 201030338 gaatcacatc gagccactga aa 22 <210〉2 <211> 23 <212> DNA <213>人工的 <220> <223>逆向引子 <400〉2 gaagaatcct gagctttggg aaa 23 <210> 3 <211> 16 <212> DNA <213>人工的 <220〉 <223> 鐵克曼探#KTaqman Probe) .201030338 <400> 3 cagcttcagc gagaac 16The Taqman® real-time PCR method quantifies its ratio to β-actin. Further, the primers and probes used for the measurement of the expression of the thymidine nucleotide synthetase gene use the primers and probes shown in the following SEQ ID NO: 3. Further, in the measurement of the expression amount of the β-actin gene, the primers and probes represented by the following SEQ ID NO: 4 to 6 were used. [Table 1] Gene name forward introduction 4 Reverse primer Taqman MGB probe Thymus nucleotide synthesis enzyme GAATCACATCG AGCCACTGAAA (SEQ ID NO: 1) GAAGAATCCTGA GCTTTGGGAAA (SEQ ID NO: 2) CAGCTTCAGCG AGAAC (SEQ ID NO: 3) β-actin AAGGCCAACCG CGAGAAG ( SEQ ID NO: 4) ATAGCAACGTACA TGGCTGGG (SEQ ID NO: 5) ACCCAGATCAT GTTT (SEQ ID NO: 6) In addition to the primers and probes described in Table 1, the forward reading frame of the known TS gene sequence can be used to design various orientations. Primers, reverse primers and probes. If the primer, the sequence of the probe, the type of the label, etc. are changed, the cut point may be slightly changed, but the present invention capable of predicting whether or not the selective therapeutic effect of the selective tiggio complex and cisplatin is used together with chemotherapy can be predicted. The effect has no substantial impact. [Example 2] Calculation of the cut-off point The intercept point was obtained by the statistical analysis method of the thymidine synthase gene expression amount of each patient measured in Example 1. (1) In the TS-1/synchronous group, in order to predict cases of disease control (PR+SD), the ROC analysis is used to calculate the optimal intercept point where the sum of sensitivity and specificity is the largest. It is 6.8 〇 xl 〇 -3. (2) In the TS-1/cisplatin combination group, the proportion of disease control (PR+SD) will be calculated at an effective level of 1% and 5%, each of which is 19 201030338 5·96χ1〇-3 ~6·8〇χ1〇->5.31χΐ〇-3~8〇2χ1〇-3. [Example 3] The therapeutic effect of the combined therapy using the thymidine nucleotide synthetase as an index was used to calculate the low-performance group and high performance of the thymidine synthase using the wearing point value calculated in Example 2. Group 2 groups, the implementation of the survival period analysis. The results are shown in Tables 2 to 5. Furthermore, 5-FU/cisplatin combined use, the 2-year survival rate of either TS low value and TS high value is 〇%, which is low in therapeutic effect. Moreover, since the effect of the low-value 5-FU/cisplatin combination group is lower than that of the TS low-value TS-1/cisplatin group, the 5-FU/cisplatin combination group is not shown (TS). The result of a high value). [Table 2] Cut-off point value: 6.80xl0-3 — __ The number of cases in the middle of the survival period (month) TS-1 / cisplatin combined group TS low value 39 9.9 TS-1 / cisplatin combined with group TS high value 15 3.6 Cisplatin combined group TS low value 33 ----- __ 7.0 [Table 3] Cut-off point value: 5.96χ1 (Γ3 -sj The central value of the ten-image case period (month) with group TS low value 37 ______ 9.8 Use the group ts high value 17 ___ 34.4 and use the group TS low value 31 _____ 7.0 [Table 4] Cut-off point value: ----------- -^ The number of cases The number of cases during the lifetime (month) Combined group Ts low value 33 9.8 20 201030338 TS-1 / cisplatin combined group TS high value 21 5.3 5-FU / cisplatin combined group TS low value 29 6.9 [Table 5] Cut-off point value: 8.02 χ 10_3 The number of cases in the center of the survival period Value (month) TS-1/cisplatin combined with group TS low value 43 8.4 TS-1/cisplatin combined with group TS high value 11 3.6 5-FU/cisplatin combined with group TS low value 36 7.0 TS-1/cisplatin Among the patients in the therapy, the gene expression of the thymidine synthase in the tumor tissue was low, and the central value during the survival period was significantly different from that of the patient with high expression, indicating a high fatal effect. Compared with patients with low gene expression of thymidine nucleotide synthase in 5-FU/cisplatin combination therapy, the median value of the survival period of TS-1/cisplatin combination therapy is also longer, also showing Higher fatal effect. As described above, by selecting the amount of thymidine nucleotide synthase (TS) gene as an indicator to select gastric cancer patients, TS-1/cisplatin combination therapy is treated as a standard treatment to date. In contrast, it can be expected that the higher fate effect is obvious. [Simple diagram 3 (none) [Main component symbol description] (none) 21 201030338 Sequence Listing <110> Dapeng Pharmaceutical Industry Co., Ltd. <120> and a method for predicting the therapeutic effect of chemotherapy <130>2009ACTW • <150> JP2008-333267 <151> 2008-12-26 <160> V 6 <170> Patemln Version 3.4 <210><211> 22 <212> DNA <213> Artificial <220><223> Forward introduction <400> 1 201030338 gaatcacatc gagccactga aa 22 <210>2 <211> 23 <212&gt ; DNA <213> Artificial <220><223> Reverse Primer <400>2 gaagaatcct gagctttggg aaa 23 <210> 3 <211> 16 <212> DNA <213> Artificial <220><223>曼探#KTaqman Probe) .201030338 <400> 3 cagcttcagc gagaac 16

