201143766 六、發明說明： 【發明所屬之技術領域】 本發明係關於一種新穎之抗腫瘤劑及將太平洋紫杉醇及 卡鉑組合而成之抗腫瘤劑之抗腫瘤效果增強劑，該抗腫瘤 劑係將太平洋紫杉醇、卡鉑及（Z)-5-[(l，2-二氫-2-氧代_3H_ 0引0朵-3 -亞基）曱基]2,4-二甲基-1H-0比嗜· -3 -丙酸（以下稱為 「TSU-68」）或其鹽組合而成，該抗腫瘤劑之抗腫瘤效果 增強劑係以TSU-68或其鹽作為有效成分。 【先前技術】 一般認為太平洋紫杉醇或卡鉑等抗腫瘤劑係藉由對腫瘤 細胞之殺細胞作用而表現出抗腫瘤效果。先前，作為針對 發展、復發之肺癌或卵巢癌之化學療法，採用併用太平洋 紫杉醇及卡翻之治療法（以下稱為「太平洋紫杉醇+卡翻併 用療法」）作為標準治療法。該併用療法係具有強大之抗 腫瘤效果之治療法’但認為延長生命之效果並不充分，亦 s忍為對於復發或轉移亦有一定之極限（非專利文獻1、非專 利文獻2)。 又，對太平洋紫杉醇+卡鉑併用療法中，進而併用針對 血管内皮生長因子（以下稱為「VEGF」）之單株抗體且具有 血管新生抑制作用之貝伐單抗的治療法進行研究（非專利 文獻3)。然而，貝伐單抗係抗體醫藥品，而且，就副作用 之觀點而言，該併用療法會帶來問題。因此，尋求一種副 作用較少且更有用之治療法。 (z)-3-[(2,4-一甲基。比σ各_5_基）亞甲基]-2-吲。朵嗣（以下稱 156616.doc 201143766 為「TSU-16」）係藉由阻礙作為VEGF受體之Flk l(以下亦 稱為KDR」）之胳胺酸的瑞破化，抑制腫瘤組織中血管 新生，從而阻斷氧及營養之供給，抑制腫瘤之增殖及轉移 的低分子化合物（專利文獻υ。並且，揭示有藉由於太平洋 紫杉醇+卡鉑併用療法中併用添加有TSU_丨6的3劑，從而增 強抗腫瘤效果（專利文獻2、非專利文獻4)。該治療法係對 發展、復發之肺癌或卵巢癌具有較高之治療效果的有用之 療法’但尋求一種更有用之治療法。 另一方面，已知TSU-68具有與TSU-16相同之氧代吲哚 骨架，阻礙Flk-Ι之酪胺酸之磷酸化。又，於體外（in vitr〇) 確認TSU-68除Flk-1以外，亦阻礙參與細胞内訊號傳達之 源自血小板之生長因子（以下稱為「PDGF」）受體、纖維母 細胞生長因子（以下稱為「FGF」）受體等之酪胺酸磷酸 化。進而，對皮下移植有各種人癌細胞株之裸鼠體内（in vivo)模型中之單獨口服投予TSU-68時之抗腫瘤效果進行 研究，結果發現對於肺癌、大腸癌、子宮癌等有腫瘤增殖 抑制效果（非專利文獻5)。進而又報告有TSU-68藉由與太 平洋紫杉醇併用，而增強抗腫瘤效果（非專利文獻6)。 [先前技術文獻] [專利文獻] [專利文獻1]國際公開WO1996-0401 16公報 [專利文獻2]國際公開WO2001-049287公報 [非專利文獻] [非專利文獻 1]N. Engl. J. Med· 346: 92, 2002。 156616.doc 201143766 [非專利文獻2] J. Natl· Cancer Inst. 95: 1320, 2003。 [非專利文獻3] N. Engl. J. Med. 355: 2542, 2006。 [非專利文獻 4] Proc. Am· Soc. Clin. Oncol. 20: abstr 389, 2001 〇 [非專利文獻 5] Cancer Res. 60: 4152, 2000。 [非專利文獻6]第60次曰本癌學會總會抄錄集58〇: abstr 2024, 2001 〇 【發明内容】 [發明所欲解決之問題] 本發明之目的在於提供一種顯示出明顯之抗腫瘤效果、 尤其是腫瘤增殖延遲效果，且副作用較少之新穎的抗腫瘤 劑及抗腫瘤效果增強劑。 [解決問題之技術手段] 本發明者#於上述情況，為了開發更有助於延長患者之 生存時間的癌症治療法’而對將太平洋紫杉醇+卡始併用 療法與其他抗腫瘤劑加以組合之新穎的併用療法進行反覆 研究，結果確認藉由併用作為參與血管新生之vegf、 PDGF等受體赂胺酸激酶之阻礙劑的則_68，而使太平洋 紫杉醇+卡翻併用療法之抗腫瘤效果明顯增強，另一方 面’未增強副作用之產生，從而完成本發明。於抗腫瘤劑 中重新併用其他抗腫瘤劑之情形時，通常隨著抗腫瘤效果 之增強’副作用亦增強，但令人驚奇的是如本發明所示可 同時實現明顯㈣之抗腫瘤效果、尤其是腫瘤增殖延遲效 果與較低之副作用之產生風險。 156616.doc 201143766 即，本發明提供以下1)〜7) β 1) 一種抗腫瘤劑，其係將太平洋紫杉醇、卡鉑及（ζ)_ 5-[(1，2-二氫-2-氧代_3Η令朵_3_亞基）甲基]24二曱基_ιη_ 。比0各-3 -丙酸或其鹽組合而成。 2) 如1)之抗腫瘤劑，其中太平洋紫杉醇、卡鉑及（ζ)_5_ [(1’2-二氫-2-氧代_3Η_吲哚_3_亞基）曱基]2,4_二曱基_ιη-吡 咯-3-丙酸或其鹽之莫耳比（太平洋紫杉醇：卡鉑：（ζ)_5· [(1’2-二氫-2-氧代_3Η-吲哚-3-亞基）曱基]2,4-二曱基·1Η-吡 咯-3-丙酸或其鹽）為1 : 0 ^500:0 54000。 3) 如1)之抗腫瘤劑，其中投予太平洋紫杉醇丨〜⑺⑼ mg/m (每體表面積）/day、卡始 0.1〜1〇〇 mg/mL/min(AUC)、 (Z)-5-[(l，2-二氫-2-氧代-3H-叫卜朵-3-亞基）曱基]2,4-二曱基-1H-。比咯-3-丙酸或其鹽50〜3000 mg/day。 4) 如1)至3)中任一項之抗腫瘤劑，其係將含有太平洋 紫杉醇之製劑、含有卡鉑之製劑及含有二氫·2_ 氧代_3H-吲哚-3-亞基）曱基]2,4-二曱基_1H-吡咯-3-丙酸或 其鹽之製劑組合而成。 5) 如1)至4)中任一項之抗腫瘤劑，其係包含含有太平 洋紫杉醇之製劑、含有卡鉑之製劑及含有，2_二 氫-2-氧代-3H-吲哚-3-亞基）曱基]2,4-二甲基-1H-吡咯-3-丙 酸或其鹽之製劑的套組製劑。 6) 如1)至5)中任一項之抗腫瘤劑，其中含有太平洋紫 杉醇之製劑及含有卡鉑之製劑係藉由靜脈内、肌肉内或皮 下之投予路徑而投予，含有（Z)-5-[(l，2-二氫-2-氧代-3H-吲 I56616.doc -6- 201143766 °朵·3-亞基）曱基]2,4-二曱基-1H-吡咯-3-丙酸或其鹽之製劑 係藉由口服之投予路徑而投予。 7) 一種抗腫瘤劑之抗腫瘤效果增強劑，其係以（z)_5_ [(1，2·二氫-2-氧代-3H-吲哚-3-亞基）曱基]2,4-二甲基-1H-吡 咯-3-丙酸或其鹽作為有效成分與太平洋紫杉醇及卡鉑組合 而成。 8) 一種併用療法的抗腫瘤效果增強劑，其係以（z)_5_ [(1，2-二氫-2-氧代-3H-吲哚-3-亞基）曱基]2,4-二甲基-m-吡 各3 -丙酸或其鹽作為有效成分與含有太平洋紫杉醇之抗腫 瘤劑及含有卡鉑之抗腫瘤劑併用。 9) 如7)或8)之抗腫瘤效果增強劑，其中（ζ)·5_[(1，2•二 氫-2-氧代-3Η-吲哚-3-亞基）曱基]2,4-二甲基-1Η-吡咯-3-丙 酸或其鹽之投予量為50〜3000 mg/day。 1〇) 一種併用太平洋紫杉醇、卡鉑及〇5_[(1，2_二氫_ 2-氧代-3H-吲哚_3_亞基）甲基]2,4_二甲基·1H_吡咯_3丙酸 或其鹽之方法’其係對腫瘤患者進行治療之方法。 11) 如10)之方法，其中投予太平洋紫杉醇卜丨❹⑽ mg/m2(每體表面積）/day、卡鉑 〇」〜_ mg/mL/min(AUC)、 (Z)-5-[(l，2-二氫-2-氧代-3H-吲哚-3-亞基）甲基]2,4-二甲基· ΙΗ-吼咯-3-丙酸或其鹽50〜3000 mg/day。 12) 如1〇)或u)之方法，其中太平洋紫杉醇及卡鉑係藉 由靜脈内、肌肉内或皮下之投予路徑而投予，（z)_5_[(1，2_ 二氫-2-氧代-3H-吲哚_3_亞基）甲基]2,4_二甲基_1H_吡咯-3-丙酸或其鹽係藉由口服之投予路徑而投予。 156616.doc 201143766 13) 一種太平洋紫杉醇、卡始及（Ζ)-5-[(1，2-二氫-2·氧 代-3Η导朵-3-亞基）曱基]2,4_二甲基丙酸或其 鹽之組合，其係用以治療腫瘤。 14) 如13)之組合，其中太平洋紫杉醇、卡鉑及（Ζ)-5-[(1，2-二氫-2-氧代·3]^卜朵_3亞基）甲基]2υ基_ιη“比 咯-3-丙酸或其鹽之莫耳比（太平洋紫杉醇：卡鉑：（ζ)_5_ [(1，2-二氫-2-氧代_3Η•十朵_3亞基）甲基]2,4二甲基_ιη“比 咯-3-丙酸或其鹽）為1 : 〇 ^500:0 5〜1〇〇〇。 15) 如13)之組合，其中投予太平洋紫杉醇卜l〇〇〇 mg/m2 (每體表面積）/day、卡鉑 〇uoo mg/mL/min(AUC)、（z)_5_ [(1，2-二氫-2-氧代_3H_吲哚_3_亞基）甲基]2,4·二甲基1H吡 咯-3-丙酸或其鹽50〜3000 mg/day。 16) 如13)至15)中任一項之組合，其係含有太平洋紫杉 醇之製劑、含有卡鉑之製劑及含有（z)_5_[(1，2_二氫_2_氧 代-3H_吲哚-3-亞基）曱基]2,4-二曱基-1H-吡咯-3-丙酸或其 鹽之製劑的組合》 17) 如13)至16)中任一項之組合，其係包含含有太平洋 紫杉醇之製劑、含有卡鉑之製劑及含有（Z)-5-[(l，2-二氫-2-氧代-3H-吲哚-3-亞基）曱基]2,4-二甲基-1H-吡咯-3-丙酸或 其鹽之製劑的套組製劑。 18) 如13)至18)中任一項之組合，其中含有太平洋紫杉 醇之製劑及含有卡鉑之製劑係藉由靜脈内、肌肉内或皮下 之投予路徑而投予，含有（Z)-5-[(l，2-二氫-2-氧代-3H-吲 哚-3-亞基）曱基]2,4-二曱基-1H-。比咯-3-丙酸或其鹽之製劑 156616.doc 201143766 係藉由口服之投予路徑而投予。 19) 一種（Z)-5-[(l，2-二氫 _2_ 氧代-3Η_ 吲哚 _3_ 亞基）曱 基]2,4-二曱基-1Η-吡咯-3-丙酸或其鹽，其係用作將太平洋 紫杉醇及卡銘組合而成之抗腫瘤劑的抗腫瘤效果增強劑。 20) —種（Z)-5-[(l，2-二氫-2-氧代 _3Η_, „朵 _3 亞基）甲 基]2,4-二甲基_ιη·吡咯-3-丙酸或其鹽，其係用作併用含有 太平洋紫杉醇之抗腫瘤劑及含有卡鉑之抗腫瘤劑之療法的 抗腫瘤效果增強劑。 21) 如19)或20)之化合物，其中投予（ζ)_5_[(12二氫_2_ 氧代-3Η-。引哚_3_亞基）甲基]2,4_二甲基吡咯小丙酸或 其鹽 50〜3000 mg/day。 22) 一種用以製造抗腫瘤劑之用途，其中該抗腫瘤劑 為太平洋紫杉醇、卡鉑及（Ζ)_5·[(1，2_二氫_2_氧代_3H_吲哚_ 3·亞基）甲基]2,4-二甲基-1H-吡咯-3-丙酸或其鹽之組合。 23) 如22)之用途，其中太平洋紫杉醇、卡鉑及（z)_5_ [(1，2_二氫_2-氧代_3Η·吲哚-3-亞基）甲基]2,4-二曱基-1H-吡 咯_3_丙酸或其鹽之莫耳比（太平洋紫杉醇：卡鉑：（z)_5_ [(1，2-二氫_2-氧代-3H-吲哚-3-亞基）曱基]2,4-二曱基-m-吡 "各-3-丙酸或其鹽）為1 : 0.1〜500:0.5〜1000。 24) 如22)之用途’其中投予太平洋紫杉醇1〜1000 mg/m2 (母體表面積）/day、卡鉑οι〜1〇〇、（Z)-5-[(1，2-二氫_2-氧代_311_吲哚_3_亞基）甲基]2,4_二甲基_111_吡 各3丙g夂或其鹽5〇〜3000 mg/day。 25) 如22)至24)中任一項之用途，其中該抗腫瘤劑係含 1566I6.doc 201143766 有太平洋紫杉醇之製劑、含有卡鉑之製劑及含有（Z)-5-[(1，2-二氫-2·氧代_3H-吲哚-3-亞基）甲基]2,4_二曱基 咯-3-丙酸或其鹽之製劑的組合。 26) 如22)至25)中任一項之用途，其中該抗腫瘤劑係包 含含有太平洋紫杉醇之製劑、含有卡鉑之製劑及含有（Z)-5-[(1’2-二氫-2-氧代_阳_吲哚_3-亞基）曱基]2,4-二曱基-1H-。比洛-3-丙酸或其鹽之製劑的套組製劑。 27) 如22)至26)中任一項之用途，其中含有太平洋紫杉 醇之製劑及含有卡翻之製劑係藉由靜脈内、肌肉内或皮下 之投予路徑而投予，含有二氫-2-氧代_3Η·吲 °朵-3-亞基）曱基]2,4-二曱基-1Η-吡咯-3-丙酸或其鹽之製劑 係藉由口服之投予路徑而投予。 28) —種（Z)-5-[(l，2-二氫-2-氧代-3Η-吲哚-3-亞基）曱 基]2,4-二甲基-1Η-吡咯-3-丙酸或其鹽之用途，其係用以製 造將太平洋紫杉醇及卡鉑組合而成之抗腫瘤劑的抗腫瘤效 果增強劑。 29) —種（Z)-5_[(l，2-二氫-2-氧代-3Η-吲哚 _3_亞基）甲 基]2,4-二甲基-1Η-吡咯-3-丙酸或其鹽之用途，其係用以製 造併用含有太平洋紫杉醇之抗腫瘤劑及含有卡鉑之抗腫瘤 劑之療法的抗腫瘤效果增強劑。 30) 如28)或29)之用途’其中投予（ζ)·5_[(1，2二氫_2_氧 代-3Η-吲哚-3-亞基）甲基]2,4-二甲基_1Η-吡咯丙酸或其 鹽 50〜3〇〇〇 mg/day。 [發明之效果] 156616.doc •10· 201143766 本發明之將太平洋紫杉醇、卡鉑及TSU-68或其鹽組合而 成的抗腫瘤劑與併用先前之抗腫瘤劑相比較，實現明顯較 南之抗腫瘤效果’例如減少腫瘤體積或抑制腫瘤增殖等效 果’且意外地未増強副作用之產生。因此，藉由使用本發 明之抗腫瘤劑’腫瘤患者可獲得更長之生存時間。 【實施方式】 本發明中所使用之太平洋紫杉醇係由（_)_ (13’2^，43,511，73,88，服，133)-4，10-二乙酿氧基_2_苯甲 醯氧基-5,20-環氧_〖，7_二羥基_9_氧前列腺“^烯-^基 (R,3S)3本甲醯基胺基_2_經基_3_苯基丙酸g旨所示之公知 的化合物’例如可依據j Am_ Chem. Soc. 93: 2325，1971所 記載之方法而製造。 太平洋紫杉醇係如下之化合物：單獨投予時，阻礙細胞 骨架之微管之解聚合，使細胞週期於G2/M期停止而阻礙 細胞分裂，藉此發揮抗腫瘤效果，並對卵巢癌、非小細胞 肺癌、乳癌、胃癌、子宮體癌等顯示出有用性。 本發明中所使用之卡鉑係由順-二胺（丨，丨_環丁烷二羧酸 酉曰）翻（II)所示之公知的化合物，例如可依據美國專利 414〇7〇7號公報所記載之方法而製造。 卡翻係如下化合物：單獨投予時，藉由與細胞内之Dna 結合而引起DNA之功能障礙及DNA鏈之斷裂，藉此殺滅腫 瘤細胞’對頭頸癌、肺小細胞癌、睾丸腫瘤、卵巢癌、子 宮頸癌、惡性淋巴瘤、非小細胞肺癌等顯示出有用性。 本發明中所使用之TSU-68係由（Z)-5-[(l，2，-二氫_2-氧代- 156616.doc 201143766 3Η-Μ·3-亞基）甲基]2,4_二曱基备料3_丙酸所示之 公知的勝卜1>卿受體等之路胺酸激酶阻礙劑，已知單 獨投予時，實現針對肝癌、肺癌、大腸癌、子宮癌等實體 癌之抗腫瘤效果。TS⑽或其鹽可藉由公知之方法，例如 日本專利特表20()2-5163職公報所記載之方法而製造。 作為TSU_68H要為藥學上所料之鹽則無特別限 制，例如可例示藉由與鹽酸、氫漠酸、硫酸、硝酸、碟酸 等無機酸’或甲磺酸、乙磺酸，苯磺酸、水楊酸等有 機酸進行反應而獲得之鹽。 本發明之抗腫瘤劑中用以組合太平洋紫杉醇、卡鉑及 TSU-68或其鹽之各有效成分的比例只要在實現抗腫瘤效果 之範圍内，則無特別限制，例如，作為丨天量，只要相對 於太平洋i杉醇1莫耳，卡鉑較佳為設為〇uoo莫耳左 右、更佳為0.5〜1〇〇莫耳左右、尤佳為卜5〇莫耳左右； TSU 68或其鹽較佳為没為〇 5〜ι 〇〇〇莫耳左右進而佳為 1〜500莫耳左右、尤佳為3〜5〇莫耳左右即可。 本發明之抗腫瘤劑或抗腫瘤效果增強劑中之各有效成分 之投予量，只要為實現其抗腫瘤效果或增強抗腫瘤效果之 量則無特別限制，根據患者之年齡、癌種、病期 '有無轉 移、治療史、有無其他抗腫瘤劑等患者之狀態而適當設 定。太平洋紫杉醇之投予量較佳為biOOO mg/m2(每體表 面積）/day，更佳為10〜500 mg/m2/day，尤佳為5〇〜3〇〇 mg/m2/day。卡始之投予量較佳為3〜3〇〇〇 mg/rn2/day，更佳 為 1 0〜2000 mg/m2/day ’ 尤佳為 200〜1 〇〇〇 mg/m2/day。TSU- 156616.doc -12- 201143766 68或其鹽之投予量較佳為5〇〜3〇〇〇 mg/day，更佳為 2〇0~1500 mg/day，尤佳為 4〇〇 〜8〇〇 mg/day。再者，關於卡 I白之投予里’亦例如可藉由Calvert式、Chatelut式、 Jelhffe式、Cockcroft式，根據腎排泄功能之指標及卡鉑之 血中藥物濃度之時間曲線下面積（以下稱為「AUC」）而適 當設定。