TW200526777A - Combinations for the treatment of proliferative diseases - Google Patents

Combinations for the treatment of proliferative diseases Download PDF

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Publication number
TW200526777A
TW200526777A TW093133826A TW93133826A TW200526777A TW 200526777 A TW200526777 A TW 200526777A TW 093133826 A TW093133826 A TW 093133826A TW 93133826 A TW93133826 A TW 93133826A TW 200526777 A TW200526777 A TW 200526777A
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cell
compound
reduces
biological activity
preparation
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TW093133826A
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Chinese (zh)
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M James Nichols
Margaret S Lee
Curtis Keith
Yanzhen Zhang
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Combinatorx Inc
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Priority claimed from US10/855,130 external-priority patent/US20050100508A1/en
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Publication of TW200526777A publication Critical patent/TW200526777A/en

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
    • G01N33/5008—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics
    • G01N33/5011—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for testing or evaluating the effect of chemical or biological compounds, e.g. drugs, cosmetics for testing antineoplastic activity
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • A61K31/22—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids of acyclic acids, e.g. pravastatin
    • A61K31/225—Polycarboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/914—Hydrolases (3)
    • G01N2333/916—Hydrolases (3) acting on ester bonds (3.1), e.g. phosphatases (3.1.3), phospholipases C or phospholipases D (3.1.4)

Abstract

The invention features combinations of drugs for the treatment of proliferative diseases (e.g., cancer). The invention also features methods for identifying new combination therapies for the treatment of cancer and other proliferative diseases.

Description

200526777 九、發明說明： 【發明所屬之技術領域】 本發明係有關於癌症與其他增生性疾病的治療。 【先前技術】 癌症是一種不正常細胞會不受控制地生長的疾病。癌細胞突破正 常細胞（其生命有限）上的障礙，而無限制地生長。由於癌細胞持續地 生長，可能使基因的改變（genetic alterations)持續，直到癌細胞本 身表現較侵犯性的生長表型（aggressive growth phenotype)。如果不 予以治療’癌細胞會經由淋巴系統或血流轉移（metastasis)至身體的 其他部位，而可能破壞健康的組織。 治療癌症的阻礙在於即使同一種形式的癌都具有相當大的異質性 (heterogeneity)。舉例來說，有些癌具有侵入組織的能力，並且展現 其侵入式的生長，其特色為轉移（metastasis)。對病人來說，這些腫 瘤通常會導致不幸的結果。最後’腫瘤異質性（heterogeneity)導致多 重抗藥性（multiple drug resistance)的現象，即對於廣泛且結構上 無相關的細胞毒性（cytotoxic)抗癌化合物產生抗藥性（J. H. Gerlach et al·，Caz/cer 5:25-46 (1986))。進行性抗藥性 (progressive drug resistance)的潛在因素可能如 J. H. Goldie and Andrew J. ’Coldman, 44:3643-3653 (1984)所述地 係由於診斷期之腫瘤内的一小群抗藥性細胞（例如：突變細胞）所致。 以單一藥物治療此類腫瘤可緩解腫瘤，原因是由於藥物殺死主要的藥 物敏感細胞（drug-sensitive cells)，而造成腫瘤的縮小。然而，隨 著藥物敏感細胞消失，剩下的抗藥性細胞可繼續增生，並且在最後控 制了腫瘤的細胞族群。因此，在癌症的化學療法中，為什麼轉移性癌 (metastatic cancers)會對所有治療法發展出多效性抗性 1084-6646-PF；Chiumeow 5 200526777 (pleiotropic resistance)以及其機制是最迫切需要了解的問題。 目前需要能夠用於各種腫瘤形式並且特別適用於侵入性腫瘤的抗 癌治療法。而重要的是該治療必須有效並且具有最小的宿主（h〇st)毒 性。儘管在癌症的治療歷史上已長期使用多種藥物組合，特別是多重 抗藥性癌症（multiple drug resistant cancer)的治療，但仍舊難以 預測使用組合治療是否能得到正面的結果。 【發明内容】 基於上述目的，本發明載明治療增生性疾病（例如：癌）的組合物 (compositions)、方法與套組（kits)。 首先，本發明載明一種組合物，該組合物包括一降低有絲分裂驅 動蛋白（mitotic kinesin)之生物活性的第一製劑與一降低蛋白絡胺 酸磷酸酶（protein tyrosine phosphatase)之生物活性的第二製劑。 本發明也特別載明一種方法，該方法係用以治療患有增生性疾病 的病人或用以抑制病人體内增生性疾病的發展，而該方法係投與該病 人一降低有絲分裂驅動蛋白（mitotic kinesin)之生物活性的第一製 劑與一降低蛋白酪胺酸磷酸酶（protein tyrosine phosphatase)之生 物活性的第二製劑。而該二製劑最好同時投與或在14天内、7天内、 1天内、1小時内分別足量地投與，以治療該病人。 本發明也特別載明一種減少細胞增生的方法，該方法係以降低有 絲分裂驅動蛋白之生物活性的第一製劑以及降低蛋白酪胺酸磷酸酶之 生物活性的第二製劑接觸細胞。 該方法與組合物進一步地包括一額外的抗增生劑，例如：抗癌劍 (anticancer agent) 〇 另一方面，本發明特別載明一種確定組合的方法’而該組合可用 以治療增生性疾病。在此方法中，在禮嚴以（丄)一降低有線 6 1084-6646-PF;Chiumeow 200526777 分裂驅動蛋白生物活性的製劑與（i i) 一候選化合物接觸增生的細胞 (例如：癌細胞或癌細胞株（cancer cell line))。然後以適當的分析 試驗確定該製劑與候選化合物的組合是否減少細胞增生（相較於以該 製劑接觸但未以候選化合物接觸之細胞的增生）。若細胞增生減少即確 定該組合係可用於治療增生性疾病的組合。 另一方面’本發明特別載明另一種確定組合的方法，而該組合可 用以治療增生性疾病。該方法包括以下步驟：（a)確定降低蛋白酪胺酸 磷酸酶生物活性的化合物；（b)在邀々（ye 以降低有絲分裂驅動 蛋白生物活性之製劑以及步驟（a)所確定之化合物接觸增生的細胞；以 及（C)確定該製劑與步驟（a)所確定之化合物的組合是否減少細胞增生 (相較於以該製劑接觸但未以步驟（a)所確定的化合物接觸，或以步驟 (a)所確定之化合物接觸但未以該製劑接觸之細胞的增生），若細胞增 生減少即確定該組合係可用於治療增生性疾病的組合。 由任一上述的觀點來看，降低有絲分裂驅動蛋白生物活性之製劑 的例子包括·有絲分裂驅動蛋白抑制劑（mit〇tic kinesin inhibitor) ’減少有絲分裂驅動蛋白表現量的反義化合物（antisense compound)或干涉核醣核酸化合物（RNAi compound)，顯性抑制有絲分 裂驅動蛋白（dominant negative mitotic kinesin)，將此顯性抑制有 絲为裂驅動蛋白澤碼（enc〇ding)的表現載體（expressi〇I1 vector)，結 合有絲分裂驅動蛋白並且降低有絲分裂驅動蛋白生物活性的抗體，或 曙光激酶抑制劑（aurora kinase inhibitor)。而該降低有絲分裂驅動 蛋白生物活性的製劑最好能降低HsEg5/KSP的生物活性。主要的有絲 女裂驅動蛋白生物活性（mit〇tic kinesin biological activities) 為酶活性（enzymatic activity)、運動活性（motor activity)以及結 合活性（binding activity)。 另一方面’本發明特別載明另一種確定化合物的方法，談化合物 1084-6646-PF；Chiumeow 7 200526777 係用以治療增生性疾病。該方法包括以下步驟：（a)提供增生的細胞， 该細胞具有降低的有絲分裂驅動蛋白生物活性；（b)以一候選化合物接 觸該細胞；以及（C)確定該候選化合物是否減少細胞增生（相較於未以 候選化合物接觸的細胞），若細胞增生減少即確定該化合物係可用於治 療增生性疾病的化合物。 另一方面，本發明特別載明另一種確定組合的方法，該組合係用 以治療增生性疾病。該方法包括以下步驟：（a)在禮命（ie 以一 降低蛋白酿胺酸磷酸酶（protein tyrosine phosphatase)生物活性的 製劑與一候選化合物接觸增生的細胞；以及（b)確定該製劑與該候選化 合物的組合是否減少細胞增生（相較於以該製劑接觸而未以該候選化 合物接觸之細胞的增生），若細胞增生減少即確定該組合係可用於治療 增生性疾病的組合。 由相關的觀點來看，本發明特別載明一種確定組合的方法，該組 合係用以治療增生性疾病。該方法包括以下步驟：（a)確定一降低有絲 分裂驅動蛋白生物活性的化合物；（b)在禮分F/iro)以降低蛋白路 胺酸麟酸酶生物活性之製劑以及步驟（a)所確定之化合物接觸增生的 細胞；以及（c)確定該製劑與步驟（a)所確定之化合物的組合是否減少 細胞增生（相較於以該製劑接觸但未以步驟（a)所確定的化合物接觸， 或以步驟（a)所確定之化合物接觸但未以該製劑接觸之細胞的增生）， 若細胞增生減少即確定該組合係可用於治療增生性疾病的組合。 由任一上述的觀點來看，該降低蛋白酪胺酸磷酸酶生物活性的製 劑為蛋白酿胺酸填酸酶抑制劑（protein tyrosine phosphatase inhibitor)，減少蛋白酪胺酸磷酸酶表現量的反義化合物（antisense compound)或干涉核酶核酸化合物（RNAi compound)、顯性抑制蛋白胳 胺酸填酸酶（dominant negative protein tyrosine phosphatase)， 將該顯性抑制蛋白酪胺酸磷酸觀譯碼(encod ing)的表覌載體 1084-6646-PF；Chiumeow 8 200526777 (expression vector)，結合蛋白酪胺酸磷酸酶並且降低蛋白酪胺酸磷 酸酶生物活性的抗體’或法尼基轉移酶抑制劑（farnesyltransferase inhibitor)。該降低蛋白酪胺酸磷酸酶之生物活性的製劑係選自蛋白 酪胺酸填酸酶ΙΒ(ΡΤΡΙΒ)、再生肝之鱗酸酶-1(PRL-1)、再生肝之填酸 酶-2、再生肝之磷酸酶〜3、Src同源磷酸酶-KSHP-1)、Src同源磷酸 酶-2(SHP-2)、MAPK磷酸酶-kMKP—d、MAPK磷酸酶-2、細胞分裂週期 14(CDC14)、細胞分裂週期25A(CDC25A)、細胞分裂週期25B(CDC25B) 以及細胞分裂週期25C(CDC25〇。 另一方面，本發明特別載明另一種確定化合物的方法，該化合物 係用以治療增生性疾病。該方法包括以下步驟··（a)提供增生的細胞， 該細胞具有降低的蛋白酪胺酸磷酸酶生物活性；（b)以一候選化合物接 觸該細胞；以及（c)確定該候選化合物是否減少細胞增生（相較於未以 該候選化合物接觸的細胞），若細胞增生減少即確定該化合物係可用於 治療增生性疾病的化合物。 由上述任一觀點來看，該細胞最好為癌細胞或來自癌細胞株的細 胞。 “更有效的（more effective)，’係指一種方法、組合物或套組表 現出更大的效力（efficacy)、具較低毒性、更安全、更方便、具較佳 的耐受性（better tolerated)或價格較便宜’或比其他方法、組合物 或套組提供更令人滿意的治療。而熟悉此技術的醫師可利用適當的標 準方法評估效力。 “有絲分裂驅動蛋白抑制劑，，係指一種製劑，該製劑結合有絲分 裂驅動蛋白並且顯著地降低（例如··至少10%、20%、30%或以上的降低 量）該有絲分裂驅動蛋白的生物活性。有絲分裂驅動蛋白的生物活性包 括：酶活性（例如：三磷酸腺苷酶活性（ATPase activity))、運動活性 (例如：力（force)的產生）以及結合活性C例如：胞內運動，器(motor) l〇84-6646-PF；Chiumeow 9 200526777 結合至微管或其所載物（cargo))。 “顯著抑制（dominant negative)”係指一種包含至少一突變的 蛋白質，該突變使蛋白質失去其生理活性，因此在蛋白質之一般型或 野生型複製（normal or wild-type copy)的存在下’此突變體（mutant) 的表現導致一般複製（normal copy)失活或活性降低。因此，該突變體 的活性“高於”一般複製的活性，所以即使一般複製存在，生物功能 仍然降低。有一實施例需要蛋白質之二複製體的二聚物（dimer)，因此 即使一般與突變的複製體（copy)存在，也不會產生活性；另一實施例 為當該突變體結合至或“吸收”其他蛋白質（該蛋白質為一般複製體 的功能所必須）時，這些其他蛋白質的量便不夠供應一般複製體 (normal copy)的活化。 “蛋白酿胺酸構酸酶（protein tyrosine phosphatase) ” 或 “PTPase”係指一種酶，該酶在一蛋白質基質上將一酪胺酸殘基 (tyrosine residue)脫鱗酸化（dephosphorylate) 〇 “蛋白酪胺酸磷酸酶抑制劑”係指一種製劑，該製劑結合蛋白酪 胺酸磷酸酶並且抑制（例如：至少抑制10%、20%、30%或以上）該蛋白 酪胺酸磷酸酶的生物活性。 “雙特異性麟酸酶（dual specificity phosphatase)” 係指一種 蛋白磷酸酶，該蛋白磷酸酶可使酪胺酸殘基以及在相同蛋白質基質上 的絲胺酸或經丁胺酸殘基（serine or threonine residue)脫填酸化。 雙特異性磷酸酶包括MAPK磷酸酶-1 (MKP-1)、MAPK磷酸酶-2以及細胞 分裂週期磷酸酶家族（cell division cycle phosphatase family)(例 如：細胞分裂週期14(CDC14)、細胞分裂週期25A、細胞分裂週期25B、 以及細胞分裂週期25C)。雙特異性磷酸酶被視為蛋白酪胺酸磷酸酶。 “抗增生劑（antiproliferative agent)”係指一種單獨抑制細 胞增生的化合物。本發明之抗增生劑包、、括：览化^ 1084-6646-PF;Chiumeow 10 200526777 agents)、鉑劑（platinum agents)、抗代謝物質（antimetabolites)、 拓樸異構酶抑制劑（topoisomerase inhibitors)、抗腫瘤抗生素 (antitumor antibiotics)、抗有絲分裂劑（antimitotic agents)、芳 香酶抑制劑（aromatase inhibitors)、胸苷酸合酶抑制劑 (thymidylate synthase inhibitors)、去氧核醣核酸拮抗劑（DNA antagonists)、法尼基轉移酶抑制劑（farnesyltransferase inhibitors)、幫浦抑制劑（pump inhibitors)、組織蛋白乙醯轉移酶 抑制劑（histone acetyltransferase inhibitors)、金屬蛋白酶抑制 劑（metalloproteinase inhibitors)、核糖核甘還原酶抑制劑 (ribonucleoside reductase inhibitors)、腫瘤壞死因子 α 激動劑與 拮抗劑（TNF alpha agonists and antagonists)、内皮素 Α 受體拮抗 劑（endothelin A receptor antagonists)、網膜酸受體激動劑 (retinoic acid receptor agonists)、免疫調節劑 (immunomodulators)、荷爾蒙與抗荷爾蒙劑（hormonal and antihormonal agents)、光動力學劑（photodynamic agents)以及路胺 酸激酶抑制劑（tyrosine kinase inhibitors)。 “抑制細胞增生”係指在邀;^(//3 Γ//7Ί9)或在邀7/pr〇)可測 量到細胞之生長速率減緩、停止或逆轉。利用適當的分析試驗（例如·· 此處所述的細胞生長分析試驗（cell growth assay))確定細胞的生長 速率，而生長速率最好減緩20%、30%、50%、60%、70%、80%或90%。 一般來說，生長速率逆轉通常也會啟始或加速腫瘤細胞内細胞死亡之 壞死或凋亡（necrotic or apoptotic)的機制。 “有效量”係指本發明之組合中的化合物量，該化合物量為抑制 禮冷腫瘤細胞生長所需的量。在本發明中，用以治療增生性疾病（例 如··癌）之活性化合物的有效量當根據投藥方式、個體的年齡、種族、 性別、受影響的器官、體重以及一般的健康狀況而改變。最後，主治 1084-6646-PF;Chiumeow 11 200526777 醫師或獸醫將決定適當的投與量與劑量。 “低劑量”係指比一特定化合物（該化合物係配製成特定的投與 形式以治療任何人類的疾病與症狀）之最低標準建議劑量至少低 5%(例如：至少10%、20%、50%、80%、90%或甚至95%)的劑量。 “高劑量”係指比一特定化合物（該化合物係用以治療任何人類 的疾病與症狀）之最高標準建議劑量至少高5%(例如：至少10%、20%、 50%、100%、200%或甚至 300%)的劑量。 “藥學上可接受的（pharmaceutically acceptable)”係指當分 子實體與組合物投與至病人時，該分子實體與組合物未產生有害的、 過敏的或其他難應付的反應。 此處所用之“藥學上可接受的載體（pharmaceutically acceptable carrier) ”包括任何以及所有溶劑、散佈媒劑 (dispersion media)、塗層（coatings)、抗菌與抗真菌劑 (antibacterial and antifungal agents)、等張與吸收延遲劑 (isotonic and absorption delaying agents)以及相似物。將該等介 質與製劑作為藥學活性基質的技術為習知技術。 “病人”係指任何動物（例如：人類）。可用本發明之方法、組合 物與套組治療的非人類動物包括··馬、狗、貓、豬、山羊、兔子、倉 鼠、狼子、天竺鼠、大鼠、小鼠、姊f蜴、蛇、綿羊、牛、魚與鳥。 使用於本發明的化合物包括此處所述之任何藥學上可接受形式的 化合物，包括其同分異構物（isomers)(例如··非鏡像異構物 (diastereomers)與鏡像異構物（enantiomers))、鹽類、溶劑合物 (solvates)與多形體（polymorphs)，以及此處所述之化合物的消旋混 合物（racemic mixtures) 〇 本發明之其他特色與優點將描述於下列的實施方式與申請專利範 圍。 1084-6646-PF；Chiumeow 12 200526777 【實施方式】 本發明係提供治療增生性疾病的組合物、方法與套組。 正常細胞具有信號傳遞的機制（signaling mechanisms)，可經由 一程序調節生長、有絲分裂（mitosis)、分化（differentiation)、細 胞功能以及細胞死亡。調節這些功能之信號傳遞的缺陷可能造成不受 控制的生長與增生，而產生癌、增生（hyperplasias)、血管再狹窄 (restenosis)、心肌肥大（cardiac hypertrophy)、免疫疾病（immune disorders)以及炎症（inflammatory disorders) ° 有絲分裂驅動蛋白（mitotic kinesins)為有絲分裂時的必要胞内 運動器（motors)，其控制紡錘體集合與維持、染色體連接紡錘體並適 當地位於其上、建立兩極的（bipolar)紡錘體以及維持紡錘體内的力量 使染色體移向相對的兩極。有絲分裂驅動蛋白功能的擾亂會引起有絲 分裂紡錘體的畸形與功能不良，而經常造成細胞週期停止與細胞死亡。 蛋白赂胺酸磷酸酶（protein tyrosine phosphatases (PTPases)) 為細胞内的信號傳遞分子，蛋白酪胺酸磷酸酶使得蛋白質基質上的酪 胺酸殘基脫磷酸化，從而調節某些細胞的功能。在正常細胞中，蛋白 酪胺酸磷酸酶通常與蛋白酪胺酸激酶共同作用，然後經由蛋白酪胺酸 殘基的碟酸化（phosphorylation)調整一系列的信號傳遞。蛋白質上之 酿胺酸殘基的填酸化與去攝酸化（dephosphorylation)控制細胞生長 與增生、細胞週期進行（cell cycle progression)、細胞支架完整性 (cytoskeletal integrity)、分化以及代謝。在各種轉移性與癌細胞 株t，蛋白酪胺酸磷酸酶IB(PTPIB)與再生肝之磷酸酶（Phosphatases of Regenerating Liver)家族（再生肝之磷酸酶-1CPRL-1)、再生肝之 磷酸酶-2與再生肝之填酸酶-3)會過度表現。例如，在轉移性大腸直 腸癌（metatstatic colorectal cancers)中，再生肝之鱗酸J每-3(也稱 1084-6646-PF;Chiumeow 13 200526777 為PTP4A3)的表現量相對地較高（Saha et al.，Science 294: 1343-1346, 2001.)。再生肝之磷酸酶-i局部分佈於有絲分裂紡錘體， 並且為有絲分裂進行與染色體分離所需的物質。再生肝之磷酸酶（PRL phosphatases)促進細胞遷移、侵入與轉移，而這些蛋白酪胺酸填酸酶 (PTPases)的抑制會抑制邀命之癌細胞與動物模式中之腫瘤的增生。 吾人之前證明氣普馬嗪（chl〇rpromazi ne)與喷他脒（pentamidine) 之組合可共同作用降低細胞增生（美國專利第6, 569, 853號）。現在吾 人證明氯普馬嗪的作用為有絲分裂驅動蛋白（mitotic kinesins)的抑 制劑。而喷他脉則經證實為再生肝之填酸酶（PRL phosphatases)的抑 制劑（Pathaketal.，Mol. Cancer Ther· 1:1255-1264，2002)。 基於上述的觀察，吾人推斷一降低有絲分裂驅動蛋白生物活性之 製劑與一降低蛋白酪胺酸磷酸酶活性之製劑的組合可用以降低細胞增 生，因此可用以治療增生性疾病。 有絲分裂驅動蛋白（Mitotic kinesins) 有絲分裂驅動蛋白包括：HsEg5/KSP、KIFC3、CH02、MKLP、MCAK、 Kin2、Kif4、MPP1、CENP-E、NYREN62、L0C8464 以及 KIF8。其他的有 絲分裂驅動蛋白描述於美國專利案號6, 414, 121、6, 582, 958、 6,544,766、6,492，158、6,455,293、6,440,731、6,437，115、 6, 420, 162、6, 399, 346、6, 395, 540、6, 383, 796、6, 379, 941 以及 6, 248, 594。代表性之有絲分裂驅動蛋白的基因銀行登錄號（GenBank Accession Nos.)列於表 1 ° 1084-6646-PF;Chiumeow 14 200526777 表1 人類有絲分裂驅動蛋白 蛋白質名稱 基因銀行登錄號 Eg5/KSP AA857025, U37426, X85137 KIFC3 BC001211 MKLP1 AI131325, AU133373, X67155 MCAK AL046197, U63743 KIN2 Y08319 KIF4 AF071592 MPP1 AL117496 CENP-E Z15005 CH02 AL021366 HsNYREN62 AF155117 HsL0C8464 NM_032559 I KIF8 AB001436 1200526777 IX. Description of the invention: [Technical field to which the invention belongs] The present invention relates to the treatment of cancer and other proliferative diseases. [Prior art] Cancer is a disease in which abnormal cells grow uncontrollably. Cancer cells break through barriers on normal cells (of which life is limited) and grow indefinitely. Because cancer cells continue to grow, genetic alterations may continue until the cancer cells themselves exhibit a more aggressive growth phenotype. If left untreated, cancer cells will metastasize to other parts of the body via the lymphatic system or the bloodstream, which may destroy healthy tissue. The obstacle to treating cancer is that even the same form of cancer has considerable heterogeneity. For example, some cancers have the ability to invade tissues and exhibit their invasive growth, which is characterized by metastasis. For patients, these tumors often lead to unfortunate results. Finally, tumor heterogeneity leads to the phenomenon of multiple drug resistance, that is, resistance to a wide range of structurally unrelated cytotoxic anticancer compounds (JH Gerlach et al., Caz / cer 5: 25-46 (1986)). The underlying factors of progressive drug resistance may be as described in JH Goldie and Andrew J. 'Coldman, 44: 3643-3653 (1984) due to a small group of drug-resistant cells (eg, : Mutant cells). Treating such tumors with a single drug can alleviate the tumor because the drug kills the main drug-sensitive cells, causing the tumor to shrink. However, as the drug-sensitive cells disappear, the remaining drug-resistant cells can continue to proliferate and ultimately control the cell population of the tumor. Therefore, in the chemotherapy of cancer, why metastatic cancers develop pleiotropic resistance to all treatments 1084-6646-PF; Chiumeow 5 200526777 (pleiotropic resistance) and its mechanism are most urgently needed to understand The problem. There is currently a need for anti-cancer therapies that can be used in a variety of tumor forms and are particularly suitable for invasive tumors. It is important that the treatment is effective and has minimal host (host) toxicity. Although multiple drug combinations have been used for a long time in the history of cancer treatment, especially for multiple drug resistant cancer, it is still difficult to predict whether positive results will be obtained with combination therapy. [Summary of the Invention] Based on the above objectives, the present invention describes compositions, methods and kits for treating proliferative diseases (eg, cancer). First, the present invention describes a composition comprising a first agent that reduces the biological activity of mitotic kinesin and a second agent that reduces the biological activity of protein tyrosine phosphatase preparation. The invention also specifically describes a method for treating a patient suffering from a proliferative disease or for inhibiting the development of a proliferative disease in the patient, and the method is administered to the patient to reduce kinesin) and a second agent that reduces the biological activity of protein tyrosine phosphatase. The two preparations are preferably administered simultaneously or in sufficient quantities within 14 days, 7 days, 1 day, and 1 hour, respectively, to treat the patient. The present invention also specifically describes a method for reducing cell proliferation by contacting a cell with a first agent that reduces the biological activity of mitotic kinesin and a second agent that reduces the biological activity of protein tyrosine phosphatase. The method and composition further includes an additional anti-proliferative agent, such as an anticancer agent. On the other hand, the present invention specifically sets out a method for determining a combination ', and the combination can be used to treat a proliferative disease. In this method, (i) a preparation that reduces the wired 6 1084-6646-PF; Chiumeow 200526777 division kinesin biological activity is contacted with (ii) a candidate compound to proliferate cells (eg, cancer cells or cancer cells) Strain (cancer cell line)). Appropriate analytical tests are then used to determine whether the combination of the formulation with the candidate compound reduces cell proliferation (compared to the proliferation of cells contacted with the formulation but not with the candidate compound). If the cell proliferation is reduced, the combination is