<210> 4 <211> 18 <212> DNA <213〉人工的 <220> <223>順向引子 <400> 4 aaggccaacc gcgagaag 18 <210> 5 <211> 21 <212> DNA <213>人工的 201030338 <220> <223>逆向引子 <400〉5 atagcaacgt acatggctgg g 21<210> 4 <211> 18 <212> DNA <213>manual <220><223> forward introduction <400> 4 aaggccaacc gcgagaag 18 <210> 5 <211><212> DNA <213> Artificial 201030338 <220><223> Reverse Primer <400>5 atagcaacgt acatggctgg g 21

<210〉6 <211> 15 <212> DNA <213>人工的 <220> <223〉鐵克曼探4f(TaqmanPrObe)<210>6 <211> 15 <212> DNA <213>Manual <220><223>>TekmanPrObe

<400〉6 acccagatcatgttt 15 4<400〉6 acccagatcatgttt 15 4

Claims (1)

.201030338 七、申請專利範圍： 1. 一種治療效果預測方法，其係預測對胃癌患者的替吉奥 複合劑（combination preparation 〇f tegafur，gimeraeii and oteracil potassium，替加氟-吉美嘧啶-奥替拉西奸複 合劑）與順鉑（cisplatin)之併用化學療法的治療效果者， 且包含下述步驟（1)〜(2): (1) 測定步驟，係測定採取自患者之可能含有癌細胞的.201030338 VII. Scope of application: 1. A method for predicting the therapeutic effect, which predicts the combination of tifimodin for gastric cancer patients (combination preparation 〇f tegafur, gimeraeii and oteracil potassium, tegafur-gimeril-otacil The medicinal therapeutic effect of cisplatin combined with cisplatin includes the following steps (1) to (2): (1) The measurement step is performed by measuring the possible cancer cells from the patient. 生物試樣中所含之胸腺核苷酸合成酵素基因之表現 量者； (2) 預測步驟，係與預先設定之對應的截點比較，當以 上述步驟（1)所得到之表現量較低時，即預測該併用 化學療法對患者顯示充分治療效果的可能性高。 2·如申請專利範圍第1項之方法，其中㈣奥複合劑之各 有效成分的莫耳比為： 替吉奧：吉美射：奥替拉西卸=1 : 〇4 :】。 3. -種由替吉奥複合劑及順銘所構成之抗腫瘤劑，其特徵 在於：對癌症患者實施併用化學躲，且該癌症患者係 根據如申4專利範圍第丨或2項之方法，_測為選擇該 併用化學療法她衫分治療效果之可紐高者。μ 一種胃癌的治療方法，其特徵在於：對癌 用化學瘆法，Β分十> Α 心π只他併 式’、、〜5症〜'者係根據如申請專利範圍第丄 或2項之方法，被預測為料、想 充分治療效果之可預能選擇該供用化學療法會顯示 -種由替吉奥複合劑及順麵所構成之抗腫瘤劑的用 201030338 途，係用以對癌症患者實施併用化學療法者，其中癌症 患者係根據如申請專利範圍第1或2項之方法，被預測為 選擇該併用化學療法會顯示充分治療效果之可能性高 者。 6. —種引子對，係用以測定胸線核苷酸合成酵素之表現量 者，且包含序列編號1之順向引子及序列編號2之逆向引 子。 7. 如申請專利範圍第6項之引子對，其係用於預測對於包 含替吉奥複合劑之化學療法的治療效果者。 8. 如申請專利範圍第7項之引子對，其係用於預測對胃癌 患者之替吉奥複合劑及順鉑的併用化學療法之治療效 果者。 9. 一種用於預測對於包含替吉奥複合劑之化學療法的治 療效果之套組，其包含：由序列編號1之順向引子及序 列編號2之逆向引子所構成，用以測定胸腺核苷酸合成 酵素表現量之引子對。 10. 如申請專利範圍第9項之套組，其係用於預測對胃癌患 者之替吉奥複合劑及順鉑的併用化學療法之治療效果 者。 11. 如申請專利範圍第10項之套組，其進一步含有序列編號 3之探針。 201030338 四、指定代表圖： (一) 本案指定代表圖為：（無） (二) 本代表圖之元件符號簡單說明： (無） 五、本案若有化學式時，請揭示最能顯示發明特徵的化學式：The amount of expression of the thymine nucleotide synthetase gene contained in the biological sample; (2) the prediction step is compared with a preset cut-off point, and the performance obtained by the above step (1) is low. At that time, it is predicted that the possibility of using a chemotherapy to show a sufficient therapeutic effect to a patient is high. 2. If the method of claim 1 is applied, the molar ratio of each active ingredient of the (4) ao compound is: Tiggio: Jigme Shot: Ottilasi Discharge = 1: 〇 4 :]. 