腎排泄功能之指標可以例如患者之肌酸酐清除值 (CCR 值，Creatinine Clearance Rate)、血尿素氮值（BUN 值，Blood Urea Nitrogen Level)、腎小球濾過率（GFR值，201143766 VI. Description of the Invention: [Technical Field] The present invention relates to a novel antitumor agent and an antitumor agent for an antitumor agent comprising a combination of paclitaxel and carboplatin, the antitumor agent Pacific paclitaxel, carboplatin, and (Z)-5-[(l,2-dihydro-2-oxo_3H_ 0-involved-3-ytyl)indenyl]2,4-dimethyl-1H- 0 is a combination of meto-3-propionic acid (hereinafter referred to as "TSU-68") or a salt thereof, and the antitumor effect enhancer of the antitumor agent is TSU-68 or a salt thereof as an active ingredient. [Prior Art] Antitumor agents such as paclitaxel or carboplatin are generally considered to exhibit an antitumor effect by cytocidal action on tumor cells. Previously, as a chemotherapy for the development and recurrence of lung cancer or ovarian cancer, a combination of paclitaxel and cardiotherapy (hereinafter referred to as "pacific paclitaxel plus card therapy") was used as a standard treatment. This combination therapy has a strong therapeutic effect against tumor effects, but it is considered that the effect of prolonging life is not sufficient, and there is also a limit to recurrence or metastasis (Non-Patent Document 1 and Non-Patent Document 2). In addition, in the combination of paclitaxel and carboplatin, the treatment of bevacizumab with angiogenesis inhibitory effect on vascular endothelial growth factor (hereinafter referred to as "VEGF") is used in combination (non-patent) Document 3). However, bevacizumab is an antibody drug, and this combination therapy causes problems in terms of side effects. Therefore, a treatment with less side effects and more usefulness is sought. (z)-3-[(2,4-Methyl. Ratio σ____) methylene]-2-oxime.嗣 嗣 (hereinafter referred to as 156616.doc 201143766 for "TSU-16") inhibits angiogenesis in tumor tissues by blocking the ruthenium of lysine which is a Flk l (hereinafter also referred to as KDR) as a VEGF receptor. a low-molecular compound that blocks the supply of oxygen and nutrients and inhibits the proliferation and metastasis of tumors (Patent Document υ. Also, it is revealed that three doses of TSU_丨6 added by the combination of paclitaxel and carboplatin are disclosed. Thereby, the anti-tumor effect is enhanced (Patent Document 2, Non-Patent Document 4). This treatment method is a useful therapy for developing a recurrent lung cancer or ovarian cancer with a high therapeutic effect' but seeks a more useful treatment method. On the one hand, it is known that TSU-68 has the same oxo-indole skeleton as TSU-16, which hinders the phosphorylation of tyrosine of Flk-Ι. In addition, it is confirmed in vitro (in vitr〇) that TSU-68 is in addition to Flk-1. In addition, it also inhibits tyrosine phosphorylation of platelet-derived growth factor (hereinafter referred to as "PDGF") receptor, fibroblast growth factor (hereinafter referred to as "FGF") receptor, which is involved in intracellular signal transmission. Further, subcutaneous transplantation The anti-tumor effect of oral administration of TSU-68 alone in a nude mouse model of human cancer cell lines was studied, and it was found that tumor growth inhibition effects were observed for lung cancer, colon cancer, and uterine cancer. Patent Document 5) Further reported that TSU-68 enhances the antitumor effect by using it in combination with paclitaxel (Non-Patent Document 6). [Prior Art Document] [Patent Document] [Patent Document 1] International Publication WO1996-0401 [Publication Document 2] International Publication WO2001-049287 [Non-Patent Document] [Non-Patent Document 1] N. Engl. J. Med. 346: 92, 2002. 156616.doc 201143766 [Non-Patent Document 2] J. Natl. Cancer Inst. 95: 1320, 2003. [Non-Patent Document 3] N. Engl. J. Med. 355: 2542, 2006. [Non-Patent Document 4] Proc. Am. Soc. Clin. Oncol. 20: abstr 389, 2001 〇 [Non-Patent Document 5] Cancer Res. 60: 4152, 2000. [Non-Patent Document 6] The 60th sputum of the Society of Cancer Society transcripts 58 〇: abstr 2024, 2001 〇 [Summary of the Invention] [Invention The problem to be solved] The object of the present invention is to provide a remarkable anti-tumor effect, In particular, a novel antitumor agent and an antitumor effect enhancer having a tumor growth delay effect and having few side effects. [Technical means for solving the problem] In the above case, in order to develop, it is more advantageous to prolong the survival time of the patient. The cancer treatment method's repeated research on the novel combined therapy combining paclitaxel + card combination therapy with other anti-tumor agents, and the results confirmed that the combination of vegf, PDGF and other receptors is involved in angiogenesis. The inhibitor of the kinase is _68, and the anti-tumor effect of the paclitaxel plus card therapy is significantly enhanced, and on the other hand, the occurrence of side effects is not enhanced, thereby completing the present invention. When re-using other anti-tumor agents in an anti-tumor agent, the side effects are generally enhanced as the anti-tumor effect is enhanced, but it is surprising that the anti-tumor effect (i) can be simultaneously achieved as shown in the present invention. It is the risk of delayed tumor growth and the risk of lower side effects. 156616.doc 201143766 That is, the present invention provides the following 1) to 7) β 1) an antitumor agent which comprises paclitaxel, carboplatin and (ζ)_ 5-[(1,2-dihydro-2-oxo) Generation _3 Η令朵_3_亚基)methyl]24 曱 __ιη_. It is a combination of 0--3-propionic acid or a salt thereof. 2) an antitumor agent such as 1), wherein paclitaxel, carboplatin and (ζ)_5_[(1'2-dihydro-2-oxo_3Η_吲哚_3_subunit) fluorenyl]2, Molar ratio of 4_dimercapto_ιη-pyrrole-3-propionic acid or its salt (Pacific paclitaxel: carboplatin: (ζ)_5· [(1'2-dihydro-2-oxo_3Η-吲) Indole-3-indenyl) indenyl] 2,4-dimercapto-indolylpyrrole-3-propionic acid or a salt thereof is 1:0 ^500:0 54000. 3) An antitumor agent according to 1), wherein paclitaxel 丨~(7)(9)(9) mg/m (per body surface area)/day, card start 0.1~1〇〇mg/mL/min (AUC), (Z)-5 -[(l,2-dihydro-2-oxo-3H-called bado-3-ylidene) fluorenyl] 2,4-dimercapto-1H-. Biloxi-3-propionic acid or its salt 50~3000 mg/day. 4) The antitumor agent according to any one of 1) to 3) which comprises a formulation of paclitaxel, a preparation containing carboplatin, and a dihydro-2-yl-oxo-3H-indol-3-subunit) A combination of a thiol]2,4-dimercapto-1H-pyrrole-3-propionic acid or a salt thereof. 5) The antitumor agent according to any one of 1) to 4, which comprises a formulation containing paclitaxel, a formulation containing carboplatin, and a compound containing 2, dihydro-2-oxo-3H-indole-3 a kit preparation of a preparation of -ylidene]mercapto]2,4-dimethyl-1H-pyrrol-3-propionic acid or a salt thereof. 6) The antitumor agent according to any one of 1) to 5, wherein the preparation containing paclitaxel and the preparation containing carboplatin are administered by intravenous, intramuscular or subcutaneous administration, and contain (Z) )-5-[(l,2-dihydro-2-oxo-3H-oxime I56616.doc -6- 201143766 ° Dol 3-substyl) fluorenyl] 2,4-dimercapto-1H-pyrrole The formulation of -3-propionic acid or a salt thereof is administered by an oral administration route. 7) An antitumor effect enhancer of an antitumor agent, which is (z)_5_[(1,2·dihydro-2-oxo-3H-indol-3-ylidene) fluorenyl] 2,4 -Dimethyl-1H-pyrrol-3-propionic acid or a salt thereof is used as an active ingredient in combination with paclitaxel and carboplatin. 8) An anti-tumor effect enhancer for combination therapy with (z)_5_[(1,2-dihydro-2-oxo-3H-indol-3-ylidene) fluorenyl]2,4- Dimethyl-m-pyridyl 3-propionic acid or a salt thereof is used as an active ingredient in combination with an antitumor agent containing paclitaxel and an antitumor agent containing carboplatin. 