determined to be a combination that can be used to treat a proliferative disease. On the other hand, the present invention specifically describes another method for determining a combination which can be used to treat a proliferative disease. The method includes the following steps: (a) identifying a compound that reduces the biological activity of a protein tyrosine phosphatase; (b) inducing a preparation that reduces the biological activity of a mitogen kinesin and inducing contact proliferation of the compound identified in step (a) And (C) determine whether the combination of the formulation with the compound identified in step (a) reduces cell proliferation (as compared to contact with the formulation but not with the compound identified in step (a), or with step ( a) Proliferation of cells identified by contact with the compound but not with the preparation), and if the cell proliferation decreases, the combination is determined to be a combination that can be used to treat a proliferative disease. From any of the above points, reducing mitogen-driven proteins Examples of biologically active preparations include mitotic kinesin inhibitor 'antisense compound or RNAi compound which reduces the expression of mitotic kinesin, which significantly inhibits mitotic drive Protein (dominant negative mitotic kinesin) An expression vector expressing protein (encoding), an antibody that binds to mitotic kinesin and reduces the biological activity of mitotic kinesin, or an aurora kinase inhibitor, which reduces mitotic kinesin The active preparation is best to reduce the biological activity of HsEg5 / KSP. The main mitotic kinesin biological activities are enzymatic activity, motor activity, and binding activity ( binding activity). On the other hand, the present invention specifically sets forth another method for identifying compounds, talking about compound 1084-6646-PF; Chiumeow 7 200526777 is used to treat proliferative diseases. The method includes the following steps: (a) providing proliferation Cells that have reduced mitotic kinesin biological activity; (b) contacting the cell with a candidate compound; and (C) determining whether the candidate compound reduces cell proliferation (compared to cells not contacted with the candidate compound), If cell proliferation is reduced, the compound is determined to be Compounds for the treatment of proliferative diseases. On the other hand, the present invention specifically sets forth another method for determining a combination for treating proliferative diseases. The method includes the following steps: A preparation that reduces the biological activity of protein tyrosine phosphatase contacts a candidate compound to proliferate cells; and (b) determines whether the combination of the preparation and the candidate compound reduces cell proliferation (compared to contact with the preparation) And the proliferation of cells not contacted with the candidate compound), if the cell proliferation is reduced, it is determined that the combination is a combination that can be used to treat a proliferative disease. From a related point of view, the present invention specifically sets out a method for determining a combination for treating a proliferative disease. The method includes the following steps: (a) identifying a compound that reduces the biological activity of mitotic kinesin; (b) formulating F / iro in order to reduce the biological activity of protein glutamyllinase and the determination in step (a) Contacting the compound with proliferating cells; and (c) determining whether the combination of the formulation with the compound identified in step (a) reduces cell proliferation (as compared to contact with the formulation but not with the compound identified in step (a), Or the proliferation of cells contacted with the compound identified in step (a) but not with the preparation), if the cell proliferation is reduced, it is determined that the combination is a combination that can be used to treat a proliferative disease. From any of the above viewpoints, the preparation that reduces the biological activity of protein tyrosine phosphatase is a protein tyrosine phosphatase inhibitor, which is an antisense that reduces the expression of protein tyrosine phosphatase Antisense compound, RNAi compound, dominant inhibitory protein, negative negative protein tyrosine phosphatase, decode the dominant inhibitory protein tyrosine phosphate ) Epitope vector 1084-6646-PF; Chiumeow 8 200526777 (expression vector), an antibody that binds to protein tyrosine phosphatase and reduces protein tyrosine phosphatase biological activity 'or farnesyl transferase inhibitor ). The preparation for reducing the biological activity of protein tyrosine phosphatase is selected from the group consisting of protein tyrosine glutamase IB (PTPIB), regenerative liver lyase-1 (PRL-1), and regenerating liver glutamase-2 Phosphatase of regenerating liver ~ 3, Src homophosphatase-KSHP-1), Src homophosphatase-2 (SHP-2), MAPK phosphatase-kMKP-d, MAPK phosphatase-2, cell division cycle 14 (CDC14), cell division cycle 25A (CDC25A), cell division cycle 25B (CDC25B), and cell division cycle 25C (CDC25.) On the other hand, the present invention specifically sets forth another method for determining a compound which is used for Treating a proliferative disease. The method includes the steps of: (a) providing a proliferating cell having reduced protein tyrosine phosphatase biological activity; (b) contacting the cell with a candidate compound; and (c) determining Whether the candidate compound reduces cell proliferation (compared to cells not contacted with the candidate compound), if the cell proliferation is reduced, it is determined that the compound is a compound that can be used to treat a proliferative disease. From any of the above points of view, the cell is the most Good for cancer cells or from cancer Cells of a cell line. "More effective," means a method, composition, or set that exhibits greater efficacy, is less toxic, is safer, more convenient, and has better performance. Better tolerated or less expensive 'or to provide a more satisfactory treatment than other methods, compositions or kits. Physicians familiar with this technique can assess efficacy using appropriate standard methods. "Mitotic kinesin inhibition Agent, means a preparation that binds to mitogen kinesin and significantly reduces (eg, at least 10%, 20%, 30% or more of the reduction) the biological activity of the mitogen kinesin. Activities include: enzyme activity (such as: ATPase activity), motor activity (such as: the production of force) and binding activity C, such as: intracellular motor, motor 0884-6646-PF Chiumeow 9 200526777 binds to microtubules or their cargo). "Dominant negative" refers to a protein that contains at least one mutation that causes the protein to lose its physiological activity, and therefore in the presence of a normal or wild-type copy of the protein The expression of mutants results in inactivation or reduced activity of normal copy. Therefore, the activity of this mutant is "higher" than that of general replication, so even if general replication exists, the biological function is still reduced. One embodiment requires a dimer of a protein two replica, so it will not produce activity even if it generally exists with a mutant copy; another embodiment is when the mutant binds to or "absorbs" "When other proteins are required for the function of a general replica, the amount of these other proteins is insufficient to supply activation of a normal copy. "Protein tyrosine phosphatase" or "PTPase" refers to an enzyme that dephosphorylates a tyrosine residue on a protein matrix. "Protein A tyrosine phosphatase inhibitor "means a preparation that binds to a protein tyrosine phosphatase and inhibits (eg, at least 10%, 20%, 30% or more) the biological activity of the protein tyrosine phosphatase . "Dual specificity phosphatase" refers to a protein phosphatase that makes a tyrosine residue and a serine or serine residue on the same protein matrix or threonine residue). Bispecific phosphatases include MAPK phosphatase-1 (MKP-1), MAPK phosphatase-2, and the cell division cycle phosphatase family (eg, cell division cycle 14 (CDC14), cell division cycle 25A, cell division cycle 25B, and cell division cycle 25C). Bispecific phosphatases are considered protein tyrosine phosphatases. "Antiproliferative agent" refers to a compound that alone inhibits cell proliferation. The anti-proliferative agent package of the present invention includes: Chihuaow 1084-66646-PF; Chiumeow 10 200526777 agents), platinum agents, antimetabolites, and topoisomerase inhibitors ), Antitumor antibiotics (antitumor antibiotics), antimitotic agents (antimitotic agents), aromatase inhibitors (aromatase inhibitors), thymidylate synthase inhibitors (thymidylate synthase inhibitors), DNA antagonists (DNA antagonists) , Farnesyltransferase inhibitors, pump inhibitors, histone acetyltransferase inhibitors, metalloproteinase inhibitors, ribonucleoside reductase Inhibitors (ribonucleoside reductase inhibitors), tumor necrosis factor alpha agonists and antagonists (TNF alpha agonists and antagonists), endothelin A receptor antagonists (endothelin A receptor antagonists), retinoic acid receptor agonists (retinoic acid receptor agonists) ), Immune modulator (immunomodulators), hormones and antihormonal agents (hormonal and antihormonal agents), photodynamic agents (photodynamic agents) and tyrosine kinase inhibitors (tyrosine kinase inhibitors). "Inhibition of cell proliferation" means that the growth rate of the cells can be measured to be slowed, stopped or reversed at ^ (// 3 Γ // 7Ί9) or at 7 / pr0). Use appropriate analytical tests (such as the cell growth assay described here) to determine the cell growth rate, and the growth rate should preferably be slowed by 20%, 30%, 50%, 60%, 70% , 80%, or 90%. In general, reversal of growth rate usually also initiates or accelerates the necrotic or apoptotic mechanism of cell death in tumor cells. "Effective amount" refers to the amount of the compound in the combination of the present invention, which is the amount required to inhibit the growth of cold tumor cells. In the present invention, the effective amount of the active compound used to treat a proliferative disease (e.g., cancer) should be changed according to the mode of administration, the age, race, sex, affected organs, body weight, and general health of the individual. In the end, the attending 1084-6646-PF; Chiumeow 11 200526777 will determine the appropriate dosage and dose. "Low dose" means at least 5% lower than the minimum recommended dose of a particular compound (the compound is formulated for specific administration to treat any human disease or condition) (eg, at least 10%, 20%, 50%, 80%, 90% or even 95%). "High dose" means at least 5% (e.g., at least 10%, 20%, 50%, 100%, 200%) of the highest standard recommended dose for a particular compound that is used to treat any human disease or condition % Or even 300%). "Pharmaceutically acceptable" means that when a molecular entity and composition is administered to a patient, the molecular entity and composition do not produce a deleterious, allergic, or otherwise difficult to respond. As used herein, "pharmaceutically acceptable carrier" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, etc. Isotonic and absorption delaying agents and the like. Techniques using these media and preparations as pharmaceutically active matrices are conventional techniques. "Patient" means any animal (eg, human). Non-human animals that can be treated with the methods, compositions, and kits of the present invention include: Sheep, cattle, fish and birds. Compounds for use in the present invention include any of the pharmaceutically acceptable forms of the compounds described herein, including their isomers (e.g., diastereomers and enantiomers )), Salts, solvates and polymorphs, and racemic mixtures of the compounds described herein. 〇 Other features and advantages of the present invention will be described in the following embodiments and Patent application scope. 1084-6646-PF; Chiumeow 12 200526777 [Embodiments] The present invention provides compositions, methods and kits for treating proliferative diseases. Normal cells have signaling mechanisms that regulate growth, mitosis, differentiation, cell function, and cell death through a program. Defects in the signaling of these functions can cause uncontrolled growth and proliferation, which can lead to cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders, and inflammation ( inflammatory disorders) ° Mitotic kinesins are essential motors during mitosis, which control the assembly and maintenance of spindles, connect the chromosomes to the spindles and place them properly, and establish bipolar spindles The body and the forces that sustain the spindle move the chromosomes toward opposite poles. Disturbance of mitotic kinesin function can cause deformity and dysfunction of the mitotic spindle, and often cause cell cycle cessation and cell death. Protein tyrosine phosphatases (PTPases) are signaling molecules in cells. Protein tyrosine phosphatases dephosphorylate tyrosine residues on the protein matrix, thereby regulating the function of certain cells. In normal cells, protein tyrosine phosphatase usually interacts with protein tyrosine kinase, and then regulates a series of signals through the phosphorylation of protein tyrosine residues. Filling and dephosphorylation of glutamate residues on proteins controls cell growth and proliferation, cell cycle progression, cytoskeletal integrity, differentiation, and metabolism. In various metastatic and cancer cell lines, the protein tyrosine phosphatase IB (PTPIB) and the phosphatase of regenerating liver (Phosphatases of Regenerating Liver) family (regenerating liver phosphatase-1CPRL-1), regenerating liver phosphatase -2 and Regenerative Liver Enzyme-3) are overexpressed. For example, in metastatic colorectal cancers, the expression of squamate J per regenerating liver (also known as 1084-6646-PF; Chiumeow 13 200526777 is PTP4A3) is relatively high (Saha et al ., Science 294: 1343-1346, 2001.). Phosphatase-i of the regenerating liver is locally distributed on the mitotic spindle and is required for mitotic separation from chromosomes. Regenerating liver phosphatases (PRL phosphatases) promote cell migration, invasion, and metastasis. The inhibition of these proteins, tyrosine tyrosinase (PTPases), can inhibit the proliferation of cancer cells in tumors and animal models. We have previously demonstrated that the combination of chropromazi ne and pentamidine can work together to reduce cell proliferation (US Patent No. 6,569,853). We have now shown that clomazine acts as an inhibitor of mitotic kinesins. Pentamai has been proven to be an inhibitor of PRL phosphatases (Pathaketal., Mol. Cancer Ther. 1: 1255-1264, 2002). Based on the above observations, we infer that the combination of a preparation that reduces the biological activity of mitotic kinesin and a preparation that reduces the activity of protein tyrosine phosphatase can reduce cell proliferation and therefore can be used to treat proliferative diseases. Mitotic kinesins Mitotic kinesins include: HsEg5 / KSP, KIFC3, CH02, MKLP, MCAK, Kin2, Kif4, MPP1, CENP-E, NYREN62, LOC8464, and KIF8. Other mitotic kinesins are described in U.S. Patent Nos. 6,414, 121, 6, 582, 958, 6,544,766, 6,492,158, 6,455,293, 6,440,731, 6,437, 115, 6, 420, 162, 6, 399, 346, 6 , 395, 540, 6, 383, 796, 6, 379, 941, and 6, 248, 594. Representative mitotic kinesin gene bank accession numbers (GenBank Accession Nos.) Are listed in Table 1 ° 1084-6646-PF; Chiumeow 14 200526777 X85137 KIFC3 BC001211 MKLP1 AI131325, AU133373, X67155 MCAK AL046197, U63743 KIN2 Y08319 KIF4 AF071592 MPP1 AL117496 CENP-E Z15005 CH02 AL021366 HsNYREN62 AF155117 HsL0C8464 NM_032559 I KIF8 AB001436 1