3. An anti-tumor agent consisting of a Tiggio complex and a shunming, characterized in that a chemical patient is used in combination with a cancer patient, and the cancer patient is according to the method of claim 4 or 2 of the patent application. , _ measured to choose this and use chemotherapy to divide her treatment effect. μ A treatment method for gastric cancer, which is characterized in that: for the cancer chemical sputum method, Β 十 & & π π π π π π π π π π π π π π π π π π The method is predicted to be a material, and it is possible to select a therapeutic effect. The chemotherapeutic treatment will show that the anti-tumor agent consisting of the Tiggio complex and the cis-face is used in 201030338. The patient is administered and chemotherapeutic, wherein the cancer patient is predicted to be the one who is selected and uses chemotherapy to show a sufficient therapeutic effect according to the method of claim 1 or 2. 6. A primer pair for determining the amount of expression of a thoracic nucleotide synthetase, and comprising a forward primer of SEQ ID NO: 1 and an inverted primer of SEQ ID NO: 2. 7. The pair of primers in claim 6 of the patent application is used to predict the therapeutic effect on chemotherapy containing the Tiggio complex. 8. For example, the primer pair in Patent Application No. 7 is used to predict the therapeutic effect of combined chemotherapy with tigeo complex and cisplatin in patients with gastric cancer. 9. A kit for predicting the therapeutic effect of a chemotherapy comprising a tigeo complex comprising: a forward primer of SEQ ID NO: 1 and a reverse primer of SEQ ID NO: 2 for determining thymidine nucleoside A primer pair for the expression of acid synthase. 10. The kit of claim 9 is used to predict the therapeutic effect of combined chemotherapy with tigeo complex and cisplatin in patients with gastric cancer. 11. The kit of claim 10 further comprising the probe of SEQ ID NO:3. 201030338 IV. Designated representative map: (1) The representative representative of the case is: (none) (2) The symbolic symbol of the representative figure is simple: (none) 5. If there is a chemical formula in this case, please reveal the best indication of the characteristics of the invention. Chemical formula:
TW098145054A 2008-12-26 2009-12-25 Method for predicting therapeutic effect of combination chemotherapy TW201030338A (en)

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