9) an anti-tumor effect enhancer such as 7) or 8), wherein (ζ)·5_[(1,2•dihydro-2-oxo-3Η-吲哚-3-ylidene) fluorenyl]2, The dose of 4-dimethyl-1Η-pyrrole-3-propionic acid or a salt thereof is 50 to 3000 mg/day. 1〇) A combination of paclitaxel, carboplatin and hydrazine 5_[(1,2_dihydro-2-oxo-3H-indole_3_ylidene)methyl]2,4_dimethyl·1H_ A method of pyrrole-3-propionic acid or a salt thereof is a method of treating a tumor patient. 11) The method according to 10), wherein paclitaxel is administered (10) mg/m2 (per body surface area)/day, carboplatin 〜~_mg/mL/min (AUC), (Z)-5-[( l,2-Dihydro-2-oxo-3H-indole-3-ylidene)methyl]2,4-dimethyl-indole-purine-3-propionic acid or its salt 50~3000 mg/ Day. 12) A method according to 1) or u), wherein paclitaxel and carboplatin are administered by intravenous, intramuscular or subcutaneous administration, (z)_5_[(1,2_dihydro-2- Oxo-3H-indole-3-ylidene)methyl]2,4-dimethyl-1H-pyrrole-3-propionic acid or a salt thereof is administered by an oral administration route. 156616.doc 201143766 13) A paclitaxel, carbaryl and (Ζ)-5-[(1,2-dihydro-2.oxo-3Ηconducting-3-ylidene) fluorenyl]2,4_2 A combination of methylpropionic acid or a salt thereof for treating a tumor. 14) A combination of 13), wherein paclitaxel, carboplatin, and (Ζ)-5-[(1,2-dihydro-2-oxo-3]^bodo_3 subunit)methyl]2 fluorenyl _ιη" molar ratio of pyrrol-3-propionic acid or its salt (Pacific paclitaxel: carboplatin: (ζ)_5_ [(1,2-dihydro-2-oxo_3Η•10 _3 subunits) )methyl]2,4 dimethyl-ιη "pyrrol-3-propionic acid or a salt thereof" is 1: 〇^500:0 5~1〇〇〇. 15) A combination of 13), in which paclitaxel is administered, l〇〇〇mg/m2 (per body surface area)/day, carboplatin 〇uoo mg/mL/min (AUC), (z)_5_ [(1, 2-Dihydro-2-oxo_3H_吲哚_3_ylidene)methyl]2,4·dimethyl-1Hpyrrole-3-propionic acid or a salt thereof 50 to 3000 mg/day. 16) A combination according to any one of 13) to 15), which comprises a formulation of paclitaxel, a formulation containing carboplatin, and (z)_5_[(1,2_dihydro-2-oxo-3H_) Combination of a formulation of indole-3-phenyl)indenyl]2,4-dimercapto-1H-pyrrol-3-propionic acid or a salt thereof; 17) a combination according to any one of 13) to 16), It comprises a formulation containing paclitaxel, a formulation containing carboplatin, and a (Z)-5-[(l,2-dihydro-2-oxo-3H-indol-3-yl)indenyl]2 A kit preparation of a formulation of 4-dimethyl-1H-pyrrol-3-propionic acid or a salt thereof. 18) The combination according to any one of 13) to 18), wherein the preparation containing paclitaxel and the preparation containing carboplatin are administered by intravenous, intramuscular or subcutaneous administration route, containing (Z)- 5-[(l,2-Dihydro-2-oxo-3H-indol-3-yl)indenyl] 2,4-diindenyl-1H-. Formulation of bromo-3-propionic acid or a salt thereof 156616.doc 201143766 is administered by an oral administration route. 19) a (Z)-5-[(l,2-dihydro-2-oxo-3Η_吲哚_3_ylidene) fluorenyl] 2,4-dimercapto-1Η-pyrrole-3-propionic acid or The salt thereof is used as an antitumor effect enhancer for an antitumor agent obtained by combining paclitaxel and kamin. 20) —(Z)-5-[(l,2-dihydro-2-oxo_3Η_, „朵_3 subunit) methyl]2,4-dimethyl-_ιη·pyrrole-3- Propionic acid or a salt thereof, which is used as an antitumor effect enhancer for the combination of an antitumor agent containing paclitaxel and an antitumor agent containing carboplatin. 21) A compound according to 19) or 20), wherein ζ)_5_[(12 dihydro-2_ oxo-3 Η-. 哚 _3_ subunit) methyl] 2,4-dimethylpyrrole small propionic acid or its salt 50~3000 mg/day. 22) A use for the manufacture of an antitumor agent, wherein the antitumor agent is paclitaxel, carboplatin and (Ζ)_5·[(1,2_dihydro-2-oxo_3H_吲哚_3· subunit a combination of methyl]2,4-dimethyl-1H-pyrrol-3-propionic acid or a salt thereof. 23) The use of 22), wherein paclitaxel, carboplatin and (z)_5_ [(1, 2) _Dihydro-2-oxo_3Η·吲哚-3-ylidene)methyl]2,4-dimercapto-1H-pyrrole_3_propionic acid or its salt molar ratio (Pacific paclitaxel: card Platinum: (z)_5_ [(1,2-dihydro-2-oxo-3H-indol-3-yl)indenyl] 2,4-diindolyl-m-pyridyl" Propionic acid or its salt) is 1: 0.1~500: 0.5~1000. 24) As 22) 'In the course of the administration of paclitaxel 1~1000 mg/m2 (parent surface area)/day, carboplatin οι~1〇〇, (Z)-5-[(1,2-dihydro-2-oxo_311_吲哚_3_subunit)methyl]2,4-dimethyl-111-pyridyl 3 propyl g- or its salt 5 〇~3000 mg/day. 25) Any of 22) to 24) The anti-tumor agent comprises 1566I6.doc 201143766 a formulation having paclitaxel, a formulation containing carboplatin and containing (Z)-5-[(1,2-dihydro-2.oxo_3H-吲) A combination of a preparation of the indole-3-indolyl)methyl]2,4-diindolyl-3-propionic acid or a salt thereof, wherein the antitumor is used according to any one of 22) to 25) The agent comprises a formulation containing paclitaxel, a formulation containing carboplatin, and a (Z)-5-[(1'2-dihydro-2-oxo-yang_吲哚_3-subunit) fluorenyl group] a kit preparation of a formulation of 4-dimercapto-1H-.Bilo-3-propionic acid or a salt thereof. 27) The use according to any one of 22) to 26), which comprises a formulation and a content of paclitaxel The cardinal preparation is administered by intravenous, intramuscular or subcutaneous administration, and contains dihydro-2-oxo_3Η·吲°-3-ylidene] sulfhydryl]2,4-di The preparation of keto-pyrrol-3-propionic acid or a salt thereof is administered by an oral administration route. 28) - (Z)-5-[(l,2-dihydro-2-oxo) -3Η-吲哚-3-indolyl)indenyl] 2,4-dimethyl-1Η-pyrrole-3-propionic acid or a salt thereof for use in the manufacture of a combination of paclitaxel and carboplatin Antitumor effect enhancer for antitumor agents. 29) —(Z)-5_[(l,2-Dihydro-2-oxo-3Η-吲哚_3_ylidene)methyl]2,4-dimethyl-1Η-pyrrole-3- The use of propionic acid or a salt thereof for the manufacture and use of an antitumor effect enhancer comprising a paclitaxel-containing antitumor agent and a carboplatin-containing antitumor agent. 30) For the use of 28) or 29) 'wherein (ζ)·5_[(1,2 dihydro-2-oxo-3Η-indol-3-ylidene)methyl]2,4-di Methyl-1-indole-pyrrolidic acid or a salt thereof is 50 to 3 mg/day. [Effects of the Invention] 156616.doc •10· 201143766 The antitumor agent of the present invention which combines paclitaxel, carboplatin and TSU-68 or a salt thereof is compared with the prior antitumor agent, and is substantially more southward. The anti-tumor effect 'for example, reducing tumor volume or inhibiting tumor proliferation and the like' and unexpectedly does not force the occurrence of side effects. Therefore, a longer survival time can be obtained by using the antitumor agent of the present invention. [Embodiment] The paclitaxel used in the present invention is (_)_(13'2^, 43,511,73,88, serving, 133)-4,10-diethyloxy-2-benzamide. Oxy-5,20-epoxy_[7,7-dihydroxy-9-oxoprostate"^-yl (R,3S)3-methionylamino-2_trans-base_3_phenylpropane A well-known compound represented by the acid g can be produced, for example, according to the method described in j Am. Chem. Soc. 93: 2325, 1971. Pacific paclitaxel is a compound which inhibits microtubules of the cytoskeleton when administered alone. Depolymerization, which stops the cell cycle in the G2/M phase and inhibits cell division, thereby exerting an antitumor effect and exhibiting usefulness for ovarian cancer, non-small cell lung cancer, breast cancer, gastric cancer, endometrial cancer, and the like. The carboplatin used is a known compound represented by cis-diamine (丨, 丨-cyclobutanedicarboxylate) (II), and can be, for example, described in U.S. Patent No. 4,414,7. It is manufactured by the method. The card is the following compound: when administered alone, it can kill DNA dysfunction