HsEg5/KSP已被複製並且定性（其例見Blangy et al·，Cell， 83:1159-69 (1995); Galgioetal·， J. Cell Biol·， 135:399-414, 1996;Whiteheadetal·，J· Cell Sci·，111:2551 -2561，1998;Kaiser， et al.， J. Biol· Chem·， 274:18925-31， 1999 ; GenBank accession numbers: X85137，NM 004523)。已有報告報導 KSP 之耒螺 (/^osop/?y/a)(Heck et al·，J· Cell Biol·，123:665-79，1993)與 ?^/A^i{Xenopus)(Xe Quellec et ά\. , Mol. Cell Biol., 11:3395-8, 1991)的同源基因。根據報告，耒螺KLP61F/KRP130已純化成自然體 (native form)(Cole， et al·， J· Biol. Chem·， 269:22913-22916， 1994)，於大腸桿菌（尤 中表現（Barton，etal·，Mol. Biol. Cell， 6:1563-74，1995)，並且具有能動性（motility)與三磷酸腺苷酶活性 (ATPase activities)(Cole， et al., supra; Barton, et al·， supra)。# A # Eg5/KSP表現於大腸桿菌並且具能動性活性 (motility activity)(Sawin, et al., Nature, 359:540-3, 1992; Lockhart and Cross, Biochemistry, 35:2365-73, 1996; Crevel, et 1084-6646-PF;Chiumeow 15 200526777 al，J. Mol. Biol·, 273:160-170，1997)與三磷酸腺苷酶活性 (Lockhart and Cross, supra; Crevel et al·， supra) 〇 除了 KSP之外，其他BimC家族的成員包括：BimC、CIN8、cut7、 KIP卜 KLP61F(Bartonetal·，Mol. Biol· Cell· 6:1563-1574，1995; Cottingham & Hoyt， J_ Cell Biol. 138:1041-1053， 1997; DeZwaan et al., J. Cell Biol. 138:1023-1040, 1997; Gaglio et al., J. Cell Biol. 135:399-414, 1996; Geiser et al., Mol. Biol. Cell 8:1035-1050, 1997; Heck etal., J. Cell Biol. 123:665-679, 1993; Hoyt et al·， J. Cell Biol. 118:109-120， 1992; Hoyt et al·，HsEg5 / KSP has been copied and characterized (for examples, see Blangy et al., Cell, 83: 1159-69 (1995); Galgioetal., J. Cell Biol., 135: 399-414, 1996; Whiteheadetal., J. Cell Sci., 111: 2551-2561, 1998; Kaiser, et al., J. Biol. Chem., 274: 18925-31, 1999; GenBank accession numbers: X85137, NM 004523). It has been reported that KSP (/ ^ osop /? Y / a) (Heck et al., J. Cell Biol., 123: 665-79, 1993) and? ^ / A ^ i {Xenopus) (Xe Quellec et ά \., Mol. Cell Biol., 11: 3395-8, 1991). According to the report, Oncomelania snail KLP61F / KRP130 has been purified into a native form (Cole, et al., J. Biol. Chem., 269: 22913-22916, 1994), and has been expressed in E. coli (Youzhong (Barton, etal., Mol. Biol. Cell, 6: 1563-74, 1995), and has motility and ATPase activities (Cole, et al., supra; Barton, et al., supra). # A # Eg5 / KSP is expressed in E. coli and has motility activity (Sawin, et al., Nature, 359: 540-3, 1992; Lockhart and Cross, Biochemistry, 35: 2365-73, 1996; Crevel , et 1084-6646-PF; Chiumeow 15 200526777 al, J. Mol. Biol ·, 273: 160-170, 1997) and adenosine triphosphate activity (Lockhart and Cross, supra; Crevel et al ·, supra). Except for KSP In addition, other members of the BimC family include: BimC, CIN8, cut7, KIP and KLP61F (Bartonetal ·, Mol. Biol · Cell · 6: 1563-1574, 1995; Cottingham & Hoyt, J_ Cell Biol. 138: 1041-1053 , 1997; DeZwaan et al., J. Cell Biol. 138: 1023-1040, 1997; Gaglio et al., J. Cell Biol. 135: 399-414, 1 996; Geiser et al., Mol. Biol. Cell 8: 1035-1050, 1997; Heck etal., J. Cell Biol. 123: 665-679, 1993; Hoyt et al., J. Cell Biol. 118: 109 -120, 1992; Hoyt et al.,

Genetics 135:35-44， 1993; Huyett et al. , J. Cell Sci. 111:295-301, 1998; Miller et al. , Mol. Biol. Cell 9:2051-2068, 1998; Roof et al., J. Cell Biol. 118:95-108, 1992; Sanders et al., J. Cell Biol. 137:417-431, 1997; Sanders et al. , Mol. Biol. Cell 8:1025-0133, 1997; Sanders et al. , J. Cell Biol. 128:617-624， 1995; Sanders & Hoyt, Cell 70:451-458， 1992; Sharp et al·，J· Cell Biol· 144:125-138，1999; Straight et al·，J· Cell Biol. 143:687-694, 1998; Whitehead & Rattner, J. Cell Sci. 111:2551-2561, 1998; Wilson etal., J. Cell Sci. 110:451-464, 1997)。 有絲分裂驅動蛋白的生物活性包括：其影響三磷酸腺苷（ATP)水解 的能力；微管結合（microtubule binding);滑動（gliding)與聚合作 用 / 解聚作用（polymerization/depolymerization)(在微管動力學 (microtubule dynamics)上的作用）；結合至紡錘體的其他蛋白質；結 合至與細胞週期控制（cell-cycle control)有關的蛋白質；作為其他 酶的基質，例如：激酶（kinases)或蛋白酶（proteases);以及專一的 驅動蛋白細胞活性（specif ickinesia cel Id 1084-6646-PF；Chiumeow 16 200526777 紡錘體極（spindle pole)分離。 分析有絲分裂驅動蛋白生物活性的方法為習知技術。例如’能動 性（motility)的分析方法範例描述於 Hall，etal·，1996，Biophys· J.，71:3467-3476 ； Turner et al., 1996，Anal. Biochem. 242:20-25；Gittes et al., 1996, Biophys. J. 70:418-429；Shirakawa etal·，1995，J· Exp. Biol· 198: 1809-1815; Winkelmannetal·， 1 995，Biophys· J. 68: 2444-2453 ;以及 Winkelmann et al·，1995, Biophys. J. 68:72S。也可使用習知技術中用來確定三磷酸腺苷酶水 解活性（ATPase hydrolysis activity)的方法。1999 年 3 月 18 日申 請的美國申請序號（U.S· application Ser· No· )09/314, 464 敘述該 等分析，並且以引用的方式全部併入本文中。其他方式也可使用。例 如，可量化從驅動蛋白釋出的磷酸根（P0。在一實施例中，三磷酸腺 普水解活性分析係利用〇·3摩爾（M)過氯酸（perchloric acid(PCA)) 與孔雀綠試劑（malachite green reagent)(8. 27毫摩爾（mM)鉬酸鈉 IKsodium molybdate II)，0.33 毫摩爾孔雀綠草酸鹽（malachite green oxalate)以及〇· 8毫摩爾Triton X-100)。在該分析中，10微 升（#L)的反應在90微升之0.3摩爾的冷過氣酸中冷卻。吾人使用磷 酸鹽標準品，因此數據可轉換成奈摩爾（nM)之釋出的無機磷酸鹽。當 所有反應與標準品在過氯酸中冷卻時，將1〇〇微升的孔雀綠試劑添加 至例如微量滴定盤（microtiter plate)的孔（well)中。該混合物進行 反應10-15分鐘，然後在650奈米（nm)吸光度（absorbance)下讀取此 盤。如果使用填酸鹽標準品，則吸附讀數（absorbance readings)可轉 換成奈摩爾（nM)之磷酸根（Pi)，並且相對於時間作圖。另外，習知技 術中的三礎酸腺脊酶（ATPase)分析包括螢光素酶分析（luc if erase assay) 0 驅動蛋白推動區（kinesin motor domains)的三磷酸腺苷酶活性也 1084~6646-PF;Chiumeow 17 200526777 可用來監測調節劑（modulating agents)的作用。有一實施例係於缺乏 微管（microtubules)之情況下進行驅動蛋白的三磷酸腺苷酶分析。另 一實施例則在微管存在下進行三鱗酸腺普酶分析。在上述的分析中可 偵測到不同形式的調節劑。在一實施例中，調節劑的作用與微管以及 三磷酸腺苷（ATP)的濃度無關。在另一實施例中，該製劑對於驅動蛋白 三磷酸腺脊酶（kinesin ATPase)的作用會隨著三填酸腺脊、微管或兩 者的濃度升高而降低。而在另一實施例中，該調節劑的作用隨著三磷 酸腺苷、微管或兩者的濃度升高而增加。 在禮夕/試，驗（//7 F/iro)中降低有絲分裂驅動蛋白之生物活性的製 劑可接著以禮戌試驗hra)篩選。體内篩選的方法包括細胞週期分 佈（cell cycle distribution)、細胞生存力（cell viability)的分析 或有絲分裂紡錘體之存在（presence)、形態學（morphology)、活性、 分佈或含量的分析。舉例來說，利用流式細胞儀（flow cytometry)監 測細胞族群之細胞週期分佈的方法為熟悉此技術的人員所知，該方法 係用以確定細胞生存力（其例見美國專利案號6, 617, 115)。 有絲分裂驅動蛋白抑制劑（Mitotic kinesin inhibitors) 有絲分裂驅動蛋白抑制劑包括：氯普馬嘻（chlorpromazine)、莫 那斯翠（音譯 monasterol)、特喷朵 E(音譯 terpendole E)、HR22C16 以及SB715992。其他的有絲分裂驅動蛋白抑制劑為以下所述的化合 物：Hopkins et al·，Biochemistry 39:2805，2000，Hotha et al·， AngewChem· Inst· Ed· 42:2379，2003，專利合作條約公開案號（PCT Publication Nos.)WO01/98278 、 W002/057244 、 W002/079169 、 W002/057244 、 W002/056880 、 W003/050122 、 W003/050064 、 W003/049679 、 W003/049678 、 W003/049527 、 W003/079973 與 W003/039460，以及美國專利申請公開案號（U· S. Patent Application Publication Nos. )2002/0165240、2003/0008888、2003/0127621 與 10 84-6646-PF; Chiumeow 18 200526777 2002/0143026 ;以及美國專利案號 6, 437, 115、6, 545, 004、 6, 562, 831、6, 569, 853與6, 630, 479，而氣普馬嗪相似物敘述於美國 專利申請案號（U.S. Patent Application No· )10/617,424(其例見式 ⑴）。 蛋白酪胺酸磷酸酶（Protein tyrosine phosphatases) 蛋白酪胺酸磷酸酶包括：再生肝之磷酸酶家族（PRL family)(再生 肝之磷酸酶-1、再生肝之磷酸酶-2與再生肝之磷酸酶-3)、蛋白酪胺 酸磷酸酶1B(PTP1B)、Src同源磷酸酶-1(SHP-1)、Src同源磷酸酶-2、 MAPK磷酸酶-1、MAPK磷酸酶-2、細胞分裂週期14CCDC14)、細胞分裂 週期25A(CDC25A)、細胞分裂週期25B(CDC25B)、細胞分裂週期 25C(CDC25C)、蛋白酪胺酸磷酸酶（PTP)以及蛋白酪胺酸磷酸酶 -BL(PTP-BL)。蛋白酪胺酸磷酸酶之生物活性包括在基質上之酪胺酸殘 基的去麟酸化（dephosphorylation)。具代表性之酿胺酸填酸酶的基因 銀行登錄號（GenBank Accession Nos.)列於表2。 表2 人類蛋白酪胺酸磷酸酶 1 蛋白質名稱 基因銀行登錄號(GenBank Accession No.) 再生肝之磷酸酶-1(PRL-1) AJ420505, BI222469, U48296 再生肝之磷酸酶-2 AF208850, BI552091, L48723 再生肝之磷酸酶-3 AF041434, BC003105 蛋白酪胺酸磷酸酶ΙΒ(ΡΤΡΙΒ) AU117677, M33689 Src同源磷酸酶-l(SHP-l) BC002523, BG754792, M77273, BM742181, AF178946 Src同源磷酸酶-2 AU123593, BF515187, BX537632, D13540 MAPK 磷酸酶-l(MKP-l) U01669, X68277 MAPK鱗酸酶-2 BC014565, U21108, U48807, AL137704 細胞分裂週期14ACCDC14A) AF000367, AF064102, AF064103 細胞分裂週期14B AF023158, AF064104 細胞分裂週期25A M81933 細胞分裂週期25B M81934, Z68092, AF036233 細胞分裂週期25C M34065, Z29077, AJ304504, M34065 蛋白酪胺酸磷酸酶α (PTPalpha) M36033 蛋白酪胺酸雄酸酶-BL D21210, D21209, D21211, U12128 蛋白赂胺酸磷酸酶抑制劑（Protein tyrosine phosphatase 1084-6646-PF；Chiumeow 19 200526777 inhibitors) 蛋白酪胺酸磷酸酶的抑制劑包括：喷他脒（pentamidine)、左旋咪 ^(levamisole) ' (ketoconazole)、雙過氧化叙（bisperoxovanadium) 化合物（例如·· Scrivens et al·，Mol. Cancer Ther· 2:1053-1059, 2003與美國專利案號6, 642,221所述的化合物），釩酸鹽與複合物 (vanadate salts and complexes)(例如··原鈒酸納（sodium orthovanadate))，dephosphatin，dnacinAl，dnacinA2，STI-571， 蘇拉明（suramin)，石肖酸鎵（gallium nitrate)，葡萄糖酸録納（sodium stibogluconate)，亞録酸葡胺（meglumine antimonite)，2-（2-硫醇 乙 醇 ）-3 - 甲 基 -1，4- 萘 酉昆 (2-(2-mercaptoethanol)-3-methyl-1，4-naphthoquinone)，2, 5-雙 (4-脒基苯基）呋喃-雙 -0-甲基胺肟 (2, 5-bis(4-amidinophenyl)furan-bis-〇-methylamidoxime)( — 般戶斤 知的DB289(Immtech))，美國專利案號5, 843, 980所揭露的2, 5-雙（4-脒基苯基）咲喃（2,5-bis(4-amidinophenyl)furan)(DB75， Immtech)，以及 Pestell et al·，Oncogene 19:6607-6612，2000、 Lyon etal·，Nat· Rev· Drug Discov· 1:961 -976，2002、Ducruetet al·，Bioorg· Med· Chem· 8:1451-1466，2000、美國專利申請公開案 號（U.S. Patent Application Publication Nos.)2003/0114703 、 2003/0144338與2003/0161893,以及專利合作條約專利公開案號（PCT Patent Publication Nos. )W099/46237、W003/06788 與 W003/070158 所描述的化合物。其他的相似物皆在任何美國專利案號5,428,051 ; 5, 521，189 ; 5, 602, 172 ; 5,643,935 ; 5,723,495 ; 5, 843, 980 ; 6, 008, 247 ; 6, 025, 398 ; 6, 172, 104 ; 6, 214, 883 ; 6, 326, 395，以及美 國專利申請公開案號US 2001/0044468與US 2002/0019437所提供的 分子式範圍内，而噴他脒相似物描述於美國專利申請案號 1084-6646-PF;Chiumeow 20 200526777 10/617, 424(其例見式（π))。其他的蛋白酪胺酸磷酸酶抑制劑可利用 如 Lazo et al.(〇nc〇i_ Res· 13:347-352，2003)，專利合作條約公 開案號（PCT Publication Nos· )WO97/40379、W003/003001 與 W003/035621，以及美國專利案號5, 443, 962與5, 958, 719所述的方法 確認。 其他的生物活性抑制劑（Other biological activity inhibitors) 除了使用結合有絲分裂驅動蛋白與蛋白酪胺酸磷酸酶的化合物來 降低生物活性外，也可使用其他的有絲分裂驅動蛋白與蛋白酪胺酸磷 酸酶生物活性抑制劑。該等抑制劑包括：降低標靶蛋白或核醣核酸含 量的化合物（例如：反義化合物（antisense compounds)、雙股核酷核 酸（dsRNA)、核酸代酶（ribozymes))以及為了結合同類（例如：編碼相 同的顯著抑制蛋白（dominant negative proteins)或多核普酸 (polynucleotides))而與内生性有絲分裂驅動蛋白或蛋白酪胺酸磷酸 酶競爭的化合物。 反義化合物 透過使用指向（directed to)核醣核酸（該核醣核酸編碼標粗蛋白） 的反義化合物，可降低有絲分裂驅動蛋白和/或蛋白酪胺酸磷酸酶的生 物活性。適合作此用途的有絲分裂驅動蛋白反義化合物已為人所熟知 (其例見美國專利案號 6, 472, 52卜 W003/030832 #&Maneyetal.，J· Cell Biol·，1998，142··787-801)，而抑制蛋白酪胺酸磷酸酶的反義 化合物亦為人所熟知（其例見美國專利公開案號2003/0083285以及 Weil et al.，Biotechniques 33:1244，2002)。利用標準技術可確認 用以降低有絲分裂驅動蛋白的其他反義化合物。例如，利用核醣核酸 第二結構折疊程序（RNA secondary structure folding program)(例 如：MFOLD)，可預測標靶有絲分裂驅動蛋白或蛋白酪胺酸磷酸酶信使 核醣核酸（target mitotic kinesin or protein tyrosine phosphatase 1084-6646-PF;Chiumeow 21 200526777 mRNA)的影響區域（M. Zuker，D_ H_ Mathews & D· Η· Turner， Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide. In: RNA Biochemistry and Biotechnology, J. Barciszewski & B. F. C. Clark, eds., NATO AS I Series, Kluwer Academic Publishers, (1999))。利用 200 個驗基（其 中的殘基可找到互補的鹼基而形成鹼基對鍵）之窗預測次最優的折 疊，而該次最優折疊具有預測之信使核醣核酸的最安定折疊5%以内的 自由能值（Sub-optimal folds with a free energy value within 5% of the predicted most stable fold of the mRNA are predicted using a window of 200 bases within which a residue can find a complimentary base to form a base pair bond) 〇 將未形成驗基對 的開放區域與每個次最優折疊加總，而一般認為預測為開放區域者更 容易結合至反義核酸驗基低聚物（antisense nucleobase oligomers)。其他的反義設計方法描述於以下的例子：美國專利案號 6, 472, 521、Antisense Nucleic Acid Drug Dev. 1997 7:439-444、 Nucleic Acids Research 28:2597-2604，2000、以及 Nucleic Acids Research 31:4989-4994， 2003。 核核酸干擾（RNA interference) 透過使用核醣核酸干擾（RNAi)，可降低有絲分裂驅動蛋白和/或蛋 白赂胺酸攝酸酶的生物活性，核醣核酸干擾係使用例如列入考慮之指 向（directed to)有絲分裂驅動蛋白或蛋白酪胺酸麟酸酶的雙股核 核酸（dsRNA)或小干擾核酵核酸（small interfering RNA (siRNA))(其 例見 Miyamoto et al·，Prog. Cell Cycle Res. 5:349-360，2003 ; 美國專利申請公開案號2003/0157030)。設計該等核醣核酸干擾的方 法為習知技術。例如，01 igoengine(Seattle，WA)所提供用以設計干 擾核醣核酸（interfering RNA)的軟體。 1084-6646-PF;Chiumeow 22 200526777 顯著抑制蛋白（Dominant negative proteins) 熟悉此技術的人員知道如何製備顯著抑制的有絲分裂驅動蛋白與 蛋白酪胺酸磷酸酶。該等顯著抑制蛋白的例子如Gupta et al·，J. Exp Med., 186:473-478, 1997 ； Maegawa et al., j. Biol. Chem 274:30236-30243， 1999; Woodford-Thomas et al.， J. Cell Biol. 117:401-414, 1992 所述。 曙光激酶抑制劑（Aurora kinase inhibitors) 曙光激酶已經證明為一新家族的蛋白激酶，可調節有絲分裂紡錘 體的結構與功能。曙光激酶之一標靶包括有絲分裂驅動蛋白。因此， 根據本發明之方法、組合物或套組，曙光激酶抑制劑可與降低蛋白路 胺酸磷酸酶生物活性的化合物併用。 有三種曙光激酶：曙光-A、曙光-B與曙光-C。曙光-A包括：AIRK1、Genetics 135: 35-44, 1993; Huyett et al., J. Cell Sci. 111: 295-301, 1998; Miller et al., Mol. Biol. Cell 9: 2051-2068, 1998; Roof et al., J. Cell Biol. 118: 95-108, 1992; Sanders et al., J. Cell Biol. 137: 417-431, 1997; Sanders et al., Mol. Biol. Cell 8: 1025-0133, 1997; Sanders et al., J. Cell Biol. 128: 617-624, 1995; Sanders & Hoyt, Cell 70: 451-458, 1992; Sharp et al., J. Cell Biol. 144: 125-138, 1999; Straight et al., J. Cell Biol. 143: 687-694, 1998; Whitehead & Rattner, J. Cell Sci. 111: 2551-2561, 1998; Wilson etal., J. Cell Sci. 110: 451-464, 1997). The biological activities of mitotic kinesin include: its ability to affect the hydrolysis of adenosine triphosphate (ATP); microtubule binding; gliding and polymerization / depolymerization (in microtubule dynamics) dynamics); other proteins that bind to the spindle; proteins that are involved in cell-cycle control; serve as a substrate for other enzymes, such as kinases or proteases; and Specific kinesin cell activity (specifickinesia cel Id 1084-6646-PF; Chiumeow 16 200526777 Spindle pole separation. Methods for analyzing the biological activity of mitogen kinesin are conventional techniques. For example, the analysis of motility Examples of methods are described in Hall, etal ·, 1996, Biophys · J., 71: 3467-3476; Turner et al., 1996, Anal. Biochem. 242: 20-25; Gittes et al., 1996, Biophys. J. 70: 418-429; Shirakawa etal., 1995, J. Exp. Biol. 198: 1809-1815; Winkelmannetal., 1 995, Biophys. J. 68: 2444 -2453; and Winkelmann et al., 1995, Biophys. J. 68: 72S. The method used to determine ATPase hydrolysis activity in conventional techniques can also be used. United States of America applied on March 18, 1999 Application Serial No. (US · Application Ser · No ·) 09/314, 464 describes these analyses and is incorporated herein by reference in its entirety. Other methods can also be used. For example, the phosphate released from kinesin can be quantified (P0. In one embodiment, the analysis of adenosine triphosphate hydrolysis activity uses 0.3 mole (M) perchloric acid (PCA)) and malachite green reagent (8.27 mmol). (MM) sodium molybdate IKsodium molybdate II), 0.33 mmol of malachite green oxalate, and 0.8 mmol of Triton X-100). In this analysis, 10 microliters (#L) of the reaction was cooled in 90 microliters of 0.3 moles of cold peroxyacid. I use phosphate standards, so the data can be converted to nanomolar (nM) released inorganic phosphate. When all reactions and standards are cooled in perchloric acid, 100 microliters of malachite green reagent is added to, for example, a microtiter plate well. The mixture was allowed to react for 10-15 minutes, and then the disc was read at 650 nanometer (nm) absorbance. If salt-filling standards are used, absorption readings can be converted to nanomolar (nM) phosphate (Pi) and plotted against time. In addition, tribasic adenosine spinal enzyme (ATPase) analysis in the conventional technology includes luciferase analysis (luc if erase assay) 0 kinesin motor domains (kinesin motor domains) triphosphate adenosidase activity is also 1084 ~ 6646-PF; Chiumeow 17 200526777 can be used to monitor the effects of modulating agents. One example is the analysis of kinesin adenosine triphosphate in the absence of microtubules. In another example, adenosine triphosphate was analyzed in the presence of microtubules. Different forms of modulators can be detected in the above analysis. In one embodiment, the effect of the modulator is independent of the concentration of microtubules and adenosine triphosphate (ATP). In another embodiment, the effect of the formulation on kinesin ATPase decreases with increasing concentrations of triacid ridges, microtubules, or both. In another embodiment, the effect of the modulator increases with increasing concentrations of adenosine triphosphate, microtubules, or both. Agents that reduce the biological activity of mitotic kinesin in the Lixi / Test, (// 7 F / iro) test can then be screened by the Liye Test (hra). Methods for in vivo screening include cell cycle distribution, cell viability analysis, or mitotic spindle presence, morphology, activity, distribution, or content analysis. For example, a method for monitoring the cell cycle distribution of a cell population using flow cytometry is known to those skilled in the art. This method is used to determine cell viability (for example, see US Patent No. 6, 617, 115). Mitotic kinesin inhibitors Mitotic kinesin inhibitors include: chlorpromazine, monasterol, terpendole E, HR22C16, and SB715992. Other mitogen kinesin inhibitors are compounds described below: Hopkins et al., Biochemistry 39: 2805, 2000, Hotha et al., AngewChem. Inst. Ed. 42: 2379, 2003, Patent Cooperation Treaty Publication No. ( PCT Publication Nos.) WO01 / 98278, W002 / 057244, W002 / 079169, W002 / 057244, W002 / 056880, W003 / 050122, W003 / 050064, W003 / 049679, W003 / 049678, W003 / 049527, W003 / 079973, and W003 / 039460, and U.S. Patent Application Publication Nos. 2002/0165240, 2003/0008888, 2003/0127621, and 10 84-6646-PF; Chiumeow 18 200526777 2002/0143026; and U.S. patents Case Nos. 6, 437, 115, 6, 545, 004, 6, 562, 831, 6, 569, 853 and 6, 630, 479, and the analogs of gasprazine are described in US Patent Application (US Patent Application No.) 10 / 617,424 (for an example, see Equation ⑴). Protein tyrosine phosphatases Protein tyrosine phosphatases include: PRL family (Regenerating Liver Phosphatase-1, Regenerating Liver Phosphatase-1, Regenerating Liver Phosphatase-2 and Regenerating Liver Phosphatase) Enzyme-3), protein tyrosine phosphatase 1B (PTP1B), Src homophosphatase-1 (SHP-1), Src homophosphatase-2, MAPK phosphatase-1, MAPK phosphatase-2, cells Division cycle 14 (CCDC14), cell division cycle 25A (CDC25A), cell division cycle 25B (CDC25B), cell division cycle 25C (CDC25C), protein tyrosine phosphatase (PTP), and protein tyrosine phosphatase-BL (PTP- BL). The biological activity of protein tyrosine phosphatase includes dephosphorylation of tyrosine residues on the substrate. Gene Bank Accession Nos., Which are representative of the amino acid filling enzymes, are listed in Table 2. Table 2 Human protein tyrosine phosphatase 1 Protein name GeneBank Accession No. Regenerating liver phosphatase-1 (PRL-1) AJ420505, BI222469, U48296 Regenerating liver phosphatase-2 AF208850, BI552091, L48723 Phosphatase-3 of regenerating liver AF041434, BC003105 protein tyrosine phosphatase ΙΒ (ΡΤΡΙΒ) AU117677, M33689 Src homophosphatase-1 (SHP-1) BC002523, BG754792, M77273, BM742181, AF178946 Src homophosphatase -2 AU123593, BF515187, BX537632, D13540 MAPK phosphatase-l (MKP-l) U01669, X68277 MAPK Leucinase-2 BC014565, U21108, U48807, AL137704 Cell division cycle 14ACCDC14A) AF000367, AF064102, AF064103 Cell division cycle 14B AF023158 , AF064104 cell division cycle 25A M81933 cell division cycle 25B M81934, Z68092, AF036233 cell division cycle 25C M34065, Z29077, AJ304504, M34065 protein tyrosine phosphatase α (PTPalpha) M36033 protein tyrosine androsinase-BL D21210, D21209 , D21211, U12128 Protein tyrosine phosphatase 1084-6646-PF; Chiumeow 19 200526777 inhibitors Egg Inhibitors of white tyrosine phosphatase include: pentamidine, levamisole '(ketoconazole), and bisperoxovanadium compounds (eg, Scrivens et al., Mol. Cancer Ther 2: 1053-1059, 2003 and compounds described in U.S. Patent No. 6,642,221), vanadate salts and complexes (e.g., sodium orthovanadate), dephosphatin, dnacinAl, dnacinA2, STI-571, suramin, gallium nitrate, sodium stibogluconate, meglumine antimonite, 2- (2-thiol Ethanol) -3 -methyl-1,4-naphthoquinone (2- (2-mercaptoethanol) -3-methyl-1,4-naphthoquinone), 2, 5-bis (4-fluorenylphenyl) furan- Bis-0-methylamine oxime (2, 5-bis (4-amidinophenyl) furan-bis-〇-methylamidoxime) (DB289 (Immtech)), US Patent No. 5,843,980 The disclosed 2,5-bis (4-amidinophenyl) furan (2,5-bis (4-amidinophenyl) furan) (DB75, Immtech), and Pestell et al., Oncoge ne 19: 6607-6612, 2000, Lyon etal ·, Nat · Rev · Drug Discov 1: 961 -976, 2002, Ducruetet al ·, Bioorg · Med · Chem · 8: 1451-1466, 2000, US Patent Application Publication As described in US Patent Application Publication Nos. 2003/0114703, 2003/0144338 and 2003/0161893, as well as PCT Patent Publication Nos. W099 / 46237, W003 / 06788 and W003 / 070158 compound of. Other analogs are in any U.S. Patent No. 5,428,051; 5,521,189; 5,602,172; 5,643,935; 5,723,495; 5,843,980; 6,008,247; 6,025,398; 6,172 , 104; 6, 214, 883; 6, 326, 395, and within the range of molecular formulas provided by U.S. Patent Application Publication Nos. US 2001/0044468 and US 2002/0019437, and the analogs of pentamidine are described in the U.S. patent application No. 1084-6646-PF; Chiumeow 20 200526777 10/617, 424 (for an example, see formula (π)). Other protein tyrosine phosphatase inhibitors can be used, for example, Lazo et al. (〇ncoi_Res. 13: 347-352, 2003), PCT Publication Nos. WO97 / 40379, W003 / 003001 and W003 / 035621, and the methods described in U.S. Patent Nos. 5,443,962 and 5,958,719. Other biological activity inhibitors In addition to using mitotic kinesins and protein tyrosine phosphatase compounds to reduce biological activity, other mitotic kinesins and protein tyrosine phosphatase biological activities can also be used Inhibitor. These inhibitors include: compounds that reduce the target protein or ribonucleic acid content (eg, antisense compounds, double-stranded RNA (dsRNA), ribozymes), and to bind similar (eg: Compounds that encode the same significant negative proteins or polynucleotides and compete with endogenous mitotic kinesins or protein tyrosine phosphatases. Antisense Compounds The use of antisense compounds directed to ribonucleic acid, which encodes the crude protein, reduces the biological activity of mitotic kinesins and / or protein tyrosine phosphatases. Mitotic kinesin antisense compounds suitable for this purpose are well known (see, for example, U.S. Patent No. 6, 472, 52 and W003 / 030832 # & Maneyetal., J. Cell Biol., 1998, 142 ... 787-801), and antisense compounds that inhibit protein tyrosine phosphatase are also well known (for examples, see U.S. Patent Publication No. 2003/0083285 and Weil et al., Biotechniques 33: 1244, 2002). Other antisense compounds used to reduce mitotic kinesin can be identified using standard techniques. For example, RNA secondary structure folding program (eg, MFOLD) can be used to predict target mitotic kinesin or protein tyrosine phosphatase 1084- 6646-PF; Chiumeow 21 200526777 mRNA) (M. Zuker, D_H_ Mathews & D. Turner, Algorithms and Thermodynamics for RNA Secondary Structure Prediction: A Practical Guide. In: RNA Biochemistry and Biotechnology, J. Barciszewski & BFC Clark, eds., NATO AS I Series, Kluwer Academic Publishers, (1999)). Use the window of 200 test bases (where residues can find complementary bases to form base-pair bonds) to predict a suboptimal fold that has a predicted most stable fold of the messenger RNA 5% Sub-optimal folds with a free energy value within 5% of the predicted most stable fold of the mRNA are predicted using a window of 200 bases within which a residue can find a complimentary base to form a base pair bond ) 〇 Summing open regions that do not form a base pair with each suboptimal fold, and it is generally believed that those predicted to be open regions are more likely to bind to antisense nucleobase oligomers. Other antisense design methods are described in the following examples: U.S. Patent No. 6,472,521, Antisense Nucleic Acid Drug Dev. 1997 7: 439-444, Nucleic Acids Research 28: 2597-2604, 2000, and Nucleic Acids Research 31: 4989-4994, 2003. RNA interference Reduces the biological activity of mitotic kinesin and / or protein glycine photonase through the use of RNA interference. RNA interference uses, for example, directed to Double-stranded nucleic acid (dsRNA) or small interfering RNA (siRNA) of mitotic kinesin or protein tyrosinate enzyme (for examples, see Miyamoto et al., Prog. Cell Cycle Res. 5: 349-360, 2003; U.S. Patent Application Publication No. 2003/0157030). Methods for designing such RNA interference are known techniques. For example, 01 igoengine (Seattle, WA) provides software for designing interfering RNA. 1084-6646-PF; Chiumeow 22 200526777 Dominant negative proteins Those skilled in the art know how to prepare significantly inhibited mitotic kinesins and protein tyrosine phosphatases. Examples of such significant inhibitory proteins are Gupta et al., J. Exp Med., 186: 473-478, 1997; Maegawa et al., J. Biol. Chem 274: 30236-30243, 1999; Woodford-Thomas et al. ., J. Cell Biol. 117: 401-414, 1992. Aurora kinase inhibitors Aurora kinase inhibitors have been shown to be a new family of protein kinases that regulate the structure and function of mitotic spindles. One of the targets of Dawning kinases includes mitotic kinesins. Therefore, according to the method, composition or kit of the present invention, a dawning kinase inhibitor can be used in combination with a compound that reduces the biological activity of a protein glutamate phosphatase. There are three Dawning kinases: Dawning-A, Dawning-B and Dawning-C. Dawning-A includes: AIRK1,

DmAurora、HsAurora-2、HsAIK、HsSTK15、CeAIR-1、MmARKl、MmAYK卜 MmlAK1 與 XIEg2。曙光-B 包括：AIRK-2、DmIAL-1、HsAurora-l、HsAIK2、 HsAIM-1、HsSTK12、CeAIR-2、MmARK2 與 XAIRK2。曙光-C 包括： HsAIK3(Adams，et al.，Trends Cell Biol· 11:49-54，2001)。 曙光激酶抑制劑包括：VX-528與ZM447439 ;其他的曙光激酶抑制 劑描述於例如美國專利申請公開案號2003/0105090與美國專利案號 6, 610, 677，6, 593, 357 與 6, 528, 509 當中。 法尼基轉移酶抑制劑（Farnesyltransferase inhibitors) 法尼基轉移酶抑制劑改變再生肝之填酸酶（PRL phosphatases)的 生物活性，並因此可與本發明之方法、組合物或套組中降低有絲分裂 驅動蛋白活性的化合物併用。法尼基轉移酶抑制劑包括：argiabin， lonafarnib，BAY-43-9006，tipifarnib，芥子醇（perillyl alc〇h〇l)， FTI-277 與 BMS-214662,以及 Kohl，Ann· NY Acad· Sci. 886:91-102， 1999，美國專利申請公開案號 2003/0199544、2003/0199542、 1084-6646-PF;Chiumeow 23 200526777 2003/0087940、2002/0086884、2002/0049327 與 2002/0019527，美國 專利案號6,586,461與6,500,841，以及W003/004489等所描述的化 合物。 治療法（Therapy) 本發明之化合物可用以治療癌以及其他具有過度增生之細胞 (hyperproliferative cells)的疾病。治療可單獨施行或與其他療法 (例如：手術、放射治療、化學療法、免疫療法、抗血管新生療法 (anti-angiogenesis therapy)或基因療法（gene therapy))併用。另 外，具有較高之發展腫瘤或其他增生性疾病風險的病人（例如：在遺傳 上具有患病傾向或之前曾患該病的人）可接受預防性的治療，以抑制或 延遲過度增生。組合治療（combination therapy)的持續時間當根據所 治療之疾病或失調的形式、病人的年紀與狀況、病人的疾病期與疾病 形式以及病人對於治療的反應而定。治療可斷斷續續地進行，其中包 含休息期，如此病人的身體才有機會從任何未預料的副作用中回復。 本發明之方法、組合物與套組如期望地比其他方法、組合物與套組更 有效。“更有效”係指一種方法、組合物或套組呈現較高的效力 (efficacy)、具較低毒性、較安全，更方便，具較佳的耐受性（better tolerated)或價格較便宜，或比其他方法、組合物或套組提供更令人 滿意的治療。 癌不受限地包括：白血病（leukemias)(例如：急性白血病（acute leukemia)、急性淋巴細胞性白血病（acute lymphocytic leukemia)、 急性骨髓性白血病（acute myelocytic leukemia)、急性骨趙細胞白企 病（acute myeloblastic leukemia)、急性前骨髓細胞白血病（acute promyelocytic leukemia)、急性骨髓單核細胞性白血病（acute myelomonocytic leukemia)、急性單核球白血病（acute monocytic leukemia)、急性紅白血病（acute erythroleukemia)、慢性白血病 1084-6646-PF；Chiumeow 24 200526777 (chronic leukemia)、慢性骨髓性白血病（chronic myelocytic leukemia)、慢性淋巴細胞性白血病（chronic lymphocytic leukemia))、真性多紅血球症（polycythemia vera)、淋巴瘤 (lymphoma)(霍奇金氏病（Hodgkin，s disease)、非霍奇金氏病 (non-Hodgkin ’ s disease)) 、 Waldenstrom 氏巨球蛋白血症 (Waldenstrom’ s macroglobulinemia)、重鏈病（heavy chain disease) 以及實性瘤（solid tumors)，例如：肉瘤（sarcomas)與癌 (carcinomas)(例如：纖維肉瘤（fibrosarcoma)、黏液肉瘤 (myxosarcoma)、月旨肉瘤（1 iposarcoma)、軟骨肉瘤（chondrosarcoma)、 骨原性肉瘤（osteogenic sarcoma)、脊索瘤（chordoma)、血管肉瘤 (angiosarcoma)、内皮肉瘤（endotheliosarcoma)、淋巴管肉瘤 (1 ymphang i osar coma) 、 淋 巴管内 皮肉瘤 (lymphangioendotheliosarcoma)、滑液膜瘤（synovioma)、中皮瘤 (mesothelioma)、骨幹骨肉瘤（Ewing’ s tumor)、平滑肌肉瘤 (leiomyosarcoma)、橫紋肌肉瘤（rhabdomyosarcoma)、結腸癌（colon carcinoma)、胰腺癌（pancreatic cancer)、乳癌（breast cancer)、 卵巢癌（ovarian cancer)、前列腺癌（prostate cancer)、鱗狀上皮細 胞癌（squamous cell carcinoma)、基底細胞癌（basal cell carcinoma)、腺癌（adenocarcinoma)、汗腺癌（sweat gland carcinoma)、皮脂腺癌（sebaceous gland carcinoma)、乳突癌 (papillary carcinoma)、乳突腺癌（papillary adenocarcinomas)、 囊腺癌（cystadenocarcinoma)、髓質癌（medullary carcinoma)、支氣 管上皮癌（bronchogenic carcinoma)、腎細胞癌（renal cell carcinoma)、肝癌（hepatoma)、膽管癌（bile duct carcinoma)、絨毛 膜癌（choriocarcinoma)、精原細胞瘤（seminoma)、胚胎性癌 (embryonal carcinoma)、威耳姆氏腫瘤（Wilm’ s tum、Qr)、子宮頸癌 1084-6646-PF;Chiumeow 25 200526777 (cervical cancer)、子宮癌（uterine cancer)、睪丸癌（testicular cancer)、肺癌（lung carcinoma)、小細胞肺癌（small cell lung carcinoma)、膀胱癌（bladder carcinoma)、上皮細胞癌（epithelial carcinoma)、神經膠質瘤（glioma)、星狀細胞瘤（astrocytoma)、神經 管胚細胞瘤（medulloblastoma)、顱咽管瘤（craniopharyngioma)、室 管膜瘤（ependymoma)、松果腺瘤（pinealoma)、血管母細胞瘤 (hemangioblastoma)、聽覺神經瘤（acoustic neuroma)、寡樹突細胞 瘤（oligodendroglioma)、神經鞘瘤（schwannoma)、腦脊髓膜瘤 (meningioma)、黑色素瘤（melanoma)、神經胚細胞瘤（neuroblastoma) 以及視網膜胚細胞瘤（retinoblastoma))。 其他可利用本發明之組合與方法來治療的增生性疾病包括淋巴增 生疾病（lymphoproliferative disorders)與牛皮癣（psoriasis)。 “淋巴增生疾病”係指淋巴系統之細胞（例如：T細胞與B細胞）不正 常增生的疾病。 此外，治療可包括其他抗增生劑與本發明之組合的併用。例如， 當治療癌症時，該組合可與抗癌劑併用，如表3所列的製劑。 10 84-6646-PF；Chiumeow 26 200526777 表3 烷化劑 (Alkylating agents) 白消安（Busulfan) 丙卡巴肼(procarbazine) 達卡巴嗪(dacarbazine) 六甲蜜胺(altretamine) 異環磷酿胺（ifosfamide) 雌莫司》Y(estramustine phosphate) 六甲密胺(hexamethylmelamine)氮芬(mechlorethamine) 塞替派(th i 〇 t epa ) 鏈佐星(s t r ep t ozoc i η ) 達卡巴嗪(dacarbazine) 替莫σ坐胺(temozolomide) 洛莫司汀（lomustine) 司莫司汀(Semustine) 環磷酸胺(cy c 1 ophospham i de )順翻（c i sp 1 at i n) 苯丁 酸氮芬(chlorambuci 1) 銘劑 (Platinum agents) 螺麵（sp i r op 1 a t i n) 洛翻（1 obap 1 a t i n ) ( Ae t erna) 四氯環己始（tetraplatin) 賽特鉑 奥馬翻（ormap 1 at i η) ( satrap 1 at i n) (Johnson Mat they) 異丙翻（iproplatin) BBR-3464(Hoffmann-La Roche) ZD-0473(AnorMED) SM-11355(Sumitomo) 奥沙利麵(oxaliplatin) AP-5280(Access) 卡麵（carbop 1 at i n) 抗代謝物質 (Antimetabolites) 氮胞（azacytidine) 三甲曲沙（trimetrexate) 氮尿苔(F1 oxur idine) 脫氧助間型霉素(deoxy cof ormyc i n ) 2 -氯脫氧腺甘酸 喷司他丁(pentostatin) (2-ch 1 orodeoxy adenos i ne ) 經基尿素(hydroxyurea) 6 -疏嘌吟（6 -mer cap t opur i ne )地西他濱（dec i t ab i ne ) ( SuperGen ) 6-硫氫基鳥糞嘌呤 克勞飛拉賓 (6 - thioguanine) (音譯 clofarabine)(Bioenvision) 阿糖胞苷(cy tarab i ne ) 伊洛福芬（i ro f u 1 ven) (MG I Pharma ) 2-氟脫氧胞核苔 DMDC(Hoffmann-La Roche) (2-fluorodeoxy cytidine) (ethynylcytidine)CTaiho) 曱氨蝶呤(methotrexate) 健擇(gemcitabine) 穆戴克斯(tomudex) 截瘤達(capecitabine) 氟達拉濱（f 1 udarab i ne) 雷替曲塞(raltitrexed) 1084-6646-PF； Chiumeow 27 200526777 表3(續) 拓樸異構酶抑制齊 (Topoisomerase inhibitors) i 安η丫咬（amsacrine) exatecan mesylate(Daiichi) 表阿霉素(ep i rubi c i n) quinamed(ChemGenex) 依託泊 ^(etoposide) gi matecan (S i gma-Tau) 替尼泊普(ten i pos i de)或米托蒽醌(m i toxantrone) d i f 1 omotecan (Beaufour-1 psen) 7-乙基-10-羥基-喜樹鹼 TAS-103(Taiho) (7 - ethyl-10-hydroxy-camptothecin) 依沙產星（elsamitrucin)(Spectrum) dexrazoxanet(TopoTarget) J-107088(Merck & Co) pixantrone(Novuspharma) BNP-1350(BioNumerik) Rebeccamycin 相似物(Exelixis) CKD-602(Chong Kun Dang) BBR-3576(Novuspharma) Kff-2170(Kyowa Hakko) 魯比替康(rubitecan)(SuperGen) 經基喜樹驗 伊立替康（irinotecan)(CPT-ll) (hydroxycamptothecin)(SN-38) 拓樸替康(topotecan) 抗腫瘤抗生素 (Antitumor antibiotics) 放線菌素(dac t i nomy c i n ) azonaf ide (放線菌素 D(actinomycin D)) anthrapyrazole valrubicin 〇比洛蒽醌(oxant razo 1 e ) 柔紅黴素(daunorub i c i n) (daunomy c i n) 洛索葱醌（1 osoxan t r one) therarubicin bleomycinic acid 伊達比星（idarubicin) MEN-10755 (Menar ini) rubidazone GPX-100(Gem Pharmaceuticals) 普卡霉素(plicamycin) 表阿霉素(epirubicin) 泊非霉素(porf iromycin) 米妥蒽醌(mitoxantrone) 米妥 Μ醌(mi toxantrone) (novantrone) 氨萘非特(amonaf ide) 抗有絲分裂劑 (Antimitotic agents) 秋水仙素(colchicine) E7010 (Abbott) 長春花驗(vinblastine) PG~TXL(Cell Therapeutics) 長春地辛（vindesine) IDN 5109(Bayer) dolastatin 10(NCI) A 105972(Abbott) 利索新（(rhizoxin)(Fujisawa) A 204197(Abbott) mivobulin(Warner-Lambert) LU 223651(BASF) 西馬多丁(cemadotin)(BASF) D 24851 (ASTAMedica) RPR 109881A(Aventis) ER-86526(Eisai) TXD 258(Aventis) combretastatin A4(BMS) 埃博霉素 B(epothilone B)(Novartis) isohomohalichondrin-B(PharmaMar) Γ 900607(Tularik) ZD 6126(AstraZeneca) Γ 138067(Tularik) AZ10992(Asahi) 念珠藻環肽52(cryptophycin 52)(Eli Lilly) IDN-5109(Indena) 長春氟寧(vinf lunine)(Fabre) AVLB(Prescient NeuroPharma) auristatin PE(Teikoku Hormone) 氮雜埃坡霉素 B(azaepothi lone B)(BMS) BMS 247550(BMS) BNP-7787(BioNumerik) BMS 184476(BMS) CA-4 prodrug(OXiGENE) BMS 188797(BMS) dolastatin-lO(NIH) taxoprexin(Protarga) CA~4(0XiGENE) SB 408075(GlaxoSmithKline) 多婦紫杉醇(docetaxel) 長春花(vinorelbine) 長春新鹼(vincristine) 太平洋紫杉醇(pac 1 i t axe 1) 芳香酶抑制劑 (Aromatase 1 inhibitors) 1 氦魯米特(aminoglutethimide) YM-511 (Yamanouchi) 阿他美坦（atamestane)(BioMedicines) 福美斯坦（formestane) 來曲唑（1 etrozo 1 e) 依西美坦（exemestane) 阿那曲嗤（anas t razo 1 e) 1084-6646-PF;Chiumeow 28 200526777 表3(續） 胸苷酸合酶抑制劑 (Thymidylate synthase inhibitors) 培美曲嗤(pemetrexed)(Eli Lilly) 謹拉曲特(nolatrexed)(Eximias) 3 ZD-9331 (BTG) CoFactor™(BioKeys) 去氧核醣核酸拮抗劑 (DNA antagonists) trabected i n(PharmaMar) edotreot i de(Novart i s) glufosfamide(Baxter International)馬構醯胺（mafosfamide) 白蛋白（albumin)+ (Baxter International) 32P(Isotope Solutions) apaziquone(Spectrum Pharmaceutica1s) thymectacin(NewBiotics) 06 苯甲基烏嘌呤 (06 benzyl guanine)(Paligent) 法尼基轉移酶抑制劑 (Farnesy1transferase inhibitors) arglabin(NuOncology Labs) tipifarnib(Johnson & Johnson) 1 onaf arni b(Scheri ng-Plough) 芥子醇 BAY-43-9006(Bayer) (perillyl alcohol)(DOR BioPharma) 幫浦抑制劑 (Pump inhibitors) CBT-1(CBA Pharma) zosuquidar trihydrochloride tariquidar(Xenova) (Eli Lilly) MS-209(Schering AG) biricodar dicitrate(Vertex) 組織蛋白乙醯轉移酶抑 制 劑 （Histone acety1transferase inhibitors) tacedinaline(Pfizer) p i va1oy1oxymethy1 butyrate(Titan) SAHA(Aton Pharma) 縮肽(depsipeptide)(Fujisawa) MS-275(Schering AG) 金屬蛋白酶抑制劑 (Metalloproteinase inhibitors) 癌立消（Neovastat) CMT-3(Col laGenex) (Aeterna Laboratories) BMS-275291(Cel1tech) 馬立馬司他(marimastat) (British Biotech) 核糖核甘還原酶抑制劑 (Ribonucleoside reductase inhibitors) gallium maltolate(Titan) tezacitabine(Aventis) triapine(Vion) didox(Molecules for Health) 腫瘤壞死因子α激動劑 與拮抗劑（TNF alpha agon i sts/antagoni sts) 維如利金(virulizin) revimid(Celgene) (Lorus Therapeutics) CDC-394(Celgene) 内皮素A受體拮抗劑 (Endothelin A receptor antagonist) atrasentan(Abbott) YM-598(Yamanouchi) ZD-4054(AstraZeneca) 網膜酸受體激動劑 (Retinoic acid receptor agonists) 芬維A胺(fenretinide) 9-順式維甲酸 (Johnson & Johnson) (alitretinoin)(Ligand) LGD-1550(Ligand) 免疫調節劑 (Immuno-moda1ators) 干擾素（interferon) dexosome 治療(Anosys) Dncophage(Ant i gen i cs) pentrix SMK(Progenics) (Australian Cancer Technology) 陳癌疫苗 ISF-154(Tragen) 〔adenocarcinoma vaccine)(Biomira)癌疫苗（cancer vaccine)(Intercell) ]TP-37(AVI BioPharma) norelin(Biostar) IRX-2(Immun〇-Rx) BLP-25(Biomira) PEP-005(Peplin Biotech) MGV(Progenics) Synchrovax 疫苗（CTL Iimnuno) E-alethine(Dovetail) 黑色素瘤（melanoma)疫苗（CTL Irnmuno)慢性淋巴細:胞白血病治療 p21 RAS 疫苗（GemVax) (CLL therapy) (Vasogen) 1084-664β-PF/Chiumeow 29 200526777 表3(續) 荷爾蒙與抗荷爾蒙劑 (Hormonal and antihormonal agents) 雌性素（estrogens) 地塞米松(dexamethasone) .