and DNA strand break by binding to Dna in the cell. Tumor cells have shown usefulness for head and neck cancer, small cell lung cancer, testicular tumor, ovarian cancer, cervical cancer, malignant lymphoma, non-small cell lung cancer, etc. The TSU-68 system used in the present invention is (Z) -5-[(l,2,-Dihydro-2-oxo-156616.doc 201143766 3Η-Μ·3-subunit)methyl] 2,4-diindenyl stock 3-propionic acid is known It is known that when it is administered alone, it is known to be effective against tumors against solid cancers such as liver cancer, lung cancer, colon cancer, and uterine cancer. TS (10) or its salt can be used by A well-known method, for example, is produced by the method described in the Japanese Patent Publication No. 20(2) 2-5163. The salt to be pharmaceutically acceptable as TSU_68H is not particularly limited, and for example, it can be exemplified by hydrochloric acid and hydrochloric acid. a salt obtained by reacting an inorganic acid such as sulfuric acid, nitric acid or a dish acid or an organic acid such as methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid or salicylic acid. The antitumor agent of the present invention is used for combining paclitaxel, The ratio of each active ingredient of carboplatin and TSU-68 or its salt is not included in the range of achieving antitumor effect. In particular, for example, as a day, as long as it is 1 mol relative to the Pacific cedar, carboplatin is preferably set to about 〇uoo Mo, more preferably 0.5 to 1 〇〇 Mo, or better. 5〇莫耳左右; TSU 68 or its salt is preferably not 〇5~ι 〇〇〇 耳 左右 进而 进而 进而 进而 佳 佳 佳 佳 佳 佳 佳 佳 佳 佳 佳 佳 佳 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 1 The administration amount of each active ingredient in the antitumor agent or the antitumor effect enhancer of the invention is not particularly limited as long as it is an antitumor effect or an antitumor effect, depending on the age, cancer type, and disease period of the patient. 'Appropriate setting for the status of patients with or without metastasis, treatment history, and other anti-tumor agents. The dosage of paclitaxel is preferably biOOOO mg/m2 (per body surface area) per day, more preferably 10 to 500 mg/m2/day, and particularly preferably 5 to 3 mg/m2/day. The dosage at the beginning of the card is preferably 3 to 3 mg/rn2/day, more preferably 10 to 2000 mg/m2/day', and particularly preferably 200 to 1 〇〇〇 mg/m2/day. The dosage of TSU-156616.doc -12- 201143766 68 or its salt is preferably 5〇~3〇〇〇mg/day, more preferably 2〇0~1500 mg/day, especially preferably 4〇〇~ 8〇〇mg/day. Furthermore, regarding the administration of the card I white, it is also possible, for example, by Calvert type, Chatelut type, Jelhffe type, Cockcroft type, according to the index of renal excretion function and the area under the time curve of the drug concentration in the blood of carboplatin (below It is called "AUC" and is set as appropriate. The index of renal excretion function can be, for example, a patient's creatinine clearance value (CCR value, Creatinine Clearance Rate), blood urea nitrogen value (BUN value, Blood Urea Nitrogen Level), glomerular filtration rate (GFR value,
Glomerular Filtration Rate)表示。卡鉑之 AUC 較佳為 0.1 〜100 mg/mL/min，更佳為 0.2 〜2〇 mg/mL/min，尤佳為 1〜10 mg/mL/min。 本發明之抗腫瘤劑或抗腫瘤效果增強劑中之各有效成分 之投予時間表只要為實現各自之抗腫瘤效果或增強抗腫瘤 效果的時間表則無特別限制，根據患者之年齡、癌種、病 期、有無轉移、治療史、有無制其他抗腫瘤劑等患者之 狀態而適當設定。列舉將投予期間之丨週期設為7〜35天， 更佳為設為14〜21天。列舉太平洋紫杉醇及卡姑於1週期過 程中分別投予1次，較佳為於丨週期中之同一天分別投予工 ••人，更佳為於1週期過程中之第i天分別投予丨次。列舉 TSU·68或其鹽於1週期期間過程中連續投予幾天。TSU_68 或其鹽可1天投予1〜3次，較佳為1天投予2次。根據患者之 狀態’可反覆該投予週期。可於投^週期期間設置Μ天以 下之藥物間歇期’較佳為不設置藥物間歇期。 因此，較佳為本發明之抗腫瘤劑中以1天量成為上述投 156616.doc 13 201143766 予量之形式而分別含有太平洋紫杉醇、卡鉑&TSU_68。 本發明之抗腫瘤劑可以將太平洋紫杉醇、卡鉑及Tsu_68 或其鹽調配成上述調配比之複合劑（含有複數種有效成分 之製劑）之形式而製劑化成單一劑型（丨劑型製劑），亦可將 上述有效成分製成單劑（含有單一有效成分之製劑）或以複 合劑之形式而製劑化成複數種劑型（多劑型製劑），以能夠 同時或錯開時間分別使用。其中，較佳為分別將含有太平 洋紫杉醇之製劑、含有卡鉑之製劑及含有TSU_68或其鹽之 製劑製備成單劑，並將該等組合以多劑型形態使用。 作為上述製劑之投予形態並無特別限制，可視治療目的 而適當選擇’纟體而言’可例示：口服劑（鍵劑、包衣鍵 劑、散劑 '顆粒劑、膠囊劑、液劑等）、注射劑、栓劑、 貼附劑、軟膏劑等。於將本發明之抗腫瘤劑製劑化成複數 種劑型之情形時，該製劑可為分別不同之投予形態，亦可 為相同之投予形態。例如，更佳為將TSU-68或其鹽製成口 服劑，較佳為將含有太平洋紫杉醇之製劑及含有卡姑之製 劑製成注射劑。 本發明之抗腫瘤劑或抗腫瘤效果增強劑只要併用投予太 平洋紫杉醇、卡駭TSU.68或其鹽，則可對每種上述製劑 刀另Mium t造、包裝、流通’又亦可將上述製劑之全部 或-部分以適於併用投予之單—封裝(套組製劑)而製造、 包裝、流通。 之 例 本發明中含有各有效成分 載體’並藉由通常公知之方 之製劑可使用藥理學上容許 法而製備。作為該載體，可 156616.doc 201143766Glomerular Filtration Rate). The AUC of carboplatin is preferably from 0.1 to 100 mg/mL/min, more preferably from 0.2 to 2 mg/mL/min, still more preferably from 1 to 10 mg/mL/min. The administration schedule of each of the active ingredients in the antitumor agent or the antitumor effect enhancer of the present invention is not particularly limited as long as it is a timetable for achieving the respective antitumor effect or enhancing the antitumor effect, depending on the age of the patient, the cancer type It is appropriately set in the state of the patient, the stage of the disease, the presence or absence of metastasis, the history of treatment, and the presence or absence of other anti-tumor agents. The cycle period during the administration period is set to 7 to 35 days, more preferably 14 to 21 days. It is exemplified that Pacific paclitaxel and Kagu are administered once during the first cycle, preferably on the same day of the sputum cycle, preferably on the ith day of the first cycle. Yuci. Listed TSU·68 or its salt was administered continuously for several days during the course of one cycle. TSU_68 or a salt thereof can be administered 1 to 3 times a day, preferably 2 times a day. The administration cycle can be repeated depending on the state of the patient. It is preferable to set the drug intermittent period below the day during the administration cycle, preferably not to set the drug intermittent period. Therefore, it is preferred that the antitumor agent of the present invention contains paclitaxel, carboplatin & TSU_68, respectively, in the form of the above-mentioned dosage of 156616.doc 13 201143766 for one day. The antitumor agent of the present invention can be formulated into a single dosage form (an sputum preparation) by formulating paclitaxel, carboplatin and Tsu_68 or a salt thereof into a compounding agent (a preparation containing a plurality of active ingredients). The above-mentioned active ingredient is formulated into a single preparation (a preparation containing a single active ingredient) or in the form of a complexing agent into a plurality of dosage forms (multi-dosage preparations), which can be used separately at the same time or at the time of staggering. Among them, a preparation containing paclitaxel, a preparation containing carboplatin, and a preparation containing TSU_68 or a salt thereof are preferably prepared as a single preparation, and these combinations are used in a multi-dose form. The form of administration of the above-mentioned preparation is not particularly limited, and an appropriate choice of 'corpus body' can be exemplified as an oral preparation (a key agent, a coating agent, a powder granule, a capsule, a liquid, etc.). , injections, suppositories, patches, ointments, and the like. In the case where the antitumor agent of the present invention is formulated into a plurality of dosage forms, the preparation may be in a different administration form or in the same administration form. For example, it is more preferable to prepare TSU-68 or a salt thereof as an oral preparation, and it is preferred to prepare a preparation containing paclitaxel and a preparation containing kagu. The anti-tumor agent or the anti-tumor effect enhancer of the present invention may be prepared, packaged, and distributed for each of the above-mentioned preparation knives as long as the administration of paclitaxel, calycein TSU.68 or a salt thereof is used in combination. All or part of the preparation is manufactured, packaged, and circulated in a single-package (set preparation) suitable for use in combination. EXAMPLES The present invention contains the respective active ingredient carriers' and can be prepared by a pharmacologically acceptable method by a generally known preparation. As the carrier, it can be 156616.doc 201143766