接合的雌性素 潑尼松(prednisone) (conjugated estrogens) 甲潑尼龍(methylprednisolone) 乙烯雌二醇(ethinyl estradiol)強體松(prednisolone) chlortrianisen 氨魯米特(aminoglutethimide) i denes t ro 1 亮丙瑞林（1 eupr o 1 i de) 己酸經孕酮 奥曲肽(oc t r eo t i de) (hydroxyprogesterone caproate)米托坦(mitotane) 甲經孕酮（medroxyprogesterone) P-04(Novogen) 睪固酮（testosterone) 2-甲氧雄二醇 丙酸睪固酮 （2-methoxyestradiol) (EntreMed) (testosterone propionate) arzoxifene(Eli Lilly) 氟經曱基睪酮（f 1 uoxymes terone)三苯氧胺(tamoxi f en) 甲基睪固 WKmethyltestosterone) toremofine 己婦雌紛(diethylstilbestrol)戈舍瑞林(goserelin) 甲地孕酮(megestrol) leuporelin 白卡羅他邁(bicalutamide) 白卡羅他邁(bicalutamide) 苯基異丁酰胺（flutamide) 尼魯米特(ni lutamide) 光動力學劑 (Photodynamic agents) talaporfin(Light Sciences) Pd-bacteriopheophorbide(Yeda) Thera 1 ux(Theratechno 1 ogies) 德Π卜啉f|(lutetium texaphyrin) 莫特沙芬礼 (Pharmacyclics) (motexafin gadolinium) 金絲桃素(hypericin) (Pharmacyclics) 激酶抑制劑 (Kinase Inhibitors) { / 9 λ { 甲磺酸伊馬替尼 EKB -569(ffyeth) (imatinib)(Novartis) kahalide F(PharmaMar) 來氟米特 CEP-701 (Cephalon) (1 ef lunomide) (Sugen/Pharmacia) CEP-751 (Cepha 1 on) ZD183 9(AstraZeneca) MLN518(Millenium) 埃羅替尼 PKC412(Novartis) (erlotinib)(Oncogene Science) Phenoxodiol(Novogen) canertinib(Pfizer) C225(ImClone) squalamine(Genaera) rhu-Mab(Genentech) SU5416(Pharmacia) MDX-H210(Medarex) SU6668(Pharmacia) 2C4(Genentech) ZD A 190( AstraZeneca ) MDX-447(Medarex) ZD6474(AstraZeneca) ABX-EGF(Abgenix) ^atalanib(Novartis) IMC-lCll(ImClone) PKI166(Novartis) Tyrphostins jW20 16 (G1 axoSmi thK line) 吉非替尼（Gef itinib)(Iressa) 5KB-509(Wyeth) 曲妥珠單抗 〔trastuzumab)(Genentech) 1084-6646-PF;Chiumeow 30 200526777 表3(續） 各種製劑 SR-27897 (膽囊收縮素 A(CCK A)抑制劑，Sanofi-Synthelabo) tocladesine (環腺苷酸(cyclic AMP)激動劑，Ribapharm) alvocidib(細胞週期蛋白依賴性激酶抑制 (CDK inhibitor), Aventis) CV-247(環氧合酶-2(C0X-2)抑制劑，Ivy Medical) P54(環氧合酶-2抑制劑，Phytopharm) CapCell™(細胞色素P450刺激劑 (CYP450 stimulant), Bavarian Nordic) GCS-100(gal3 拮抗劑，GlycoGenesys) G17DT 免疫原（immunogen) (胃泌素(gastrin)抑制劑，Aphton) efaproxiral (氧器（oxygenator), Alios Therapeutics) PI-88(乙醯肝素酶(heparanase)抑制劑，Progen) tesmilifene(組織胺拮抗劑，YM BioSciences) 組織胺(histamine)(組織胺H2受體激動劑 (histamine H2 receptor agonist), Maxim) 噻味咲啉(tiazofurin) (單磷酸次黃嘌呤脫氫酶(IMPDH)抑制劑，Ribapharm) cilengitide(整合素（integrin)拮抗劑，Merck KGaA) SR-31747 (介白素-1 (IL-1)拮抗劑，Sano f i -Synthe 1 abo) CCI_779(哺乳動物雷帕霉素靶位激酶 (mTOR kinase)抑制劑，Wyeth) exisulind (雄酸二g旨酶5型(PDE V)抑制劑，Cell Pathways) CP-461(罐酸二酯酶5型抑制劑，Cell Pathways) AG-2037C基因抗逆轉錄病毒耐藥性測試 (GART)抑制劑，Pfizer) ΪΧ - UK1 (纖溶酶原啟動物抑制劑 (plasminogen activator)抑制劑，Wi lex) PBI-1402(中性粒細胞刺激劑 (PMN stimulant), ProMetic LifeSciences) 3〇rtezomib 、 (蛋白解艘(proteasome)抑制劑，Mi 1 lennium) SRL_172(T 細胞刺激劑，SR Pharma) LK-286(麩胺硫S轉移酶 (glutathione S transferase)抑制劑，Tel ik) PT -100(生長因子激動劑 (growth factor agonist), Point Therapeutics) 米口杂妥林(m i dostaur i n) (蛋白激酶 C 抑制劑(PKC inhibitor), Novartis) 珊蝴蟲素-1 (bryostatin-1) (蛋白激酶C刺激劑，GPC Biotech) CDA-II (凋亡促進劑（apoptosis promoter), Everlife) SDX_101(凋亡促進劑，Salmedix) 美羅華（rituximab)(CD20 抗體，Genentech_ ceflatonin(凋亡促進劑，ChemGenex) BCX-1777(嘌呤核甘磷酸化酶(PNP)抑制劑，BioCryst) ranpirnase (核糖核酸酶(ribonuclease)刺激劑，Alfacell) ga 1 arubi ciη(核醣核酸合成抑制劑，Dong-A) 替拉扎明（tirapazamine) (還原劑(reducing agent), SRI International) 乙醯半胱胺酸(N-acety 1 cyste i ne)(還原劑，Zambon) R-flurbiprofen (核因數(B(NF-kappaB)抑制劑，Encore) 3CPA(核因數(B 抑制劑，Active Biotech) seocalcitol(維生素D受體激動劑，Leo) 131 -1 -TM-6 01 (去氧核酷核酸括抗劑，TransMo 1 ecu 1 ar ) 依氟烏氨酸(eflorni thine) (烏氨酸脫羧酶(ODC)抑制劑，ILEX Oncology) minodronic acid (破骨細胞(osteoc 1 ast)抑制劑，Yamanouch i) indisulam(p53 刺激劑，Eisai) apl idine(PPT 抑制劑，PharmaMar) 吉妥單抗(gemtuzumab)(CD33 抗體，Wyeth Ayerst) PG2(造血作用增進劑 (hematopoiesis enhancer, Pharmagenesis) Immunol™(三氣生漱口水 (triclosan oral rinse), Endo) triacetyluridine (尿核苔前驅藥物(uridine prodrug), Weilstat) SN-4071 (肉瘤劑（sarcoma agent), Signature BioScience) TransMID-107™(免疫毒素（immunotoxin), KS Biomedix) PCK-3145(凋亡促進劑，Procyon) doranidazole(凋亡促進劑，Pola) CHS-828(細胞毒劑(cytotoxic agent), Leo) 反式網膜酸(trans-retinoic acid) (分化劑（differentiator), NIH) MX6(凋亡促進劑，MAXIA) apomine(凋亡促進劑，ILEX Oncology) urocidin(凋亡促進劑，Bioniche) Ro-3卜7453(凋亡促進劑，La Roche) brosta 11 i c i n (凋亡促進劑，Pharmac i a) 實施例 1084-6646-PF;Chiumeow 31 200526777 以下的實施例將說明本發明，然其並不以任何方式限定本發明。 氯普馬嗪（chlorpromazine)係一種有絲分裂驅動蛋白抑制劑（mitotic kinesin inhibitor) 利用無細胞運動分析（cell free motor assay)，吾人確定氣普馬 嗪係一種有絲分裂驅動蛋白抑制劑。該分析測量在驅動蛋白運動蛋白 (kinesin motor proteins)之微管活化的三填酸腺脊酶活化 (microtubule activated ATPase activity)期間所產生的有機磷酸鹽 (Pi)。根據廠商對於反應緩衝劑、三磷酸腺苷（ATP)與微管用量的使用 說明，利用 Kinesin ATPase End Point Biochem Kit(Cytoskeleton， catalog # BK053)分析重組HsEg5/KSP驅動蛋白運動蛋白活性 (recombinant HsEg5/KSP kinesin motor protein activity) 〇 每一 反應之HsEg5/KSP驅動蛋白的最佳量為0· 8微克（# g)，而該量也為治 療量。每一分析皆在透明之96孔的1/2面積盤（clear 96 well area 1/2 plate)(Corning Inc.，Costar and cat # 3697)中進行，其反應總量 為30微升1)，而該分析包括以下條件： 1. 只包含反應缓衝劑（buffer)與三磷酸腺苷的空白反應； 2. 陰性控制反應（negative control reactions)，包含： a.微管（microtubules)與三填酸腺脊（ATP)，而不包含驅動蛋白 (kinesin protein)，或' b·驅動蛋白HsEg5/KSP(kinesin HsEg5/KSP)與三碟酸腺：g：，而不 包含微管；以及 3. 實驗反應，其中包含三填酸腺脊、驅動蛋白（kinesin)與微管， 並且含有或不含最後指定之濃度的化合物。 在加入三磷酸腺苷之前，於室溫下預置該反應15分鐘。加入三磷 酸腺甘之後’在室溫下進行反應10分鐘’然後加入70微升的CytoPhos 試劑終止反應。在室溫下靜置最後10分鐘之後，以吸光度（absorbance) 1084-6646-PF;Chiumeow 32 200526777 «DmAurora, HsAurora-2, HsAIK, HsSTK15, CeAIR-1, MmARKl, MmAYK, MmlAK1 and XIEg2. Dawn-B includes: AIRK-2, DmIAL-1, HsAurora-1, HsAIK2, HsAIM-1, HsSTK12, CeAIR-2, MmARK2, and XAIRK2. Dawning-C includes: HsAIK3 (Adams, et al., Trends Cell Biol. 11: 49-54, 2001). Dawning kinase inhibitors include: VX-528 and ZM447439; other Dawning kinase inhibitors are described in, for example, U.S. Patent Application Publication No. 2003/0105090 and U.S. Patent Nos. 6,610,677, 6,593,357 and 6,528 , Among 509. Farnesyltransferase inhibitors Farnesyltransferase inhibitors change the biological activity of PRL phosphatases in regenerative liver, and therefore can reduce mitosis in the methods, compositions or kits of the present invention Kinesin compounds are used in combination. Farnesyl transferase inhibitors include: argiabin, lonafarnib, BAY-43-9006, tipifarnib, perillyl alcOHl, FTI-277 and BMS-214662, and Kohl, Ann · NY Acad · Sci. 886: 91-102, 1999, U.S. Patent Application Publication Nos. 2003/0199544, 2003/0199542, 1084-6646-PF; Chiumeow 23 200526777 2003/0087940, 2002/0086884, 2002/0049327 and 2002/0019527, U.S. Patent Cases Compounds described in Nos. 6,586,461 and 6,500,841, and W003 / 004489 and the like. Therapy The compounds of the present invention can be used to treat cancer and other diseases with hyperproliferative cells. Treatment can be performed alone or in combination with other therapies (eg surgery, radiation therapy, chemotherapy, immunotherapy, anti-angiogenesis therapy or gene therapy). In addition, patients with a higher risk of developing tumors or other proliferative diseases (for example, people who are genetically predisposed or have had the disease before) may receive prophylactic treatment to suppress or delay hyperplasia. The duration of combination therapy depends on the form of the disease or disorder being treated, the age and condition of the patient, the stage and form of the patient's disease, and the patient's response to the treatment. Treatment can be intermittent and includes a rest period so that the patient's body has the opportunity to recover from any unintended side effects. The methods, compositions and kits of the present invention are desirably more effective than other methods, compositions and kits. "More effective" means that a method, composition or kit exhibits higher efficacy, is less toxic, is safer, more convenient, is better tolerated, or is less expensive, Or provide a more satisfactory treatment than other methods, compositions, or sets. Cancers include, without limitation, leukemias (eg, acute leukemia, acute lymphocytic leukemia), acute myelocytic leukemia, and acute osteoclast leukemia ( acute myeloblastic leukemia), acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia, acute erythroleukemia, chronic leukemia 1084-6646-PF; Chiumeow 24 200526777 (chronic leukemia), chronic myelocytic leukemia, chronic lymphocytic leukemia), polycythemia vera, lymphoma (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease ) And solid tumors umors), for example: sarcomas and carcinomas (for example: fibrosarcoma, myxosarcoma, 1 iposarcoma, chondrosarcoma, osteogenic sarcoma ), Chordoma, angiosarcoma, endotheliosarcoma, lymphatic sarcoma (1 ymphang i osar coma), lymphatic endothelial sarcoma (lymphangioendotheliosarcoma), synovial tumor (synovioma), mesothelioma (mesothelioma), backbone osteosarcoma (Ewing's tumor), leiomyosarcoma, rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer cancer, prostate cancer, squamous cell carcinoma, basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma ), Papillary carcinoma, papillar carcinoma y adenocarcinomas), cystadenocarcinoma, medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, villus Membrane cancer (choriocarcinoma), seminoma, embryonic cancer (embryonal carcinoma), Wilm's tumor (Wilm's tum, Qr), cervical cancer 1084-6646-PF; Chiumeow 25 200526777 (cervical cancer, uterine cancer, testicular cancer, lung cancer, small cell lung cancer, bladder cancer, epithelial cancer, glial Glioma, astrocytoma, medulloblastoma, craniopharyngioma, epidymoma, pinealoma, hemangioblastoma (hemangioblastoma), acoustic neuroma, oligodendroglioma, schwannoma noma), meningioma, melanoma, neuroblastoma, and retinoblastoma). Other proliferative diseases that can be treated using the combinations and methods of the present invention include lymphoproliferative disorders and psoriasis. "Lymphoproliferative disease" refers to a disease in which the cells of the lymphatic system (such as T cells and B cells) do not proliferate. In addition, treatment may include the combined use of other antiproliferative agents in combination with the present invention. For example, when treating cancer, the combination can be used in combination with anticancer agents, such as the formulations listed in Table 3. 10 84-6646-PF; Chiumeow 26 200526777 Table 3 Alkylating agents Busulfan procarbazine dacarbazine altretamine ifosfamide ) Estramustine phosphate Y estramustine phosphate hexamethylmelamine mechlorethamine th i 〇 t epa str ep t ozoc i η dacarbazine temo σ temozolomide lomustine Semustine cy c 1 ophospham i de ci sp 1 at in chlorambuci 1 Agents (spir ir 1 atin) Lo ob (1 obap 1 atin) (Ae t erna) tetraplatin (tetraplatin) Setap Omar (ormap 1 at i η) (satrap 1 at in (Johnson Mat they) Iproplatin BBR-3464 (Hoffmann-La Roche) ZD-0473 (AnorMED) SM-11355 (Sumitomo) Oxaliplatin AP-5280 (Access) Card Noodles (carbop 1 at in) Antimetabolites azacytidine trimet rexate) F1 oxur idine deoxy cof ormyc in 2-chlorodeoxyadenosine adenosine pentostatin (2-ch 1 orodeoxy adenos i ne) via hydroxyurea ) 6-mer cap t opur i ne dec it ab i ne (SuperGen) 6-thioguanoguanine Claufenabin (6-thioguanine) (Transliteration clofarabine (Bioenvision) cy tarab i ne i ro fu 1 ven (MG I Pharma) DMDC (Hoffmann-La Roche) (2-fluorodeoxy cytidine ) (ethynylcytidine) CTaiho) methotrexate gemcitabine tomudex capecitabine f 1 udarab i ne raltitrexed 1084 -6646-PF; Chiumeow 27 200526777 Table 3 (continued) Topoisomerase inhibitors i amsacrine exatecan mesylate (Daiichi) ep i rubi cin quinamed (ChemGenex ) Etoposide gi matecan (S i gma-Tau) teni pos i de or mi toxantrone dif 1 omotecan (Beaufour-1 psen) 7-ethyl-10-hydroxy-camptothecin TAS-103 (Taiho) (7-ethyl-10-hydroxy-camptothecin) elsamitrucin (Spectrum) dexrazoxanet (TopoTarget) J-107088 (Merck & Co) pixantrone (Novuspharma) BNP-1350 (BioNumerik) Rebeccamycin Analog (Exelixis) CKD-602 (Chong Kun Dang) BBR-3576 (Novuspharma) Kff-2170 (Kyowa Hakko) (rubitecan) (SuperGen) irinotecan (CPT-ll) (hydroxycamptothecin) (SN-38) topotecan antitumor antibiotics dac ti nomy cin) azonaf ide (actinomycin D) anthrapyrazole valrubicin 〇oxant razo 1 e daunorub icin (daunomy cin) 1 osoxan tr one therarubicin bleomycinic acid idarubicin MEN-10755 (Menar ini) rubidazone GPX-100 (Gem Pharmaceuticals) pukamycin (plicamycin) epirubicin (porf iromycin) mitoxantrone (mitoxantrone) mi toxantrone (novan trone) amonaf ide antimitotic agents colchicine E7010 (Abbott) vinblastine PG ~ TXL (Cell Therapeutics) vindesine IDN 5109 (Bayer) dolastatin 10 (NCI) A 105972 (Abbott) (rhizoxin) (Fujisawa) A 204197 (Abbott) mivobulin (Warner-Lambert) LU 223651 (BASF) Cemadotin (BASF) D 24851 (ASTAMedica) RPR 109881A (Aventis) ER-86526 (Eisai) TXD 258 (Aventis) combretastatin A4 (BMS) Epothilone B (Epothilone B) (Novartis) isohomohalichondrin-B (PharmaMar) Γ 900607 (Tularik) ZD 6126 (AstraZeneca) Γ 138067 (Tularik) AZ10992 (Asahi) Candida cyclic peptide 52 (cryptophycin 52) (Eli Lilly) IDN-5109 (Indena) vinf lunine (Fabre) AVLB (Prescient NeuroPharma) auristatin PE (Teikoku Hormone) aza Epothilone B (azaepothi lone B) (BMS) BMS 247550 (BMS) BNP-7787 (BioNumerik) BMS 184476 (BMS) CA-4 prodrug (OXiGENE) BMS 188797 (BMS) dolastatin-lO (NIH) taxoprexin (Protarga ) CA ~ 4 (0XiGENE) SB 408075 (GlaxoSmithKline) Paclitaxel (do cetaxel vinorelbine vincristine pac 1 it axe 1 aromatase 1 inhibitors 1 aminoglutethimide YM-511 (Yamanouchi) atamestane) (BioMedicines) formestane letrozole (1 etrozo 1 e) exemestane (anas t razo 1 e) 1084-6646-PF; Chiumeow 28 200526777 Table 3 (continued) Thymidylate synthase inhibitors Pemetrexed (Eli Lilly) Nolatrexed (Eximias) 3 ZD-9331 (BTG) CoFactor ™ (BioKeys) DNA Antagonist (DNA antagonists) trabected in (PharmaMar) edotreot i de (Novart is) glufosfamide (Baxter International) mafosfamide albumin (Baxter International) 32P (Isotope Solutions) apaziquone (Spectrum Pharmaceutica1s) thymectacin (NewBiotics) 06 benzyl guanine (Paligent) Farnesy1 transferase inhibitors arglabin (NuOncology Labs) tipifa rnib (Johnson & Johnson) 1 onaf arni b (Scheri ng-Plough) glucosinolate BAY-43-9006 (Bayer) (perillyl alcohol) (DOR BioPharma) Pump inhibitors CBT-1 (CBA Pharma) zosuquidar trihydrochloride tariquidar (Xenova) (Eli Lilly) MS-209 (Schering AG) biricodar dicitrate (Vertex) Histone acety1 transferase inhibitors tacedinaline (Pfizer) pi va1oy1oxymethy1 butyrate (Titan) Pharma Depsipeptide (Fujisawa) MS-275 (Schering AG) Metalloproteinase inhibitors Neovastat CMT-3 (Col laGenex) (Aeterna Laboratories) BMS-275291 (Cel1tech) Marimate (marimastat) (British Biotech) Ribonucleoside reductase inhibitors gallium maltolate (Titan) tezacitabine (Aventis) triapine (Vion) didox (Molecules for Health) TNF