示通常之藥劑中戶斤；+ A ^ 通用之各種載體，例如賦形劑、結合 劑、朋解劑、潤滑劑、稀 稀釋劑、么解助劑、懸浮劑、等張 劑、pH值調整劑、緩 町別穩疋劑、者色劑、調味劑、除 臭劑、無痛化劑等。 作為賦形劑，例如可列舉. 力羋.礼糖、庶糖、氯化鈉、葡萄 糖、麥茅糖、甘露播酿、土注“ 醇赤藻糖醇、木糖醇、麥芽糖醇、 :醇1葡聚糖、山梨糖醇、白蛋白、尿素、澱粉、碳酸 :嶺土、結晶纖維素、石夕醆、甲基纖維素、甘油、海 澡酸鈉、阿拉伯膠及古玄驾； 減^之混合物等。作為 精製滑石、硬脂酸鹽、对、聚乙二醇及該等之 ^物等。作為結合劑，例如可列舉：翠糖聚、葡萄糖 液、澱粉液、明膠溶液、聚 …义軟乙烯醇、聚乙烯醚、聚乙烯吡 0 各貌酮、羧〒基纖維素、蟲 〜纖再京蟲膠、甲基纖維素、乙基纖維 素 '水、乙醇、碟酸钟及兮笼+、日人，， " 甲及-亥尊之混合物等。作為崩解劑， 例如可列舉：乾燥澱粉、海萍 垮澡S文鈉、瓊脂粉末、昆布糖粉 末、碳酸氫鈉、碳酸飼、妒g他 , 鈣聚氧伸乙基山梨糖醇酐脂肪酸酯 類、十二烷基硫酸鈉、硬脂酸 干疋冲S日、澱粉、乳糖及該 萼之混合物等。作為稀釋劑，例 j列舉.水、乙醇、聚 =醇其丙二醇、乙氧化異硬脂醇、聚氧化異硬脂醇、聚 氧伸乙基山梨糖醇肝脂肪酸醋類及該等之混合物等 穩定劑，例如可列舉：焦亞硫酸納、乙二胺四乙酸'硫代 乙醇酸、硫代乳酸及該等之混合物等。作為等張劑，例如 可列舉：氯化納、賴、葡萄糖、甘油及該等之混合物 等。作為PH值調整劑及緩衝劑，例如可列舉：棒檬酸納、 156616.doc 15 201143766 檸檬酸'乙酸鈉、磷酸鈉及該等之混合物等。作為無痛化 劑’例如可列舉：鹽酸普魯卡因、鹽酸利多卡因及該等之 混合物等》 含有太平洋紫杉醇之製劑例如可列舉使用聚氧乙稀萬麻 油之製劑、使用醇之製劑、或白蛋白填充製劑（商品名： Abraxane(註冊商標））、聚麩胺酸酯化製劑等，但並不限定 於該等。 作為可藉由本發明之抗腫瘤劑或抗腫瘤效果增強劑來治 療的腫瘤並無特別限制’例如可列舉：結腸/直腸癌、肝 癌、腎癌、頭頸癌、食道癌、胃癌、膽道癌、膽囊/膽管 癌、胰腺癌、肺癌、乳癌、卵巢癌、子宮頸癌、子宮體 癌、膀胱癌、前列腺癌、睾丸腫瘤、骨/軟組織肉瘤、白 血病、惡性淋巴瘤、多發性骨髓瘤、皮膚癌、腦腫瘤、睾 丸腫瘤等，較佳為頭頸癌、肺癌、睾丸腫瘤、卵巢癌、子 宮頸癌、惡性淋巴瘤、乳癌、胃癌、子宮體癌，尤佳為肺 癌、卵巢癌。 本發明之TSU-68或其鹽即便其單獨使用亦實現抗腫瘤效 果，但藉由與太平洋紫杉醇+卡鉑併用療法併用，進而明 顯地增強太平洋紫杉醇+卡翻併用療法之抗腫瘤效果。因 此，TSU-68或其鹽作為太平洋紫杉醇+卡鈾併用療法之抗 腫 法 瘤效果增強劑較為有用。 之抗腫瘤效果增強效果及 就太平洋紫杉醇+卡鉑併用療 副作用之容許性方面而言， 、刀取2二人才又于，母1投予單位之量 佳為25 mg〜l500 mg(1天投予量為5〇 mg〜3〇〇〇 _，更 156616.doc 201143766 為100 mg〜750 mg(l天投予量為200 mg〜15〇〇 mg)，尤佳為 200 mg〜400 mg(l天投予量為400 mg〜8〇〇 mg)。 如以下之實施例所示，併用太平洋紫杉醇、卡鉑及Tsu_ 68或其鹽之本發明之抗腫瘤劑與分別單獨使用之情形或併 用2劑之情形，及將太平洋紫杉醇+卡鉑併用療法與其他血 管新生阻礙劑併用之情形相比較，抑制副作用之產生，且 可實現明顯較高之抗腫瘤效果。 [實施例] 以下表示實施例’對本發明進行進而詳細之說明。然 而’本發明並不限定於該等實施例。再者，此處「抗腫瘤 效果」或「抗腫瘤增殖效果增強作用」係根據「腫瘤增殖 之抑制」、「腫瘤增殖之延遲」、「奏效率」、「病情控 制率」或「無惡化生存時間」而進行評價。又，「副作 用」及「副作用增強作用」係根據「體重減少」而進行評 價。 實施例1 人非小細胞肺癌株A549株皮下移植模型中之太平洋紫杉 醇、卡鉑及TSU-68之併用效果 將於體外（in vivo)繼代之源自人非小細胞肺癌之A549之 約2 mm見方的片段移植入雄性裸鼠（BALB/c Nude，5週 齡 ’ CHARLES RIVER LABORATORIES JAPAN股份有限 公司）之背部皮下，於腫瘤體積（腫瘤長徑x腫瘤短徑k2)成 為約200 mm3之時間點，以平均腫瘤體積均等之方式各組 群分組為6隻。並將該分組曰作為day 1。 156616.doc • 17- 201143766 於太平洋紫杉醇+卡鉑投予組群中，太平洋紫杉醇係於 dayl及day5靜脈内投予36 mg/kg，卡鉑係於dayl靜脈内投 予50 mg/kg。於TSU-68投予組群中，TSU-68係自dayl起直 至day32為止連續口服投予200 mg/kg。又，於太平洋紫杉 醇+卡鉑+TSU-68投予組群中，以與該等相同之投予用 量、投予時間表及投予路徑併用投予太平洋紫杉醇、卡舶 及TSU-68之3劑。於對照組群中，投予藥劑之溶劑代替藥 劑。藥劑投予期間過程中及投予期間後，隔3〜4日測定小 白鼠之腫瘤徑及體重。對各藥物投予組群之抗腫瘤效果及 副作用進行評價，同時，對TSU-68之對於太平洋紫杉醇+ 卡麵併用療法的抗腫瘤效果增強作用及副作用增強作用進 行評價。 關於抗腫瘤效果之評價，係將各藥物投予組群與對照組 群相比較，於如下情形時判定為「具有抗腫瘤效果」：將 根據式1算出之相對腫瘤體積（Relative Tumor v〇lume，以 下稱為RTv」）之平均值作為指標，有藉由兩側Dunnett 檢定而使總有意義概率（p值）未達0.05之顯著的腫瘤增殖之 抑制。 [數Π 相對腫瘤體積（RTV)=dayN之腫瘤體積+day丨之腫瘤體積 作為參考，根據式2算出腫瘤增殖率（以下稱為「」） (%)之平均值。Illustrative of the usual pharmaceutical agents; + A ^ general various carriers, such as excipients, binding agents, detoxification agents, lubricants, thinner diluents, dissolving agents, suspending agents, isotonic agents, pH adjustment Agent, slow-choring, anti-static agent, coloring agent, flavoring agent, deodorant, painless agent, etc. As the excipient, for example, Lit. Sugar, Sugar, Sodium Chloride, Glucose, Wheat Glucose, Manna Brew, and Earthnote "Alcohol Alcohol, Xylitol, Maltitol, Alcohol 1 Dextran, sorbitol, albumin, urea, starch, carbonic acid: mulch, crystalline cellulose, shixi, methyl cellulose, glycerin, sodium bath, acacia and ancient Xuanjia; A mixture, etc., as a purified talc, a stearate, a p-, a polyethylene glycol, and the like. Examples of the binding agent include a syrup, a glucose solution, a starch solution, a gelatin solution, and a poly Soft vinyl alcohol, polyvinyl ether, polyvinylpyrene 0, ketone ketone, carboxymethyl cellulose, insect fiber, cyanobacteria, methyl cellulose, ethyl cellulose 'water, ethanol, acid clock and clam cage +, Japanese, " A and - Hai Zun mixture, etc. As a disintegrating agent, for example, dry starch, haiping bath S-sodium, agar powder, laminaria powder, sodium hydrogencarbonate, carbonic acid feed,妒g him, calcium polyoxyethylene ethyl sorbitan fatty acid ester, sodium lauryl sulfate, The fatty acid is dried, and the mixture of starch, lactose and the mash, etc. As a diluent, exemplified by water, ethanol, poly = alcohol, propylene glycol, ethoxylated isostearyl alcohol, polyoxylated isostearyl alcohol, Examples of the stabilizing agent such as a polyoxyalkylene sorbitol liver fatty acid vinegar and a mixture thereof, such as sodium metabisulfite, ethylenediaminetetraacetic acid, thioglycolic acid, thiolactic acid, and the like, etc. Examples of the isotonic agent include sodium chloride, lysine, glucose, glycerin, and the like. As the pH adjuster and the buffer, for example, sodium citrate, 156616.doc 15 201143766 lemon Acidic acid sodium acetate, sodium phosphate, a mixture of these, etc. As a pain-relieving agent, for example, procaine hydrochloride, lidocaine hydrochloride, and the like, etc., and a formulation containing paclitaxel can be exemplified, for example, poly a preparation of oxyethylene eucalyptus oil, a preparation using an alcohol, an albumin-filled preparation (trade name: Abraxane (registered trademark)), a polyglutamate preparation, etc., but is not limited thereto. hair The tumor to be treated by the antitumor agent or the antitumor effect enhancer is not particularly limited 'for example, colon/rectal cancer, liver cancer, kidney cancer, head and neck cancer, esophageal cancer, stomach cancer, biliary tract cancer, gallbladder/cholangiocarcinoma, Pancreatic cancer, lung cancer, breast cancer, ovarian cancer, cervical cancer, endometrial cancer, bladder cancer, prostate cancer, testicular tumor, bone/soft tissue sarcoma, leukemia, malignant lymphoma, multiple myeloma, skin cancer, brain tumor, testis The tumor or the like is preferably head and neck cancer, lung cancer, testicular tumor, ovarian cancer, cervical cancer, malignant lymphoma, breast cancer, stomach cancer, endometrial cancer, and particularly preferably lung cancer, ovarian cancer. TSU-68 or a salt thereof of the present invention Even if it is used alone, it achieves an anti-tumor effect, but by combining with paclitaxel + carboplatin, the anti-tumor effect of the paclitaxel + card combination therapy is significantly enhanced. Therefore, TSU-68 or its salt is useful as an anti-tumor effect enhancer for paclitaxel plus uranium. The anti-tumor effect enhancement effect and the admissibility of the paclitaxel + carboplatin combined with the side effects of the treatment, the knife and the 2 talents, and the amount of the mother 1 to the unit is preferably 25 mg ~ l500 mg (1 day cast The dosage is 5〇mg~3〇〇〇_, and more 156616.doc 201143766 is 100 mg~750 mg (100 days~100〇〇mg for l day), especially 200 mg~400 mg (l The dosage is from 400 mg to 8 mg per day. As shown in the following examples, the antitumor agent of the present invention is used in combination with paclitaxel, carboplatin and Tsu 68 or a salt thereof, and used alone or in combination 2 In the case of the agent, and the combination of the paclitaxel + carboplatin combination therapy and other angiogenesis inhibitors, the occurrence of side effects is suppressed, and a significantly higher antitumor effect can be achieved. [Examples] The present invention will be described in detail. However, the present invention is not limited to the embodiments. Further, the "antitumor effect" or "antitumor proliferative effect enhancing effect" herein is based on "inhibition of tumor proliferation" and " Delay in tumor proliferation" Evaluation was carried out based on "rate", "sickness control rate" or "no worsening survival time". Further, "side effects" and "side effect enhancement" were evaluated based on "weight loss". Example 1 Human non-small cell lung cancer strain A549 The combined effect of paclitaxel, carboplatin and TSU-68 in the subcutaneous transplantation model was transplanted into male nude mice in vitro by a 2 mm square fragment of A549 derived from human non-small cell lung cancer (in vivo). BALB/c Nude, 5 weeks old 'CHARLES RIVER LABORATORIES JAPAN Co., Ltd.) under the skin, at a time when the tumor volume (tumor long diameter x tumor short diameter k2) becomes about 200 mm3, and the average tumor volume is equal The group was grouped into 6. The group was treated as day 1. 156616.doc • 17- 201143766 In the paclitaxel + carboplatin group, paclitaxel was administered intravenously at 36 mg/kg on dayl and day5. Carboplatin was administered intravenously to 50 mg/kg on dayl. In the TSU-68 administration group, TSU-68 was orally administered 200 mg/kg from day 1 until day 32. Also, in paclitaxel + Carboplatin + TSU- In the 68-administered group, three doses of paclitaxel, kabo and TSU-68 were administered in the same dosage, schedule, and route of administration as the above. In the control group, the medicament was administered. The solvent is used instead of the drug. The tumor diameter and body weight of the mice are measured every 3 to 4 days after the administration period and during the administration period. The anti-tumor effect and side effects of each drug administration group are evaluated, and at the same time, TSU-68 was evaluated for the anti-tumor effect enhancement effect and side effect enhancement effect of the paclitaxel plus card surface combination therapy. Regarding the evaluation of the antitumor effect, each drug administration group was compared with the control group, and it was judged as "having an antitumor effect" in the following case: the relative tumor volume calculated according to Formula 1 (Relative Tumor v〇lume) The average value of hereinafter referred to as RTv") is used as an index, and there is a significant inhibition of tumor proliferation with a total significant probability (p value) of less than 0.05 by both Dunnett's assays. [Number of relative tumor volume (RTV) = tumor volume of dayN + tumor volume of day 作为 As a reference, the average value of the tumor growth rate (hereinafter referred to as "") (%) was calculated according to Formula 2.
[數2J 腫瘤增殖率（t/c)(%)=[(藥劑投予組群之平均RTv+對照 1566I6.doc 201143766 組群之平均RTV)]xl00 關於抗腫瘤效果增強作用之評價，將太平洋紫杉醇+卡 鉑+TSU-68投予組群與TSU-68投予組群及太平洋紫杉醇+ 卡鉑投予組群相比較，於如下情形時判定為具有抗腫瘤效 果增強作用：將平均RTV作為指標，有藉由Welch之兩側 Intersection Unit Test(IUT)而使總有意義概率（p值）未達 0.05之顯著的腫瘤增殖之抑制。 day33中之各組群之平均RTV及T/C示於表1。 [表1] 人非小細胞肺癌株A549之裸鼠皮下移植模型中併用投予 太平洋紫杉醇+卡鉑+TSU-68獲得的平均相對腫瘤體積 (RTV)及腫瘤增殖率（T/C) 投予組群 平均RTV (day33，Mean土SD) 顯著差 T/C(%) 對照 8.42±3.69 • _ TSU-68 4.55±0.59 氺 54 太平洋紫杉醇+卡鉑 5.10+1.25 本 61 太平洋紫杉醇+卡鉑+TSU-68 3.02+0.57 氺#$ 36 (氺=藉由Dunett檢定，與對照組群相比較有顯著差，#=藉 由Welch之兩側IUT，.與TSU-68投予組群相比較有顯著 差，$ =藉由Welch之兩側IUT，與太平洋紫杉醇+卡鉑投予 組群相比較有顯著差） 根據表1之結果確認，各藥物投予組群與對照組群相比 較，均顯著抑制腫瘤增殖，具有抗腫瘤效果。太平洋紫杉 醇+卡鉑+TSU-68投予組群與太平洋紫杉醇+卡鉑投予組 156616.doc -19- 201143766 群、TSU-68投予組群相比較，顯著抑制腫瘤增殖。因此確 認TSU-68對太平洋紫杉醇+卡鉑併用療法具有明顯之抗腫 瘤效果增強作用。 作為抗腫瘤效果增強作用之其他評價，算出平均RTV達 到 3為止之期間（Periods to reach 3 times Relative Tumor Volume，以下稱為「RTV3」），並算出各藥劑投予組群與 對照組群之RTV3之差作為腫瘤增殖延遲期間（Growth Delay Period，以下稱為「GDP」）。將太平洋紫杉醇+卡鉑 + TSU-68投予組群之GDP與TSU-68投予組群、太平洋紫杉 醇+卡鉑投予組群各自之GDP之合計相比較，於改善腫瘤 增殖之延遲之情形時，判定為「具有抗腫瘤效果增強作 用」。 各組群之RTV3及GDP示於表2。 [表2] 人非小細胞肺癌株A549之裸鼠皮下移植模型中併用投予 太平洋紫杉醇+卡鉑+TSU-68獲得之RTV3及腫瘤增殖延遲 期間（GDP) 投予組群 RTV3(days) GDP(days) 對照 14 - TSU-68 21 7 太平洋紫杉醇+卡鉑 18 4 太平洋紫杉醇+卡鉑+TSU-68 32 18 根據表2之結果，太平洋紫杉醇+卡鉑+TSU-68投予組群 之GDP為18天，與TSU-68投予組群、太平洋紫杉醇+卡鉑 投予組群各自之GDP合計的11天相比，改善腫瘤增殖之延 156616.doc -20- 201143766 遲。因此嫁認’ TSU-68對太平洋紫杉醇+卡翻併用療法具 有明顯之抗腫瘤效果增強作用。 關於副作用之評價，將藥物投予組群與對照組群相比 較，於如下情形時判定為「具有副作用」：將根據式3算 出之體重變化率（以下稱為「BWCj )(%)之平均值作為指 標，有藉由兩側Dunnett檢定而使總有意義概率（p值）未達 0.05之顯著的體重減少。 [數3] 體重變化率（BWC)(%)=((dayN之體重-dayl之體重）+dayl 之體重）χΐοο 關於副作用增強作用之評價，將太平洋紫杉醇+卡鉑 +TSU-68投予組群與太平洋紫杉醇+卡翻投予組群相比 較，於如下情形時判定為「具有副作用增強作用」：將平 均BWC作為指標，有藉由welch之兩側intersecti〇n Unit[Number 2J tumor proliferation rate (t/c) (%) = [(average RTv of the drug-administered group + control 1566I6.doc average RTV of the 201143766 group)] xl00 Evaluation of the anti-tumor effect enhancing effect, the paclitaxel The +Carboplatin + TSU-68 administration group was compared with the TSU-68 administration group and the Pacific paclitaxel + carboplatin administration group, and was determined to have an anti-tumor effect enhancement effect in the following cases: the average RTV was used as an indicator. There is a significant inhibition of tumor proliferation with a total meaningful probability (p value) of less than 0.05 by the Intersection Unit Test (IUT) on both sides of Welch. The average RTV and T/C of each group in day 33 are shown in Table 1. [Table 1] Human non-small cell lung cancer strain A549 was administered in a subcutaneous transplantation model of nude mice and administered with paclitaxel + carboplatin + TSU-68 to obtain mean relative tumor volume (RTV) and tumor growth rate (T/C). Group mean RTV (day33, Mean soil SD) Significant difference T/C (%) Control 8.42 ± 3.69 • _ TSU-68 4.55 ± 0.59 氺 54 Pacific paclitaxel + carboplatin 5.10 + 1.25 This 61 Pacific paclitaxel + carboplatin + TSU -68 3.02+0.57 氺#$ 36 (氺= By Dunnet's test, there is a significant difference compared with the control group, #= by the IUT on both sides of Welch, compared with the TSU-68 group. Poor, $ = by the IUT on both sides of Welch, compared with the paclitaxel + carboplatin group.) According to the results of Table 1, it was confirmed that each drug-administered group was significantly higher than the control group. It inhibits tumor proliferation and has anti-tumor effect. The paclitaxel + carboplatin + TSU-68 administration group and the paclitaxel + carboplatin administration group 156616.doc -19- 201143766 group, TSU-68 group significantly inhibited tumor proliferation. Therefore, it was confirmed that TSU-68 has a significant anti-tumor effect enhancing effect on the combination of paclitaxel and carboplatin. As another evaluation for enhancing the antitumor effect, a period of 3 times Relative Tumor Volume (hereinafter referred to as "RTV3") was calculated, and RTV3 of each drug administration group and control group was calculated. The difference is used as a tumor delay period (hereinafter referred to as "GDP"). Comparing the GDP of the paclitaxel + carboplatin + TSU-68 group with the total GDP of the TSU-68 administration group and the paclitaxel + carboplatin group, the delay in improving tumor proliferation At the time, it was judged as "having an anti-tumor effect enhancing effect". The RTV3 and GDP of each group are shown in Table 2. [Table 2] Human non-small cell lung cancer strain A549 in a subcutaneous transplantation model of nude mice, and RTV3 obtained by administration of paclitaxel + carboplatin + TSU-68 and a tumor growth delay period (GDP) were administered to the group RTV3 (days) GDP. (days) Control 14 - TSU-68 21 7 Pacific Paclitaxel + Carboplatin 18 4 Pacific Paclitaxel + Carboplatin + TSU-68 32 18 According