alpha agonist and antagonist (TNF alpha agon i sts / antagoni sts) virulizin revimid (Celgene) (Lorus Therapeutics) CDC-394 ( Celgene) Endothelin A receptor antagonist atrasentan (Abbott) YM-598 (Yamanouchi) ZD-4054 (AstraZeneca) Retinoic acid receptor agonists fenretinide 9-cis retinoic acid (Johnson & Johnson) (alitretinoin) (Ligand) LGD-1550 (Ligand) Immuno-moda1ators Interferon dexosome treatment (Anosys) Dncophage (Ant i gen i cs) pentrix SMK (Progenics) (Australian Cancer Technology) ISF-154 (Tragen) 〔adenocarcinoma vaccine (Biomira) cancer vaccine (Intercell) TP-37 (AVI BioPharma) norelin (Biostar) IRX-2 (Immun〇-Rx) BLP-25 (Biomira) PEP-005 (Peplin Biotech) MGV (Progenics) Synchrovax vaccine (CTL Iimnuno) E-alethine (Dovetail) melanoma vaccine (CTL Irnmuno) chronic lymphoid cells: Leukemia treatment p21 RAS vaccine (GeLLax) (CLL therapy) (Vasogen) 1084-664β-PF / Chiumeow 29 200526777 Table 3 (continued) Hormonal and antihormonal agents estrogens Dexamethasone. Conjugated estrogens prednisone (conjugated estrogens) methylprednisolone methyl ethinyl estradiol prednisolone chlortrianisen aminoglutethimide i denes t ro 1 Leuprolide (1 eupr o 1 i de) oc tr eo ti de (hydroxyprogesterone caproate) mitotane medroxyprogesterone P-04 (Novogen ) Testosterone (2-methoxyestradiol) (EntreMed) (testosterone propionate) arzoxifene (Eli Lilly) f 1 uoxymes terone tamoxi f en methyl WKmethyltestosterone) toremofine diethylstilbestrol goserelin megestrol leuporelin bicalutamide bicalutamide flutamide ) Ni lutamide Photodynamic agents talaporfin (Light Sciences) Pd-bacteriopheophorbide (Yeda) Thera 1 ux (Theratec hno 1 ogies) de Π 啉 状 啉 f | (lutetium texaphyrin) Pharmacyclics (motexafin gadolinium) hypericin (Pharmacyclics) kinase inhibitors (Kinase Inhibitors) {/ 9 λ {methylsulfonate Imatinib EKB -569 (ffyeth) (imatinib) (Novartis) kahalide F (PharmaMar) Leflunomide CEP-701 (Cephalon) (1 ef lunomide) (Sugen / Pharmacia) CEP-751 (Cepha 1 on) ZD183 9 (AstraZeneca) MLN518 (Millenium) Erlotinib PKC412 (Novartis) (erlotinib) (Oncogene Science) Phenoxodiol (Novogen) canertinib (Pfizer) C225 (ImClone) squalamine (Genaera) rhu-Mab (Genentech) SU5416 (Pharmacia) MDX -H210 (Medarex) SU6668 (Pharmacia) 2C4 (Genentech) ZD A 190 (AstraZeneca) MDX-447 (Medarex) ZD6474 (AstraZeneca) ABX-EGF (Abgenix) ^ atalanib (Novartis) IMC-lCll (ImClone) PKI166 (Novartis) Tyrphostins jW20 16 (G1 axoSmi thK line) Gefitinib (Iressa) 5KB-509 (Wyeth) Trastuzumab (Trastuzumab) (Genentech) 1084-6646-PF; Chiumeow 30 200526777 Table 3 (continued) ) Various preparations SR-27897 (Cholecystokinin A (CCK A) inhibitor, Sano fi-Synthelabo) tocladesine (cyclic AMP agonist, Ribaharm) alvocidib (CDK inhibitor, Aventis) CV-247 (Cyclooxygenase-2 (C0X-2) Inhibitor, Ivy Medical) P54 (Cyclooxygenase-2 inhibitor, Phytopharm) CapCell ™ (CYP450 stimulant, Bavarian Nordic) GCS-100 (gal3 antagonist, GlycoGenesys) G17DT immunogen ) (Gastrin inhibitor, Aphton) efaproxiral (oxygenator, Alios Therapeutics) PI-88 (heparanase inhibitor, Progen) tesmilifene (histamine antagonist, YM BioSciences ) Histamine (histamine H2 receptor agonist, Maxim) tiazofurin (IMPDH inhibitor, Ribapharm) cilengitide (integration Integrin antagonist, Merck KGaA) SR-31747 (interleukin-1 (IL-1) antagonist, Sano fi-Synthe 1 abo) CCI_779 (mamma kinase target inhibition by mammalian rapamycin) Agent, Wyeth) exisulind (androsine diglycinase type 5 (PDE V) inhibition Agent, Cell Pathways) CP-461 (Tube Acid Diesterase Type 5 Inhibitor, Cell Pathways) AG-2037C Gene Antiretroviral Resistance Test (GART) Inhibitor, Pfizer) Ϊ UK-UK1 (plasminogen Plasminogen activator inhibitor, Wilex) PBI-1402 (PMN stimulant, ProMetic LifeSciences) 30rtezomib, (Proteasome inhibitor, Mi 1 lennium) SRL_172 (T cell stimulant, SR Pharma) LK-286 (glutathione S transferase inhibitor, Tel ik) PT -100 (growth factor agonist, Point Therapeutics) Mitostaur in (PKC inhibitor, Novartis) bryostatin-1 (protein kinase C stimulator, GPC Biotech) CDA-II (apoptosis enhancer (Apoptosis promoter), Everlife) SDX_101 (apoptosis promoter, Salmedix) rituximab (CD20 antibody, Genentech_ ceflatonin (apoptosis promoter, ChemGenex) BCX-1777 (purine ribophosphate phosphorylase (PNP) inhibitor, BioCryst) ranpirnase (ribonuclease) Stimulant, Alfacell) ga 1 arubi ciη (Dong-A) tirapazamine (reducing agent, SRI International) N-acety 1 cyste i ne) (reducing agent, Zambon) R-flurbiprofen (nuclear factor (B (NF-kappaB) inhibitor, Encore) 3CPA (nuclear factor (B inhibitor, Active Biotech) seocalcitol (vitamin D receptor agonist, Leo) 131 -1 -TM-6 01 (deoxyribonucleic acid inhibitor, TransMo 1 ecu 1 ar) eflorni thine (urine decarboxylase (ODC) inhibitor, ILEX Oncology) minodronic acid (Osteoc 1 ast) inhibitor, Yamanouch i) indisulam (p53 stimulator, Eisai) apl idine (PPT inhibitor, PharmaMar) gemtuzumab (CD33 antibody, Wyeth Ayerst) PG2 (hematopoiesis Hemotopoiesis enhancer (Pharmagenesis) Immunol ™ (triclosan oral rinse, Endo) triacetyluridine (uridine prodrug, Weilstat) SN-4071 (sarcoma agent, Signature BioScience) TransMID-107 ™ (immunotoxin, KS Biomedix) PCK-3145 (Procyon) doranidazole (Pola) CHS-828 (cytotoxic agent, Leo) trans-retinoic acid (differentiating agent ( differentiator), NIH) MX6 (apoptosis promoter, MAXIA) apomine (apoptosis promoter, ILEX Oncology) urocidin (apoptosis promoter, Bioniche) Ro-3b 7453 (apoptosis promoter, La Roche) brosta 11 icin (Apoptotic Accelerator, Pharmac ia) Examples 1084-6646-PF; Chiumeow 31 200526777 The following examples will illustrate the present invention, but they do not limit the present invention in any way. Chlorpromazine is a mitotic kinesin inhibitor. Using cell free motor assay, we determined that gaspromazine is a mitotic kinesin inhibitor. This analysis measures the organic phosphate (Pi) produced during the microtubule activated ATPase activity of kinesin motor proteins. Recombinant HsEg5 / KSP kinesin motor was analyzed using Kinesin ATPase End Point Biochem Kit (Cytoskeleton, catalog # BK053) according to the manufacturer's instructions for the amount of reaction buffer, adenosine triphosphate (ATP) and microtubules. protein activity) 〇 The optimal amount of HsEg5 / KSP kinesin per reaction is 0.8 micrograms (# g), and this amount is also the therapeutic amount. Each analysis was performed in a clear 96 well area 1/2 plate (Corning Inc., Costar and cat # 3697) with a total reaction volume of 30 microliters1), The analysis includes the following conditions: 1. A blank reaction containing only reaction buffers and adenosine triphosphate; 2. A negative control reaction, including: a. Microtubules and tri-acid ridges (ATP), without kinesin protein, or 'b · kinesin HsEg5 / KSP (kinesin HsEg5 / KSP) and trisaline gland: g :, but without microtubules; and 3. Experimental reactions, It contains tri-acid gland ridges, kinesin and microtubules, and contains or does not contain the last specified concentration of compounds. The reaction was preset at room temperature for 15 minutes before adding adenosine triphosphate. After the addition of adenosine triphosphate, 'the reaction was performed at room temperature for 10 minutes', then 70 microliters of CytoPhos reagent was added to terminate the reaction. After standing at room temperature for the last 10 minutes, the absorbance was 1084-6646-PF; Chiumeow 32 200526777 «

没疋於 650 奈米（nm)的分光光度計（spectrophotometer)(Beckman Instruments, lnc·, Model DU 530)定量該等反應。透過減去空白樣 本的吸光度來校正粗略的吸光度值。經過與標準磷酸根（Pi)曲線比較 後’吸光度可轉換成磷酸根濃度。根據下式由磷酸根（Pi)濃度計算抑 制百分比：抑制百分比=(未處理組-處理組）/未處理組 X 100(%Inhibition=(untreated_treated)/untreated X 100)。抑制百 分比平均值由重覆的實驗產生。其結果列於表4。 表4 驅動蛋白運動活性(kinesin motor activity)的抑制百分比(η二4)_These reactions were quantified using a spectrophotometer (Beckman Instruments, lnc., Model DU 530) at 650 nanometers (nm). Correct the rough absorbance value by subtracting the absorbance of the blank sample. After comparison with the standard phosphate (Pi) curve, the 'absorbance can be converted to the phosphate concentration. Percent inhibition was calculated from the phosphate (Pi) concentration according to the following formula: Percent inhibition = (untreated group-treated group) / untreated group X 100 (% Inhibition = (untreated_treated) / untreated X 100). The average inhibition percentages were generated from repeated experiments. The results are shown in Table 4. Table 4 Percent inhibition of kinesin motor activity (η 2 4)

表普馬D 秦(Chlorpromazine)[微摩爾（// Μ) ] I 1 2 4 8 16 32 64 平均 -5.51 -11.18 17.42 52.91 85.82 97. 79 104. 54 標準差 11.87 25.94 17.54 6.99 10. 84 6.40 10.96 其他能夠降低有絲分裂驅動蛋白生物活性的吩噻嗪 (phenothiazines)包括：異丙嗪（promethazine)、硫利達嘻 (thioridazine)、三氟拉嗪（trifluoperazine)、奮乃靜 (perphenazine)、氟奮乃靜（fluphenazine)、克杜芬（clozapine)以及 丙氯拉嗪（prochlorperazine) 〇 氣普馬嗦（chi orpromazine)與喷他脒（pentamidine)的組合在禮户/HZ/? ritro)降低細胞的增生 吾人已確定喷他脒（蛋白酪胺酸磷酸酶抑制劑）與氯普馬嗪（有絲 分裂驅動蛋白抑制劑）組合在禮夕Kh r/iro)降低細胞增生的能力。在 37 ° ± 5 °C與5%二氧化碳存在下，將人類結腸腺癌細胞株 HCT116(ATCC#CCL-247)培養於補充10%胎牛血清（FBS)、2毫摩爾（mM) 麵醯胺酸（glutamine)、1%青黴菌（penicillin)與1%鏈黴素 (streptomycin)的Dulbecco改良細胞培養液（DMEM)中。抗增生分析在 384孔盤（384-well plates)中進行。將組合基質中取出之10倍貯存 溶液（6.6微升）添加至分析孔（assay wells)内的40微升培養基中。 1084-6646-PF;Chiumeow 33 200526777 利用0· 25%胰蛋白酶（trypsin)溶液使腫瘤細胞自培養燒瓶中釋出。在 培養基中稀釋細胞，然而將含有3000個細胞的2〇微升立立養基傳送至 每-分析孔内。在3rc± 〇.πτ，以5%二氧化碳培養^^(assay plates)72-80小時。在培養期之後，將加溫至37〇c± 〇· 5。〇之2〇微升 的20Mlainar Blue添加至每一分析孔。添加Alamar扪此之後的3·5 至5· 0小時，以螢光的強度定量Alamar Blue代謝。利用[几Analyst AD reader(LJL Biosystems)進行定量，而所選取的定量位置為孔中間 高度稀釋的區域，讀取的時間為1〇〇毫秒，激發光濾鏡（excitati〇n filter)設定為530奈米（nm)，而發散射濾鏡（emissi〇n filter)設定 為575奈米。有一些實驗係以waiiac Victor2 reader進行定量，其 以穩疋的月b燈控制（stabilized energy lamp control)在孔的上方進 行測量；讀取時間為100毫秒，激發光濾鏡設定為53〇奈米，而發散 射濾鏡設定為590奈米。盤讀取器（plate readers)之間無顯著差異。 利用下式計算每一孔（well)的抑制百分比（％1): 抑制百分比（％1)=[(平均之未處理孔_處理孔）/(平均之未處理 孔）]X 100 平均之未處理孔值（平均之未處理孔）係單獨以賦形劑處理之相同 刀析盤中的40個孔的平均。負抑制（negaHVe inhibition)值係處理 孔與未處理孔比較後所產生的局部差異。該數據列於表5，並且以抑 制百分比表示。 1084-6646~PF；Chiumeow 200526777 表5 氣普馬嗪(Chlorpromazine)(微摩爾） 0 4 6 7.5 9 10 12 16 20 22 暖 0 0. 63 2.9 0.11 5.4 4.1 16 22 39 56 59 0.5 1.2 -0· 13 6.1 4.3 7.9 16 31 45 64 65 1 1.9 2.2 9.1 5.5 16 21 25 56 57 68 2 3.1 3.1 5· 8 5.1 9.7 18 30 57 70 73 •r-H • νΗ 4 - 0·77 4.0 2.7 12 10 20 26 59 69 74 1 6 5 7.1 15 9.9 16 22 38 58 74 78 s CL. 9 9 13 13 22 16 37 41 68 79 88~ 12 9.9 13 15 16 18 27 46 69 82 87 _lW 15 16 20 22 35 26 40 52 78 84 92 ι 20 19 22 25 36 40 49 70 82 94 94 其他實施例 所有以上說明書中所提及的公開案與專利皆以引用的方式併入本 文。雖然本發明已以較佳實施例揭露如上，然其並非用以限定本發明， 任何熟習此技藝者，在不脫離本發明之精神和範圍内，當可作各種之 更動與潤飾。甚至，以上所述之模式中，用以實行本發明並且為熟悉 腫瘤學或相關領域者所熟知的各種修飾也包括在本發明之範圍内。 【圖式簡單說明】 無0 【主要元件符號說明】 無0 1084-6646-PF/Chiumeow 35Table Puma D Qin (Chlorpromazine) [micromole (// M)] I 1 2 4 8 16 32 64 average -5.51 -11.18 17.42 52.91 85.82 97. 79 104. 54 standard deviation 11.87 25.94 17.54 6.99 10. 84 6.40 10.96 Other phenothiazines that can reduce the biological activity of mitogen kinesin include: promethazine, thioridazine, trifluoperazine, perphenazine, fluphenazine (Fluphenazine), clozapine, and prochlorperazine 〇 The combination of chi orpromazine and pentamidine reduced the proliferation of cells in Li / HZ /? Ritro The ability of pentamidine (protein tyrosine phosphatase inhibitor) in combination with clomazine (mitotic kinesin inhibitor) to reduce cell proliferation in Kh r / iro) has been determined. Human colon adenocarcinoma cell line HCT116 (ATCC # CCL-247) was cultured in the presence of 37 ° ± 5 ° C and 5% carbon dioxide, supplemented with 10% fetal bovine serum (FBS), 2 mmol (mM) peptamine Acid (glutamine), 1% penicillin and 1% streptomycin in Dulbecco's modified cell culture medium (DMEM). Antiproliferative analysis was performed in 384-well plates. A 10-fold storage solution (6.6 µl) from the combination matrix was added to 40 µl of culture medium in assay wells. 1084-6646-PF; Chiumeow 33 200526777 The tumor cells were released from the culture flask using a 0.25% trypsin solution. The cells were diluted in the medium, however, 20 microliters of standing medium containing 3000 cells were transferred into each-analytical well. Incubate at 3rc ± .πτ with 5% carbon dioxide (assay plates) for 72-80 hours. After the incubation period, it will be warmed to 37 ° C ± 0.5. 20 microliters of 20 Mlainar Blue was added to each well. Alamar 扪 was added for 3 · 5 to 5.0 hours thereafter to quantify Alamar Blue metabolism in terms of fluorescence intensity. [Analyst AD reader (LJL Biosystems) was used for quantification, and the selected quantification position was a highly diluted area in the middle of the well. The reading time was 100 milliseconds, and the excitation light filter was set to 530. Nanometer (nm), and the emission filter (emision filter) is set to 575 nanometers. Some experiments use a Waiiac Victor2 reader for quantification, which is performed above the well with a stable energy lamp control; the reading time is 100 milliseconds, and the excitation light filter is set to 53 nm And the emission filter is set to 590 nm. There are no significant differences between plate readers. Calculate the inhibition percentage (% 1) of each well (well) using the following formula: Percent inhibition (% 1) = [(average untreated well_treated well) / (average untreated well)] X 100 mean untreated Treated well values (average untreated wells) are the average of 40 wells in the same knife plate treated with excipients alone. The negative inhibition (negaHVe inhibition) value is the local difference between treated wells and untreated wells. The data are listed in Table 5 and are expressed as percent inhibition. 1084-6646 ~ PF; Chiumeow 200526777 Table 5 Chlorpromazine (micromolar) 0 4 6 7.5 9 10 12 16 20 22 Warm 0 0.63 2.9 0.11 5.4 4.1 16 22 39 56 59 0.5 1.2 -0 · 13 6.1 4.3 7.9 16 31 45 64 65 1 1.9 2.2 9.1 5.5 16 21 25 56 57 68 2 3.1 3.1 5 · 8 5.1 9.7 18 30 57 70 73 • rH • νΗ 4-0.777 4.0 2.7 12 10 20 26 59 69 74 1 6 5 7.1 15 9.9 16 22 38 58 74 78 s CL. 9 9 13 13 22 16 37 41 68 79 88 ~ 12 9.9 13 15 16 18 27 46 69 82 87 _lW 15 16 20 22 35 26 40 52 78 84 92 ι 20 19 22 25 36 40 49 70 82 94 94 Other Examples All the publications and patents mentioned in the above description are incorporated herein by reference. Although the present invention has been disclosed as above with preferred embodiments, it is not intended to limit the present invention. Any person skilled in the art can make various changes and decorations without departing from the spirit and scope of the present invention. Furthermore, among the modes described above, various modifications for practicing the present invention and well known to those skilled in oncology or related fields are also included in the scope of the present invention. [Schematic description] No 0 [Description of main component symbols] No 0 1084-6646-PF / Chiumeow 35

Claims (1)

200526777 十、申請專利範圍： 1. 一種組合物，該組合物包括一降低有絲分裂驅動蛋白生物活性 的第一製劑與一降低蛋白酪胺酸磷酸酶生物活性的第二製劑，其中含 有足量的第一與第二製劑，當投與該組合物至一患有增生性疾病的病 人時，可治療該疾病。 2. 如申請專利範圍第1項所述的組合物，其中該第一製劑為一有 絲分裂驅動蛋白抑制劑。 3. 如申請專利範圍第1項所述的組合物，其中該第一製劑為一反 義化合物或核醣核酸干擾（RNAi)化合物，其可降低該有絲分裂驅動蛋 白的表現量。 4. 如申請專利範圍第1項所述的組合物，其中該第一製劑為一顯 著抑制有絲分裂驅動蛋白（dominant negative mitotic kinesin)或一 編碼該顯著抑制有絲分裂驅動蛋白的表現載體。 5. 如申請專利範圍第1項所述的組合物，其中該第一製劑為一抗 體，該抗體結合該有絲分裂驅動蛋白並且降低有絲分裂驅動蛋白的生 物活性。 6. 如申請專利範圍第1-5項任一項所述的組合物，其中該有絲分 裂驅動蛋白為HsEg5/KSP。 7. 如申請專利範圍第1項所述的組合物，其中該第一製劑為一曙 光激酶抑制劑（aurora kinase inhibitor)。 8. 如申請專利範圍第1項所述的組合物，其中該有絲分裂驅動蛋 白生物活性為酶活性（enzymatic activity)，運動活性（motor activity)，或結合活性（binding activity) 〇 9. 如申請專利範圍第1項所述的組合物，其中該第二製劑為一蛋 白酪胺酸磷酸酶抑制劑。 10. 如申請專利範圍第1項所述的組合物，其中談第二製劑為一反 10 84-6646-PF；Chiumeow 36 200526777 義化曰物或核醣核酸干擾（娜i)化合物，其可降低該蛋白赂胺酸鱗酸 酶的表現量。 11·如申4專利範圍第！項所述的組合物，其中該第二製劑為一顯 ^^P^j^^^si^st|$(d〇minant negatiye pr〇te.n tyr〇s.ne phosphatase)或-編碼軸著抑制蛋白㈣酸磷嘯的表現载體。 12·如申請專利範圍第1項所述的組合物，其中該第二製劑為一抗 體’該抗體結合該蛋白絡胺酸磷酸酶並且降低蛋白酪胺酸磷酸酶的生 物活性。 13·如申明專利範圍第9—12項任一項所述的組合物，其中該蛋白 酿胺酸麟酸酶為蛋白酪胺酸磷酸酶ΙΒ(ΡΤΡΙΒ)，再生肝之磷酸酶 - 1(PRL-1) ’再生肝之磷酸酶—2，再生肝之磷酸酶—3，Src同源磷酸酶 - 1(SHP-1) ’ Src 同源磷酸酶—2，MAPK 磷酸酶-l(MKP-l)，MAPK 磷酸酶 -2 ’細胞分裂週期14(CDC14)，細胞分裂週期25A(CDC25A)，細胞分裂 週期25B，或細胞分裂週期25C。 14·如申請專利範圍第1項所述的組合物，其中該第二製劑為一法 尼基轉移酶抑制劑（farnesyltransferase inhibitor)。 15·如申請專利範圍第ι_ΐ4項任一項所述的組合物，該組合物中 含有低劑量的第一或第二製劑。 16·如申請專利範圍第1-14項任一項所述的組合物，該組合物中 含有高劑量的第一或第二製劑。 17·如申請專利範圍第1-16項任一項所述的組合物，其中該組合 物係配製成局部投與形式。 18·如申請專利範圍第1_16項任一項所述的組合物，其中該組合 物係配製成全身投與（systemic administration)形式。 19. 一種治療患有增生性疾病之病人的方法，該方法包括投與該病 人以下的組合·· 1084-6646-PF；Chiumeow 37 200526777 a) —降低有絲分裂驅動蛋白生物活性的第一製劑；以及 b) —降低蛋白酪胺酸磷酸酶生物活性的第二製劑， 其中該第一製劑與第二製劑係同時或在28天内分別足量地投 與，以治療該病人。 20. 如申請專利範圍第19項所述的方法，其中該第一製劑為一有 絲分裂驅動蛋白抑制劑。 21. 如申請專利範圍第19項所述的方法，其中該第一製劑為一反 義化合物或核醣核酸干擾（RNAi)化合物，其可降低該有絲分裂驅動蛋 白的表現量。 22. 如申請專利範圍第19項所述的方法，其中該第一製劑為一顯 著抑制有絲分裂驅動蛋白（dominant negative mitotic kinesin)或編 碼該顯著抑制有絲分裂驅動蛋白的表現載體。 23. 如申請專利範圍第19項所述的方法，其中該第一製劑為一抗 體，該抗體結合該有絲分裂驅動蛋白並且降低有絲分裂驅動蛋白的生 物活性。 24. 如申請專利範圍第19-23項任一項所述的方法，其中該有絲分 裂驅動蛋白為HsEg5/KSP。 25. 如申請專利範圍第19項所述的方法，其中該第一製劑為一曙 光激酶抑制劑。 26. 如申請專利範圍第19項所述的方法，其中該第二製劑為一蛋 白酪胺酸磷酸酶抑制劑。 27. 如申請專利範圍第19項所述的方法，其中該第二製劑為一反 義化合物或核醣核酸干擾（RNAi)化合物，其可降低該蛋白酪胺酸磷酸 酶的表現量。 28. 如申請專利範圍第19項所述的方法，其中該第二製劑為一顯 著抑制蛋白酪胺酸磷酸酶或一編碼將該顯著抑制蛋白酪胺酸磷酸酶的 1084-6646-PF;Chiumeow 38 200526777 表現載體。 29. 如申請專利範圍第19項所述的方法，其中該第二製劑為一抗 體，該抗體結合該蛋白酪胺酸磷酸酶並且降低蛋白酪胺酸磷酸酶的生 物活性。 30. 如申請專利範圍第2卜25項任一項所述的方法，其中該蛋白酪 胺酸磷酸酶為蛋白酪胺酸磷酸酶ΙΒ(ΡΤΡΙΒ)，再生肝之磷酸酶 - 1(PRL-1)，再生肝之磷酸酶-2，再生肝之磷酸酶-3，Src同源磷酸酶 - 1(SHP-1)，Src 同源磷酸酶-2，MAPK 磷酸酶-l(MKP-l)，MAPK 磷酸酶 -2，細胞分裂週期14(CDC14)，細胞分裂週期25A(CDC25A)，細胞分裂 週期26B，或細胞分裂週期25C。 31. 如申請專利範圍第19項所述的方法，其中該第二製劑為一法 尼基轉移酶抑制劑。 32. 如申請專利範圍第19-31項任一項所述的方法，其中該第一與 第二製劑係於14天内分別投與。 33. 如申請專利範圍第32項所述的方法，其中該第一與第二製劑 係於7天内分別投與。 34. 如申請專利範圍第33項所述的方法，其中該第一與第二製劑 係於1天内分別投與。 35. 如申請專利範圍第19-34項任一項所述的方法，其中該第一或 第二製劑係以低劑量投與。 36. 如申請專利範圍第19-34項任一項所述的方法，其中該第一或 第二製劑係以高劑量投與。 37. 如申請專利範圍第19-36項任一項所述的方法，其中該第一或 第二製劑係局部地或全身地投與。 38. 如申請專利範圍第19-37項任一項所述的方法，其中該增生性 疾病為癌。 1084-6646-PF;Chiumeow 39 200526777 39.如申請專利範圍第38項所述的方法，其中的癌選自急性白血 病（acute leukemia)，急性淋巴細胞性白血病（acute lymphocytic leukemia)，急性骨趙性白血病（acute myelocytic leukemia)，急性 骨髓細胞白血病（acute myeloblastic leukemia)，急性前骨髓細胞白 血病（acute promyelocytic leukemia)，急性骨髓單核細胞性白血病 (acute myelomonocytic leukemia)，急性單核球白血病（acute monocytic leukemia)，急性紅白血病（acute erythroleukemia)，慢 性白血病（chronic leukemia)，慢性骨髓性白血病（chronic myelocytic leukemia)，慢性淋巴細胞性白血病（chronic lymphocytic leukemia)，真性多紅血球症（polycythemia vera)、淋巴瘤 (lymphoma)(霍奇金氏病（Hodgkin’ s disease)，非霍奇金氏病 (non-Hodgkin’ s disease)) ， Waldenstrom 氏巨球蛋白血症 (Waldenstrom’ s macroglobulinemia)，重鏈病(heavy chain disease)，纖維肉瘤（fibrosarcoma)，黏液肉瘤（myxosarcoma)，脂肉 瘤（liposarcoma)，軟骨肉瘤（chondrosarcoma)，骨原性肉瘤 (osteogenic sarcoma)，脊索瘤(chordoma)，血管肉瘤 (angiosarcoma)，内皮肉瘤（endotheliosarcoma)，淋巴管肉瘤 (1 y mphang i osar coma ) ， 淋 巴管内 皮肉瘤 (lymphangioendotheliosarcoma)，滑液膜瘤（synovioma)，中皮瘤 (mesothelioma)，骨幹骨肉瘤（Ewing’ s tumor)，平滑肌肉瘤 (leiomyosarcoma)，橫紋肌肉瘤（rhabdomyosarcoma)，結腸癌（colon carcinoma)，胰腺癌（pancreatic cancer)，乳癌（breast cancer)， 卵巢癌（ovarian cancer)，前列腺癌（prostate cancer)，鱗狀上皮細 胞癌（squamous cell carcinoma)，基底細胞癌（basal cell carcinoma)，腺癌(adenocarcinoma)，汗腺癌(sweat gland carcinoma)，皮月旨腺癌（sebaceous gland carcinoma)，乳突癌 1084-6646-PF;Chiumeow 40 200526777 (papillary carcinoma)，乳突腺癌（papi 1 lary adenocarcinomas)， 囊腺癌（cystadenocarcinoma)，髓質癌（medullary carcinoma)，支氣 管上皮癌(bronchogenic carcinoma)，腎細胞癌(renal cell carcinoma)，肝癌（hepatoma)，膽管癌（bile duct carcinoma)，絨毛 膜癌（choriocarcinoma)，精原細胞瘤（seminoma)，胚胎性癌 (embryonal carcinoma)，威耳姆氏腫瘤（Wilm’ s tumor)，子宮頸癌 (cervical cancer)，子宮癌（uterine cancer)，睪丸癌（testicular cancer)，肺癌（lung carcinoma)，小細胞肺癌（small cell lung carcinoma)，膀胱癌（bladder carcinoma)，上皮細胞癌（epithelial carcinoma)，神經膠質瘤（glioma)，星狀細胞瘤（astrocytoma)，神經 管胚細胞瘤（medulloblastoma)，顱咽管瘤（craniopharyngioma)，室 管膜瘤（ependymoma)，松果腺瘤（pinealoma)，血管母細胞瘤 (hemangioblastoma)，聽覺神經瘤（acoustic neuroma)，寡樹突細胞 瘤（oligodendroglioma)，神經鞘瘤（schwannoma)，腦脊髓膜瘤 (meningioma)，黑色素瘤（melanoma)，神經胚細胞瘤 (neuroblastoma)，以及視網膜胚細胞瘤（retin〇blastoma)。 40·如申請專利範圍第38項所述的方法，該方法進一步地包括投 與該病人一表3所列的抗增生劑。 41· 一種誘發細胞内細胞週期停止的方法，該方法包括：以一降低 有絲分裂驅動蛋白生物活性的第一製劑與一降低蛋白酪胺酸磷酸酶生 物活性的第二製劑接觸該細胞。 42· —種鑑定可用以治療增生性疾病之組合的方法，該方法包括以 下步驟： (a) 在禮;^以一降低有絲分裂驅動蛋白生物活性的製劑與一候選 化合物接觸增生的細胞；以及 (b) 相較於以該製劑接觸而未以該候選化合物接觸之細胞的增 41 1084-6646-PF;Chiumeow 200526777 . 生，確定該製劑與該候選化合物的組合是否減少細胞增生， 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的組 合0 43. 如申請專利範圍第42項所述的方法，其中該細胞為癌細胞或 來自癌細胞株的細胞。 44. 一種鑑定可用以治療增生性疾病之化合物的方法，該方法包括 以下步驟： (a) 提供增生的細胞，該細胞具有降低的有絲分裂驅動蛋白生物活 性； (b) 以一候選化合物接觸該細胞；以及 (c) 相較於未以該候選化合物接觸的細胞，確定該候選化合物是否 減少細胞增生， 其中若細胞增生減少即鑑定出該化合物係可用於治療增生性疾病 的化合物。 45. —種鑑定可用以治療增生性疾病之組合的方法，該方法包括以 下步驟： (a) 在禮分以一降低蛋白酪胺酸磷酸酶生物活性的製劑與一候選 化合物接觸增生的細胞；以及 · (b) 相較於以該製劑接觸而未以該候選化合物接觸之細胞的增 生，確定該製劑與該候選化合物的組合是否減少細胞增生， 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的 組合。 46. 如申請專利範圍第45項所述的方法，其中該細胞為癌細胞為 或來自癌細胞株的細胞。 47. 一種鑑定可用以治療增生性疾病之化合物的方法，該方法包括 以下步驟： 1084-6646-PF；Chiumeow 42 200526777 (a) 提供增生的細胞，該細胞具有降低的蛋白酪胺酸磷酸酶生物活 性； (b) 以一候選化合物接觸該細胞；以及 (c) 相較於未以該候選化合物接觸的細胞，確定該候選化合物是否 減少細胞增生， 其中若細胞增生減少即鑑定出該化合物係可用於治療增生性疾病 的化合物。 48. —種鑑定可用以治療增生性疾病之組合的方法，該方法包括以 下步驟： (a) 鑑定一降低有絲分裂驅動蛋白生物活性的化合物； (b) 在邀夕以降低蛋白酷胺酸填酸酶生物活性之製劑 以及步驟（a)所鑑定出之化合物接觸增生的細胞；以及 (c) 相較於以該製劑接觸但未以步驟（a)所鑑定出之化合物接觸， 或以步驟（a)所鑑定出之化合物接觸但未以該製劑接觸之細胞的增 生，確定該製劑與步驟（a)所鑑定出之化合物的組合是否減少細胞增 生， 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的 組合。 Φ 49. 一種鑑定可用以治療增生性疾病之組合的方法，該方法包括以 下步驟： (a) 鑑定一降低蛋白酪胺酸磷酸酶生物活性的化合物； (b) 在禮;Wiro)以降低有絲分裂驅動蛋白生物活性之製劑 以及步驟（a)所鑑定出之化合物接觸增生的細胞；以及 (c) 相較於以該製劑接觸但未以步驟（a)所鑑定出之化合物接觸， 或以步驟（a)所鑑定出之化合物接觸但未以該製劑接觸之細胞的增 生，確定該製劑與步驟（a)所鑑定出之化合物的組合是否減少細胞增 1084-6646-PF;Chiumeow 43 200526777 泰 生， 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的 組合。 50· —種套組（kit)，包括： (1) 一組合物，包含一降低有絲分裂驅動蛋白生物活性的第一製劑 與一降低蛋白酪胺酸磷酸酶生物活性的第二製劑；以及 (i i )#又與該組合物至一被診斷患有增生性疾病之病人的使用說 明。 51· —種套組，包括·· (i) 降低有絲分裂驅動蛋白生物活性的第一製劑； (ii) 一降低蛋白酪胺酸磷酸酶生物活性的第二製劑；以及 (111)投與該第一與第二製劑至一被診斷患有增生性疾病之病人 的使用說明。 52· —種套組，包括（i)一降低有絲分裂驅動蛋白生物活性的第一 製劑以及（i i)投與該降低蛋白絡胺酸鱗酸酶生物活性之第一與第二製 劑至一被診斷患有增生性疾病之病人的使用說明。 53· —種套組，包括（丨）一降低蛋白酪胺酸磷酸酶生物活性的第一 製劑以及（ii)投與該降低有絲分裂驅動蛋白生物活性之第一與第二製 劑至一被診斷患有增生性疾病之病人的使用說明。 54· —種鑑定可用以治療增生性疾病之組合的方法，該方法包括 以下步驟： (a) 在邀冷以一降低有絲分裂驅動蛋白生物活性的製劑與一候選 化合物接觸增生的細胞；以及 (b) 相較於以該製劑接觸但未以該候選化合物接觸之細胞的增 生’確疋該製劑與該候選化合物的組合是否減少細胞增生， 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的 1084-6646-PF；Chiumeow 44 200526777 組合。 55. 如申請專利範圍第54項所述的方法，其中該降低有絲分裂驅 動蛋白生物活性的製劑為有絲分裂驅動蛋白抑制劑。 56. 如申請專利範圍第54項所述的方法，其中該降低有絲分裂驅 動蛋白生物活性的製劑為一反義化合物或核醣核酸干擾（RNAi)化合 物，其可降低該有絲分裂驅動蛋白的表現量。 57. 如申請專利範圍第54項所述的方法，其中該降低有絲分裂驅 動蛋白生物活性的製劑為一顯著抑制有絲分裂驅動蛋白或一編碼該顯 著抑制有絲分裂驅動蛋白的表現載體。 58. 如申請專利範圍第54項所述的方法，其中該降低有絲分裂驅 動蛋白生物活性的製劑為一抗體，該抗體結合該有絲分裂驅動蛋白並 且降低有絲分裂驅動蛋白的生物活性。 59. 如申請專利範圍第54項所述的方法，其中該有絲分裂驅動蛋 白為 HsEg5/KSP。 60. 如申請專利範圍第54項所述的方法，其中該降低有絲分裂驅 動蛋白生物活性的製劑為一曙光激酶抑制劑。 61. 如申請專利範圍第54項所述的方法，其中該有絲分裂驅動蛋 白的生物活性為酶活性（enzymatic activity)，運動活性（motor activity)，或結合活性（binding activity) 〇 62. 如申請專利範圍第54項所述的方法，其中該細胞為癌細胞或 來自癌細胞株的細胞。 63. —種鑑定可用以治療增生性疾病之化合物的方法，該方法包括 以下步驟： (a) 提供增生的細胞，該細胞具有降低的有絲分裂驅動蛋白生物活 性； (b) 以一候選化合物接觸該細胞；以及 1084-6646-PF; Chiumeow 45 200526777 (C)相較於未以該候選化合物接觸的細胞，確定該候選化合物是否 減少細胞增生， 其中若細胞增生減少即鑑定出該化合物係可用於治療增生性疾病 的化合物。 64. 如申請專利範圍第63項所述的方法，其中該細胞為癌細胞或 來自癌細胞株的細胞。 65. —種鑑定可用以治療增生性疾病之組合的方法，該方法包括以 下步驟： (a)在以一降低蛋白酷胺酸填酸酶生物活性的製劑與一候選 化合物接觸增生的細胞；以及 (b )相較於以該製劑接觸但未以該候選化合物接觸之細胞的增 生，確定該製劑與該候選化合物的組合是否減少細胞增生， 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的 組合。 66. 如申請專利範圍第65項所述的方法，其中該降低蛋白酪胺酸 磷酸酶生物活性的製劑為一蛋白酪胺酸磷酸酶抑制劑。 67. 如申請專利範圍第65項所述的方法，其中該降低蛋白酪胺酸 磷酸酶生物活性的製劑為一反義化合物或核醣核酸干擾（R N A i)化合 物，其可降低該蛋白酪胺酸磷酸酶的表現量。 68. 如申請專利範圍第65項所述的方法，其中該降低蛋白酪胺酸 磷酸酶生物活性的製劑為一顯著抑制蛋白酪胺酸磷酸酶或一編碼該顯 著抑制蛋白酪胺酸磷酸酶的表現載體。 69. 如申請專利範圍第65項所述的方法，其中該降低蛋白酪胺酸 磷酸酶生物活性的製劑為一抗體，該抗體結合該蛋白酪胺酸磷酸酶並 且降低蛋白酪胺酸磷酸酶的生物活性。 70. 如申請專利範圍第64項所述的方法，其中該蛋白酪胺酸磷酸 1084-6646-PF/Chiumeow 46 200526777 酶為蛋白酪胺酸磷酸酶ΙΒ(ΡΤΡΙΒ)，再生肝之磷酸酶-l(PRL-l)，再生 肝之構酸酶-2，再生肝之構酸酶_3，Src同源填酸酶-1(SHP-1)，Src 同源磷酸酶-2，MAPK磷酸酶-l(MKP-l)，MAPK磷酸酶-2，細胞分裂週 期14(CDC14)，細胞分裂週期25A(CDC25A)，細胞分裂週期26Β ’或細 胞分裂週期25C。 71. 如申請專利範圍第65項所述的方法，其中該第二製劑為一法 尼基轉移酶抑制劑。 72. 如申請專利範圍第65項所述的方法，其中該細胞為癌細胞或 來自癌細胞株的細胞。 73. —種鑑定可用以治療增生性疾病之化合物的方法，該方法包括 以下步驟： (a) 提供增生的細胞，該細胞具有降低的蛋白酪胺酸磷酸酶生物活 性； (b) 以一候選化合物接觸該細胞；以及 (c) 相較於未以該候選化合物接觸的細胞，確定該候選化合物是否 減少細胞增生， 其中若細胞增生減少即鑑定出該化合物係可用於治療增生性疾病 的化合物。 74. —種鑑定可用以治療增生性疾病之組合的方法，該方法包括以 下步驟： (a) 鑑定出一降低有絲分裂驅動蛋白生物活性的化合物； (b) 在禮夕/*(//? 以降低蛋白酿胺酸填酸酶生物活性之製劑 以及步驟（a)所鑑定出的化合物接觸增生的細胞；以及 (c) 相較於以該製劑接觸但未以步驟（a)所鑑定出之化合物接觸， 或以步驟（a)所鑑定出之化合物接觸但未以該製劑接觸之細胞的增 生，確定該製劑與步驟（a)所確定之化合物的組合是否減少細胞增生， 1084-6646-PF;Chiumeow 47 200526777 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的 組合。 75. —種鑑定可用以治療增生性疾病之組合的方法，該方法包括以 下步驟： (a) 鑑定一降低蛋白酪胺酸磷酸酶生物活性的化合物； (b) 在禮// (//7 W化6〇以降低有絲分裂驅動蛋白生物活性之製劑 以及步驟（a)所鑑定出之化合物接觸增生的細胞；以及 (c) 相較於以該製劑接觸但未以步驟（a)所鑑定出之化合物接觸， 或以步驟（a)所鑑定出之化合物接觸但未以該製劑接觸之細胞的增 生，確定該製劑與步驟（a)所鑑定出之化合物的組合是否減少細胞增 生， 其中若細胞增生減少即鑑定出該組合係可用於治療增生性疾病的 組合。 1084-6646-PF;Chiumeow 48 200526777 七、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。 八、本案若有化學式時，請揭示最能顯示發明特徵的化學式： 無0 1084-6646-PF;Chiumeow200526777 10. Scope of patent application: 1. A composition comprising a first preparation for reducing the biological activity of mitotic kinesin and a second preparation for reducing the biological activity of protein tyrosine phosphatase, which contains a sufficient amount of the first preparation The first and second formulations, when administered to a patient with a proliferative disease, treat the disease. 2. The composition according to item 1 of the scope of patent application, wherein the first formulation is a mitogen kinesin inhibitor. 3. The composition according to item 1 of the patent application scope, wherein the first preparation is an antisense compound or a ribonucleic acid interference (RNAi) compound, which can reduce the expression of the mitotic driving protein. 4. The composition according to item 1 of the patent application scope, wherein the first preparation is a significant negative mitotic kinesin or a performance vector encoding the significant mitotic kinesin. 5. The composition according to item 1 of the scope of patent application, wherein the first formulation is a primary antibody, and the antibody binds to the mitotic kinesin and reduces the biological activity of the mitotic kinesin. 6. The composition according to any one of claims 1 to 5, wherein the mitotic kinesin is HsEg5 / KSP. 7. The composition according to item 1 of the scope of patent application, wherein the first preparation is an aurora kinase inhibitor. 8. The composition according to item 1 of the scope of patent application, wherein the biological activity of the mitotic kinesin is enzyme activity, motor activity, or binding activity 〇9. The composition of the scope item 1, wherein the second preparation is a protein tyrosine phosphatase inhibitor. 10. The composition as described in item 1 of the scope of patent application, wherein the second formulation is a trans 10 6.4-6646-PF; Chiumeow 36 200526777 isomerized or a RNA interference (Na) compound, which can reduce The expression of this protein is glutamylscale enzyme. 11 · If you apply for 4 patent scope! The composition according to item 2, wherein the second preparation is a display ^^ P ^ j ^^^ si ^ st | $ (d〇minant negatiye pr〇te.n tyr〇s.ne phosphatase) or-coding axis A performance vector that inhibits peptone acid phosphine. 12. The composition according to item 1 of the scope of the patent application, wherein the second preparation is a primary antibody ' The antibody binds the protein complex amino acid phosphatase and reduces the biological activity of the protein tyrosine phosphatase. 13. The composition according to any one of claims 9-12 in the declared patent scope, wherein the protein glutamate linase is protein tyrosine phosphatase ΙΒ (ΡΤΡΙΒ), and regenerating liver phosphatase-1 (PRL -1) 'Regenerating liver phosphatase-2, Regenerating liver phosphatase-3, Src homophosphatase-1 (SHP-1)' Src homophosphatase-2, MAPK phosphatase-1 (MKP-l ), MAPK phosphatase-2 'cell division cycle 14 (CDC14), cell division cycle 25A (CDC25A), cell division cycle 25B, or cell division cycle 25C. 14. The composition according to item 1 of the scope of patent application, wherein the second preparation is a farnesyltransferase inhibitor. 15. The composition according to any one of claims 1 to 4 in the scope of the patent application, which contains a low-dose first or second formulation. 16. The composition according to any one of claims 1 to 14 of the scope of patent application, which contains a high dose of the first or second formulation. 17. The composition according to any one of claims 1 to 16 of the scope of application for a patent, wherein the composition is formulated in a topical administration form. 18. The composition according to any one of claims 1 to 16 of the scope of patent application, wherein the composition is formulated in the form of systemic administration. 19. A method of treating a patient with a proliferative disease, the method comprising administering a combination of the following to the patient ... 1084-6646-PF; Chiumeow 37 200526777 a)-a first agent that reduces the biological activity of mitogen kinesin; and b) a second formulation that reduces the biological activity of the protein tyrosine phosphatase, wherein the first formulation and the second formulation are administered simultaneously or in sufficient amounts separately within 28 days to treat the patient. 20. The method of claim 19, wherein the first formulation is a mitogen kinesin inhibitor. 21. The method of claim 19, wherein the first agent is an antisense compound or a ribonucleic acid interference (RNAi) compound, which can reduce the expression of the mitotic driving protein. 22. The method of claim 19, wherein the first preparation is a dominant negative mitotic kinesin or a performance vector encoding the significant mitotic kinesin. 23. The method according to item 19 of the scope of patent application, wherein the first formulation is a primary antibody, the antibody binds to the mitotic kinesin and reduces the biological activity of the mitotic kinesin. 24. The method according to any one of claims 19-23, wherein the mitotic kinesin is HsEg5 / KSP. 25. The method of claim 19, wherein the first formulation is a dawn kinase inhibitor. 26. The method of claim 19, wherein the second preparation is a protein tyrosine phosphatase inhibitor. 27. The method of claim 19, wherein the second agent is an antisense compound or a ribonucleic acid interference (RNAi) compound, which can reduce the expression of the protein tyrosine phosphatase. 28. The method as described in item 19 of the scope of patent application, wherein the second preparation is a significant inhibitor of protein tyrosine phosphatase or a code encoding 1084-6646-PF; Chiumeow 38 200526777 Performance vector. 29. The method of claim 19, wherein the second preparation is a primary antibody, the antibody binds to the protein tyrosine phosphatase and reduces the biological activity of the protein tyrosine phosphatase. 30. The method according to any one of items 2 to 25 in the scope of the patent application, wherein the protein tyrosine phosphatase is protein tyrosine phosphatase 1B (PTPIB), which regenerates liver phosphatase-1 (PRL-1 ), Regenerating liver phosphatase-2, regenerating liver phosphatase-3, Src homophosphatase-1 (SHP-1), Src homophosphatase-2, MAPK phosphatase-1 (MKP-1), MAPK phosphatase-2, cell division cycle 14 (CDC14), cell division cycle 25A (CDC25A), cell division cycle 26B, or cell division cycle 25C. 31. The method of claim 19, wherein the second preparation is a farnesyl transferase inhibitor. 32. The method according to any one of claims 19-31, wherein the first and second preparations are administered separately within 14 days. 33. The method of claim 32, wherein the first and second preparations are administered separately within 7 days. 34. The method as described in claim 33, wherein the first and second preparations are administered separately within 1 day. 35. The method according to any one of claims 19-34, wherein the first or second formulation is administered in a low dose. 36. The method according to any one of claims 19 to 34 in the scope of patent application, wherein the first or second formulation is administered in a high dose. 37. The method according to any one of claims 19-36, wherein the first or second formulation is administered locally or systemically. 38. The method according to any one of claims 19 to 37 in the scope of patent application, wherein the proliferative disease is cancer. 