to the results of Table 2, Pacific Paclitaxel + Carboplatin + TSU-68 is administered to the group's GDP For 18 days, the improvement in tumor proliferation was delayed by 156616.doc -20- 201143766 after 11 days of total GDP of the TSU-68 administration group and the paclitaxel + carboplatin administration group. Therefore, the TSU-68 has a significant anti-tumor effect on the paclitaxel + card combination therapy. In the evaluation of the side effects, the drug administration group was compared with the control group, and it was judged as "having side effects" in the following cases: the average body weight change rate (hereinafter referred to as "BWCj" (%) calculated according to Formula 3 The value is used as an indicator, and there is a significant weight loss with a total meaningful probability (p value) of less than 0.05 by the Dunnett test on both sides. [Number 3] Weight change rate (BWC) (%) = ((dayN weight - dayl Body weight) +dayl weight) χΐοο Regarding the evaluation of side effects, the paclitaxel + carboplatin + TSU-68 group was administered to the group and the paclitaxel + card was turned into the group, which was judged as " Has side effects to enhance the effect: the average BWC as an indicator, with the sides of the welch intersecti〇n Unit
Test(IUT)而使總有意義概率值）未達〇 〇5之顯著的體重減 少。 day33之各組群之平均BWC示於表3。 [表3] 人非小細胞肺癌株A549之裸鼠皮下移植模型中併用投予 太平洋紫杉醇+卡鉑+TSU-68獲得之平均體重變化率（Bwc) --予組群 平均BWC(day33，Mean±SD) 顯著差 對照 10.8+4.4 TSU-68 ------ 10.9+3.6 卡鉑 15.6+8.0 鉑+TSU-68 13.7+3.2 _ 1566I6.doc •21 · 201143766 (*=藉由Dunett檢定，與對照組群相比較有顯著差和藉 由Welch之兩側IUT，與TSU-68投予組群相比較有顯著 差，$ =藉由Welch之兩側IUT，與太平洋紫杉醇+卡鉑投予 組群相比較有顯著差） 根據表3之結果確認各藥物投予組群與對照組群相比 較，體重減少相同，無副作用。又，太平洋紫杉醇+卡鉑 +TSU-68投予組群與太平洋紫杉醇+卡鉑投予組群及Tsu_ 68組群相比較，體重減少相同。因此確認TSU 68對太平洋 紫杉醇+卡鉑併用療法無副作用增強作用。 實施例2 人非小細胞肺癌株A549株皮下移植模型中TSU-16及TSU- 68對於太平洋紫杉醇+卡鉑併用療法的併用效果 將於體外（in vivo)繼代之源自人非小細胞肺癌之A549之 約2 mm見方的片段移植於雄性裸鼠（BALB/CAJcl-nU，5週 齡，CLEA Japan股份有限公司）之背部皮下，於腫瘤體積 成為約200 mm3之時間點以平均腫瘤體積均等之方式各組 群分組為8隻》並將該分組曰作為day 1。 於太平洋紫杉醇+卡鉑投予組群中，太平洋紫杉醇係於 dayl及day5靜脈内投予36 mg/kg，卡鉑係於dayl靜脈内投 予50 mg/kg。又，太平洋紫杉醇+卡鉑+TSU-16投予組群或 太平洋紫杉醇+卡鉑+TSU-68投予組群中，與該等併用， 丁811-16係於(13丫4、8、11、15及18靜脈内投予4〇111吕/让§， 或TSU-68係自dayl起直至day21為止連續口服投予200 mg/kg。再者，將TSU-16單獨於day4、8、11、15及18靜脈 156616.doc •22· 201143766 内投予40 mg/kg ’及將TSU_68單獨自_起直至邮為 止連續口服投予200 mg/kg’係顯示出大致相同之抗腫瘤 效果及副作用的用量及用法。於對照、组群中，投予藥劑之 溶劑代替藥劑。藥劑投予期間過程中及投予期間後，隔 3 4日測定小白鼠之腫瘤徑及體重。對各藥物投予組群之 抗腫瘤效果、副作用進行評價，同時對Tsu_i6及彻_68 對於太平洋紫杉醇+卡㈣用療法的抗腫瘤效果增強作用 及副作用增強作用進行評價。 抗腫瘤效果之評價係以與實施例丨相同之方式進行判 定。 作為參考，以與實施例丨相同之方式算出T/c(%)。 關於抗腫瘤效果增強作用之評價，將太平洋紫杉醇+卡 鉑+TSU-i 6投丨組群及太平洋紫杉醇+卡始+TSU 68投予組 群與太平洋紫杉醇+卡鉑投予組群相比較，於如下情形時 判定為「具有抗腫瘤效果增強作用」：將平均RTv作為指 標，有藉由Student之t檢定而使總有意義概率（p值）未達 0.05之顯著的腫瘤增殖之抑制。 關於太平洋紫杉醇+卡鉑+TSU_16投予組群與太平洋紫 杉醇+卡鉑+TSU-68投予組群之抗腫瘤效果增強作用，於 如下情形時判定為「具有更明顯之抗腫瘤效果增強作 用」：將平均RTV作為指標，實施Studentit檢定，於有 意義概率（P值）未達0.05之情形時存在統計學上之顯著之差 異。 day22之各組群之平均RTV及τ/c示於表4。 156616.doc •23· 201143766 [表4] 人非小細胞肺癌株A549之裸鼠皮下移植模型中併用投予 太平洋紫杉醇+卡鉑+TSU-16及併用投予太平洋紫杉醇+卡 鉑+TSU-68獲得之平均相對腫瘤體積（RTV)及腫瘤增殖率 (T/C) 投予組群 平均RTV (day22，Mean土SD) 顯著差 T/C(%) 對照 9.05+2.10 _ - 太平洋紫杉醇+卡鉑 4.1311.20 氺 46 太平洋紫杉醇+卡鉑+TSU-16 3.15±0.46 氺# 35 太平洋紫杉醇+卡鉑+TSU-68 2.2110.42 氺#& 24 (* =藉由Dunett檢定，與對照組相比較有顯著差，#=藉由 Student之t檢定，與太平洋紫杉醇+卡翻投予組群相比較有 顯著差，&=藉由Student之t檢定，與太平洋紫杉醇+卡在白 +TSU-16投予組群相比較有顯著差） 根據表4之結果確認，各藥物投予組群與對照組群相比 較，均存在顯著之腫瘤增殖之抑制，具有抗腫瘤效果。太 平洋紫杉醇+卡鉑+TSU-16投予組群及太平洋紫杉醇+卡鉑 +TSU-68投予組群與太平洋紫杉醇+卡鉑投予組群相比 較，顯著抑制腫瘤增殖。因此確認，TSU-16及TSU-68對 於太平洋紫杉醇+卡鉑併用療法具有抗腫瘤效果增強作 用。太平洋紫杉醇+卡鉑+TSU-68投予組群與太平洋紫杉 醇+卡鉑+TSU-16投予組群相比較，顯著抑制腫瘤增殖。 因此確認TSU-68比TSU-16具有更明顯之抗腫瘤效果增強 作用。 156616.doc -24- 201143766 副作用之評價以與實施例1相同之方式進行判定。 關於副作用增強作用之評價，將太平洋紫杉醇+卡鉑 +TSU-16投予組群及太平洋紫杉醇+卡鉑+TSU-68投予組群 與太平洋紫杉醇+卡鉑投予組群相比較，於如下情形時判 定為「具有副作用增強作用」：將平均BWC作為指標，有 藉由Student之t檢定而使總有意義概率（P值）未達0.05之顯 著的體重減少。 對太平洋紫杉醇+卡鉑+TSU-16投予組群及太平洋紫杉 醇+卡鉑+TSU-68投予組群，以平均BWC作為指標，實施 Student之t檢定，於有意義概率（p值）未達0.05之情形時， 判定為「於副作用增強作用方面存在差異」。 dayl 2之各組群之平均BWC之結果示於表5。 [表5] 人非小細胞肺癌株A549之裸鼠皮下移植模型中併用投予 太平洋紫杉醇+卡鉑+TSU-16及併用太平洋紫杉醇+卡鉑 +TSU-68獲得的平均體重變化率（BWC) 投予組 平均BWC (dayl2 * Mean+SD) 顯著差 對照 4.6+3.2 太平洋紫杉醇+卡鉑 4.2+8.8 • 太平洋紫杉醇+卡鉑+TSU-16 -6.4+6.2 氺#& 太平洋紫杉醇+卡鉑+TSU-68 5.7+2.4 严 (* =藉由Dunett檢定，與對照組群相比較有顯著差，#=藉 由Student之t檢定，與太平洋紫杉醇+卡鉑投予組群相比較 有顯著差，&=藉由Student之t檢定，與太平洋紫杉醇+卡 156616.doc 25· 201143766 鉑+TSU-68投予組群相比較有顯著差） 根據表5之結果確認，太平洋紫杉醇+卡鉑投予組群及太 平洋糸杉醇+卡鉑+TSU-68投予組群與對照組群相比較， 體重減少相同，且無副作用。然而，太平洋紫杉醇+卡鉑 +TSU-16技予組群與對照組群相比較，確認有顯著之體重 減少’且有副作用。太平洋紫杉醇+卡鉑+TSU-i6投予組 群與太平洋紫杉醇+卡鉑投予組群及太平洋紫杉醇+卡鉑 +TSU-68投予組群相比較，發現體重減少方面有顯著之差 異。根據該結果，確認TSU-16對於太平洋紫杉醇+卡鉑併 用療法有副作用增強作用，但確認TSU-68對於太平洋紫杉 醇+卡翻併用療法無副作用增強作用。 實施例3 以非小細胞肺癌患者為對象之TSU-68對於太平洋紫杉醇+ 卡鉑併用療法的併用效果 病例係以Stage IIIB/IV之未治療非小細胞肺癌患者作為 對象。 針對投予週期，將1週期設為自day丨起直至day2丨為止之 21天’太平洋紫杉醇係於dayl靜脈内投予200 mg/m2，卡 翻係於dayl靜脈内投予6 mg/mL/min(AUC)，TSU-68係自 dayl起直至day21為止1天分成2次連續口服投予4〇〇 mg/day 或800 mg/day。根據患者之狀態，反覆該投予週期。 為了評價抗腫瘤效果，判定各患者之最佳综合效果，並 求出奏效率（以下稱為「RR」）（％)及病情控制率（以下稱為 「DCR」）(％)。 156616.doc •26· 201143766 最佳綜合效果係依據New Guideline to Evaluate theTest (IUT) makes the total meaningful probability value) less than 显5's significant weight loss. The average BWC of each group of day 33 is shown in Table 3. [Table 3] The average body weight change rate (Bwc) obtained by administering paclitaxel + carboplatin + TSU-68 in a subcutaneous transplantation model of human non-small cell lung cancer strain A549 - the average BWC of the group (day33, Mean) ±SD) Significant difference control 10.8+4.4 TSU-68 ------ 10.9+3.6 Carboplatin 15.6+8.0 Platinum+TSU-68 13.7+3.2 _ 1566I6.doc •21 · 201143766 (*=With Dunnet's check, Compared with the control group, there was a significant difference and the IUT on both sides of Welch was significantly worse than the TSU-68 administration group. $ = by the IUT on both sides of Welch, with paclitaxel + carboplatin The group was significantly different. According to the results of Table 3, it was confirmed that each drug administration group was the same as the control group, and the body weight loss was the same, and there was no side effect. In addition, the paclitaxel + carboplatin + TSU-68 administration group was the same as the paclitaxel + carboplatin administration group and the Tsu_ 68 group. Therefore, it was confirmed that TSU 68 has no side effect enhancing effect on the combination of Pacific paclitaxel and carboplatin. Example 2 Human non-small cell lung cancer strain A549 strain subcutaneous transplantation model The combined effect of TSU-16 and TSU-68 on the combination of paclitaxel plus carboplatin therapy will be subcultured in vitro from human non-small cell lung cancer. A fragment of about 2 mm square of A549 was transplanted into the back of the male nude mouse (BALB/CAJcl-nU, 5 weeks old, CLEA Japan Co., Ltd.), and the average tumor volume was equal at the time when the tumor volume became about 200 mm3. In this way, each group is grouped into 8 pieces and the group is grouped as day 1. In the paclitaxel + carboplatin-administered group, paclitaxel was administered intravenously at daytime and day5 at 36 mg/kg, and carboplatin was administered intravenously at 50 mg/kg on dayl. In addition, the paclitaxel + carboplatin + TSU-16 administration group or the paclitaxel + carboplatin + TSU-68 was administered to the cohort, and was used in combination with Ding 811-16 (13丫4, 8, 11 , 15 and 18 intravenously administered 4 〇 111 LV / let §, or TSU-68 system from dayl until day 21 continuous oral administration of 200 mg / kg. Furthermore, TSU-16 alone on days 4, 8, 11 , 15 and 18 veins 156616.doc •22· 201143766 administered 40 mg/kg ' and continuous oral administration of 200 mg/kg from TSU_68 alone until the post showed a similar anti-tumor effect and side effects In the control and the group, the