1084-6646-PF; Chiumeow 39 200526777 39. The method according to item 38 of the scope of application for a patent, wherein the cancer is selected from the group consisting of acute leukemia, acute lymphocytic leukemia, and acute osteopetrosis Leukemia (acute myelocytic leukemia), acute myeloblastic leukemia, acute promyelocytic leukemia, acute myelomonocytic leukemia, acute monocytic leukemia ), Acute erythroleukemia, chronic leukemia, chronic myelocytic leukemia, chronic lymphocytic leukemia, polycythemia vera, lymphoma lymphoma) (Hodgkin's disease, non-Hodgkin's disease), Waldenstrom's macroglobulinemia, heavy chain disease chain disease), fibrosarcoma (Fibrosarcoma), myxosarcoma, liposarcoma, chondrosarcoma, osteogenic sarcoma, chordoma, angiosarcoma, endotheliosarcoma, lymph Tube sarcoma (1 y mphang i osar coma), lymphatic endothelial sarcoma (lymphangioendotheliosarcoma), synovial tumor (synovioma), mesothelioma (mesothelioma), osteosarcoma (Ewing's tumor), leiomyosarcoma (leiomyosarcoma), Rhabdomyosarcoma, colon cancer, pancreatic cancer, breast cancer, ovarian cancer, prostate cancer, squamous cell carcinoma , Basal cell carcinoma, adenocarcinoma, sweat gland carcinoma, sebaceous gland carcinoma, mastoid cancer 1084-6646-PF; Chiumeow 40 200526777 (papillary carcinoma) ), Papi 1 lary adenocarcinomas, cystade nocarcinoma), medullary carcinoma, bronchogenic carcinoma, renal cell carcinoma, hepatoma, bile duct carcinoma, choriocarcinoma, seminoma Seminoma, embryonic cancer, Wilm's tumor, cervical cancer, uterine cancer, testicular cancer, lung cancer ( lung cancer), small cell lung cancer, bladder cancer, epithelial carcinoma, glioma, astrocytoma, neural tuberblastoma ( medulloblastoma), craniopharyngioma, epidymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma ), Schwannoma, Meningioma, Melanoma, Neuroblast (Neuroblastoma), as well as retinoblastoma (retin〇blastoma). 40. The method of claim 38, which further comprises administering to the patient an antiproliferative agent listed in Table 3. 41. A method of inducing cell cycle arrest in a cell, the method comprising contacting the cell with a first agent that reduces the biological activity of mitogen kinesin and a second agent that reduces the biological activity of protein tyrosine phosphatase. 42. A method of identifying a combination that can be used to treat a proliferative disease, the method comprising the steps of: (a) Zai Li; ^ contacting a proliferating cell with a candidate compound that reduces the biological activity of mitogen kinesin; and ( b) increase compared to cells contacted with the preparation but not with the candidate compound 41 1084-6646-PF; Chiumeow 200526777. determine whether the combination of the preparation and the candidate compound reduces cell proliferation, where if cell proliferation Reduction means that the combination is a combination that can be used to treat a proliferative disease. 43. The method according to item 42 of the scope of the patent application, wherein the cell is a cancer cell or a cell from a cancer cell line. 44. A method for identifying a compound useful for treating a proliferative disease, the method comprising the steps of: (a) providing a proliferating cell having reduced mitogen kinesin biological activity; (b) contacting the cell with a candidate compound And (c) determining whether the candidate compound reduces cell proliferation compared to cells not contacted with the candidate compound, wherein if the cell proliferation is reduced, the compound is identified as a compound that can be used to treat a proliferative disease. 45. A method of identifying a combination that can be used to treat a proliferative disease, the method comprising the steps of: (a) contacting a candidate compound with a candidate compound for proliferative cells in a protocol that reduces the biological activity of a protein tyrosine phosphatase; And (b) determining whether the combination of the preparation and the candidate compound reduces cell proliferation compared to the proliferation of cells contacted with the preparation without contacting the candidate compound, where the combination is identified as available if the cell proliferation is reduced For the treatment of proliferative diseases. 46. The method of claim 45, wherein the cell is a cancer cell or a cell derived from a cancer cell line. 47. A method for identifying a compound useful for treating a proliferative disease, the method comprising the steps of: 1084-6646-PF; Chiumeow 42 200526777 (a) providing a proliferating cell having a reduced protein tyrosine phosphatase organism Activity; (b) contacting the cell with a candidate compound; and (c) determining whether the candidate compound reduces cell proliferation compared to cells not contacted with the candidate compound, wherein if the cell proliferation is reduced, the compound line is identified as available Compounds for the treatment of proliferative diseases. 48. A method of identifying a combination that can be used to treat a proliferative disease, the method comprising the steps of: (a) identifying a compound that reduces the biological activity of mitogen kinesin; (b) reducing the amino acid content of the protein at the invitation The enzyme biologically active preparation and the compound identified in step (a) are contacted with proliferating cells; and (c) compared to contact with the preparation but not with the compound identified in step (a), or with step (a) ) Proliferation of cells identified by the compound contacted but not by the preparation, determine whether the combination of the preparation and the compound identified in step (a) reduces cell proliferation, wherein if the cell proliferation is reduced, the combination is identified as available For the treatment of proliferative diseases. Φ 49. A method for identifying a combination that can be used to treat a proliferative disease, the method comprising the steps of: (a) identifying a compound that reduces the biological activity of protein tyrosine phosphatase; (b) Zai; Wiro) to reduce mitosis The kinesin biologically active preparation and the compound identified in step (a) are contacted with proliferating cells; and (c) compared to contact with the preparation but not with the compound identified in step (a), or in step ( a) Proliferation of cells identified by the compound contacted but not by the preparation, determine whether the combination of the preparation and the compound identified in step (a) reduces cell proliferation 1084-6646-PF; Chiumeow 43 200526777 Tyson, where If the cell proliferation is reduced, the combination is identified as a combination that can be used to treat a proliferative disease. 50 · —a kit comprising: (1) a composition comprising a first agent that reduces the biological activity of mitogen kinesin and a second agent that reduces the biological activity of protein tyrosine phosphatase; and (ii) ) # And instructions for use of the composition to a patient diagnosed with a proliferative disease. 51 · —a kit comprising: (i) a first agent that reduces the biological activity of mitogen kinesin; (ii) a second agent that reduces the biological activity of protein tyrosine phosphatase; and (111) administering the first agent Instructions for use with a second preparation to a patient diagnosed with a proliferative disease. 52 · — A kit comprising (i) a first agent that reduces the biological activity of mitotic kinesin and (ii) administration of the first and second agents that reduce the biological activity of protein melamine phosphokinase to a diagnosed Instructions for use in patients with proliferative diseases. 53 · — A kit comprising (丨) a first agent that reduces the biological activity of protein tyrosine phosphatase and (ii) administration of the first and second agents that reduce the biological activity of mitotic kinesin to a diagnosed patient Instructions for use in patients with proliferative diseases. 54. A method of identifying a combination that can be used to treat a proliferative disease, the method comprising the steps of: (a) exposing cells to proliferative contact with a candidate compound with a preparation that reduces the biological activity of mitogen kinesin; and (b) ) Compared to the proliferation of cells contacted with the preparation but not with the candidate compound ', it is determined whether the combination of the preparation and the candidate compound reduces cell proliferation, wherein if the cell proliferation is reduced, the combination is identified as being useful for treating proliferation 1084-6664-PF; Chiumeow 44 200526777 combination. 55. The method according to item 54 of the scope of patent application, wherein the agent that reduces the biological activity of a mitogen-driven protein is a mitogen-driven protein inhibitor. 56. The method according to item 54 of the scope of patent application, wherein the agent that reduces the biological activity of a mitogen-driven protein is an antisense compound or a ribonucleic acid interference (RNAi) compound, which can reduce the expression of the mitogen-driven protein. 57. The method according to item 54 of the scope of the patent application, wherein the agent that reduces the biological activity of a mitogen-driven protein is a mitotic motor protein or a performance vector encoding the mitotic motor protein. 58. The method according to item 54 of the scope of patent application, wherein the agent that reduces the biological activity of mitogen-driven protein is an antibody that binds to the mitogen-driven protein and reduces the biological activity of mitogen-driven protein. 59. The method as described in claim 54 in the patent application scope, wherein the mitotic driving protein is HsEg5 / KSP. 60. The method according to item 54 of the scope of the patent application, wherein the agent that reduces the biological activity of a mitogen-driven protein is a dawn kinase inhibitor. 61. The method according to item 54 of the scope of patent application, wherein the biological activity of the mitotic kinesin is enzyme activity, motor activity, or binding activity. The method according to the scope of item 54, wherein the cell is a cancer cell or a cell derived from a cancer cell line. 63. A method of identifying a compound that can be used to treat a proliferative disease, the method comprising the steps of: (a) providing a proliferating cell having reduced mitotic kinesin biological activity; (b) contacting the candidate with a candidate compound Cells; and 1084-6646-PF; Chiumeow 45 200526777 (C) Determine whether the candidate compound reduces cell proliferation compared to cells not contacted with the candidate compound, and if the cell proliferation is reduced, the compound line is identified as being useful for treatment Compounds for proliferative diseases. 64. The method of claim 63, wherein the cell is a cancer cell or a cell from a cancer cell line. 65. A method of identifying a combination that can be used to treat a proliferative disease, the method comprising the steps of: (a) proliferating cells in contact with a candidate compound in a formulation that reduces the biological activity of a protein glutamate; and (b) determining whether the combination of the preparation and the candidate compound reduces cell proliferation compared to the proliferation of cells contacted with the preparation but not with the candidate compound, wherein if the cell proliferation is reduced, the combination is identified as being useful for treatment A combination of proliferative diseases. 66. The method of claim 65, wherein the agent that reduces the biological activity of protein tyrosine phosphatase is a protein tyrosine phosphatase inhibitor. 67. The method of claim 65, wherein the preparation that reduces the biological activity of a protein tyrosine phosphatase is an antisense compound or a ribonucleic acid interference (RNA i) compound, which can reduce the protein tyrosine Phosphatase expression. 68. The method of claim 65, wherein the agent that reduces the biological activity of protein tyrosine phosphatase is a protein that significantly inhibits protein tyrosine phosphatase or a protein encoding the protein that significantly inhibits protein tyrosine phosphatase Performance vector. 69. The method of claim 65, wherein the preparation that reduces the biological activity of protein tyrosine phosphatase is an antibody that binds to the protein tyrosine phosphatase and reduces the protein tyrosine phosphatase Biological activity. 70. The method according to item 64 of the scope of patent application, wherein the protein tyrosine phosphate 1084-6646-PF / Chiumeow 46 200526777 enzyme is protein tyrosine phosphatase ΙΒ (ΡΤΡΙΒ), which regenerates phosphatase-1 of the liver. (PRL-1), reconstituted liver phytase-2, regenerated liver phytase-3, Src homolog-acidase-1 (SHP-1), Src homophosphatase-2, MAPK phosphatase- 1 (MKP-1), MAPK phosphatase-2, cell division cycle 14 (CDC14), cell division cycle 25A (CDC25A), cell division cycle 26B 'or cell division cycle 25C. 71. The method of claim 65, wherein the second agent is a farnesyl transferase inhibitor. 72. The method of claim 65, wherein the cell is a cancer cell or a cell from a cancer cell line. 73. A method of identifying a compound that can be used to treat a proliferative disease, the method comprising the steps of: (a) providing a proliferating cell having reduced protein tyrosine phosphatase biological activity; (b) using a candidate The compound contacts the cell; and (c) determines whether the candidate compound reduces cell proliferation compared to cells not contacted with the candidate compound, where the compound is identified as a compound useful for treating a proliferative disease if the cell proliferation is reduced. 74. A method of identifying a combination that can be used to treat a proliferative disease, the method comprising the steps of: (a) identifying a compound that reduces the biological activity of mitogen kinesin; (b) on Li Xi / * (//? To A preparation that reduces the biological activity of a protein glutamate and the cell identified by step (a) in contact with a proliferating cell; and (c) compared to a compound contacted with the preparation but not identified in step (a) Contact, or contact with the compound identified in step (a) but not in contact with the preparation of cell proliferation, determine whether the combination of the preparation and the compound determined in step (a) reduces cell proliferation, 1084-6646-PF; Chiumeow 47 200526777 Where the combination is identified as a combination that can be used to treat a proliferative disease if cell proliferation is reduced. 75. A method of identifying a combination that can be used to treat a proliferative disease, the method comprising the following steps: (a) identifying a Compounds that reduce the biological activity of protein tyrosine phosphatase; (b) Preparations for reducing the biological activity of mitotic kinesin in Li // (// 7 W60) and the steps (a) The compound identified contacts proliferative cells; and (c) compared to contact with the formulation but not with the compound identified in step (a), or contact with the compound identified in step (a) but without the formulation The proliferation of the exposed cells determines whether the combination of the preparation and the compound identified in step (a) reduces cell proliferation, and if the cell proliferation decreases, the combination is identified as a combination that can be used to treat a proliferative disease. 1084-6646- PF; Chiumeow 48 200526777 VII. Designated representative maps ... (1) The designated representative maps in this case are: None. (2) The component symbols of this representative map are simply explained: No. 8. If there is a chemical formula in this case, please disclose the best display Inventive chemical formula: None 0 1084-6646-PF; Chiumeow
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