solvent of the drug was used instead of the drug. The tumor diameter and body weight of the mice were measured at intervals of 34 days after the administration of the drug and during the administration period. The anti-tumor effect and side effects of the group were evaluated, and the anti-tumor effect and the side-effect enhancing effect of Tsu_i6 and _68 on the paclitaxel + card (4) therapy were evaluated. The evaluation of the anti-tumor effect was carried out in the same manner as in the examples. The determination is made in the same manner. As a reference, in comparison with the embodiment The T/c (%) was calculated. For the evaluation of the anti-tumor effect enhancement effect, the paclitaxel + carboplatin + TSU-i 6 administration group and the paclitaxel + card + TSU 68 were administered to the group and the paclitaxel. + Carboplatin was compared with the group, and it was judged as "enhanced anti-tumor effect" in the following cases: the average RTv was used as an index, and the total meaningful probability (p value) was less than 0.05 by Student's t-test. Significant inhibition of tumor proliferation. The anti-tumor effect of the paclitaxel + carboplatin + TSU_16 administration group and the paclitaxel + carboplatin + TSU-68 administration group was judged as "having more Significant anti-tumor effect enhancement effect: The average RTV was used as an indicator to perform the Studentit test, and there was a statistically significant difference in the case where the meaningful probability (P value) was less than 0.05. The average RTV of each group of day22 and τ/c is shown in Table 4. 156616.doc •23· 201143766 [Table 4] Human non-small cell lung cancer strain A549 was administered in a subcutaneous transplantation model of nude mice with administration of paclitaxel + carboplatin + TSU-16 and administration to the Pacific Ocean. purple The mean relative tumor volume (RTV) and tumor proliferation rate (T/C) obtained from cedar + carboplatin + TSU-68 were averaged in the group RTV (day 22, Mean soil SD). Significant difference T/C (%) Control 9.05 +2.10 _ - Pacific paclitaxel + carboplatin 4.1311.20 氺46 Pacific paclitaxel + carboplatin + TSU-16 3.15 ± 0.46 氺 # 35 Pacific paclitaxel + carboplatin + TSU-68 2.2110.42 氺#& 24 (* = lend As determined by Dunett, there was a significant difference compared with the control group, #= by Student's t-test, compared with the paclitaxel + card-turned group, there was a significant difference, &= by Student's t-test, with the Pacific Paclitaxel + card was significantly different in the white + TSU-16 group. According to the results in Table 4, there was significant inhibition of tumor proliferation compared with the control group. Tumor effect. The paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 administration group significantly inhibited tumor proliferation compared with the paclitaxel + carboplatin group. Therefore, it was confirmed that TSU-16 and TSU-68 have an anti-tumor effect enhancing effect on the paclitaxel plus carboplatin combination therapy. The paclitaxel + carboplatin + TSU-68 administration group significantly inhibited tumor proliferation compared with the paclitaxel + carboplatin + TSU-16 administration group. Therefore, it was confirmed that TSU-68 has a more pronounced antitumor effect enhancing effect than TSU-16. 156616.doc -24- 201143766 Evaluation of side effects was determined in the same manner as in Example 1. Regarding the evaluation of side effect enhancement, the paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 administration group were compared with the paclitaxel + carboplatin administration group as follows. In the case of the case, it was judged as "having a side effect enhancing effect": the average BWC was used as an index, and there was a significant weight loss with a total significant probability (P value) of less than 0.05 by Student's t-test. The paclitaxel + carboplatin + TSU-16 administration group and the paclitaxel + carboplatin + TSU-68 group were administered to the group, and the average BWC was used as the index to carry out the Student's t test. The meaningful probability (p value) was not reached. In the case of 0.05, it was judged as "there is a difference in side effect enhancement effect". The results of the average BWC of each group of dayl 2 are shown in Table 5. [Table 5] The average body weight change rate (BWC) obtained by administering paclitaxel + carboplatin + TSU-16 and paclitaxel + carboplatin + TSU-68 in a subcutaneous transplantation model of human non-small cell lung cancer strain A549. The mean BWC of the administration group (dayl2 * Mean+SD) was significantly different from the control 4.6+3.2 Pacific paclitaxel + carboplatin 4.2+8.8 • Pacific paclitaxel + carboplatin + TSU-16 -6.4+6.2 氺#& Pacific paclitaxel + carboplatin + TSU-68 5.7+2.4 Severe (* = significantly worse than the control group by Dunnet's assay, #= by Student's t-test, compared with the paclitaxel + carboplatin-administered group, &=Through Student's t test, compared with Pacific paclitaxel + card 156616.doc 25· 201143766 Platinum + TSU-68 group was significantly worse) According to the results of Table 5 confirmed, Pacific paclitaxel + carboplatin Compared with the control group, the group and the paclitaxel + carboplatin + TSU-68 group had the same weight loss and no side effects. However, the paclitaxel + carboplatin + TSU-16 technique group was compared with the control group to confirm a significant weight loss' and had side effects. The paclitaxel + carboplatin + TSU-i6 administration group compared with the paclitaxel + carboplatin-administered group and the paclitaxel + carboplatin + TSU-68 group showed significant differences in body weight loss. Based on the results, it was confirmed that TSU-16 has a side effect enhancing effect on the paclitaxel + carboplatin combination therapy, but it was confirmed that TSU-68 had no side effect enhancing effect on the paclitaxel + card combination therapy. Example 3 The combined effect of TSU-68 on the combination of paclitaxel plus carboplatin in patients with non-small cell lung cancer The case was targeted at patients with stage IIIB/IV untreated non-small cell lung cancer. For the administration cycle, one cycle was set to 21 days from day 直至 until day 2 ' 'Pacific paclitaxel was administered intravenously to 200 mg/m 2 on dayl, and card was administered intravenously on dayl 6 mg/mL/ Min (AUC), TSU-68 was divided into 2 consecutive oral administrations of 4〇〇mg/day or 800 mg/day from day 1 until day 21. The administration cycle is repeated according to the state of the patient. In order to evaluate the anti-tumor effect, the best overall effect of each patient was determined, and the efficiency (hereinafter referred to as "RR") (%) and the disease control rate (hereinafter referred to as "DCR") (%) were determined. 156616.doc •26· 201143766 The best overall effect is based on New Guideline to Evaluate the
Response to Treatment in Solid Tumor(以下稱為「recist」） (J Natl Cancer lnst 92: 205, 2〇〇〇)，藉由 CT(c〇mputed tomography，電腦斷層攝影）、MRI(magnetic imaging，磁共振成像）等影像診斷測定腫瘤徑，又，項目 雖未規定但藉由測定最低i項腫瘤標記，於確認所有標的 病變肩失之情形時，判定為「完全奏效」（以下稱為 「CR」）， 於發現與基線長徑和相比較標的病變之最長徑之和減少 30%以上之情形時，判定為「部分奏效」（以下稱為 「PR」）， 於發現與治療開始以來所記錄之最小之最長徑的和相比 較，標的病變之最長徑的和增加20%以上之情形時，或於 出現新病變之情形時，判定為「發展」（以下稱為 「PD」）， 於發現判定為PR時腫瘤縮小不充分’且判定為PD時與 治療開始以來之最小之最長徑的和相比，腫瘤增大不充分 之情形時’判定為「穩定」（以下稱為「SD」）。 RR(%)係發現為CR或PR之患者數相對於全部病例數的比 例。DCR(%)係發現為CR、PR或SD之患者數相對於全部病 例數的比例。 投予400 mg/day或800 mg/day之TSU-68時之非小細胞肺 癌患者之太平洋紫杉醇+卡鉑+TSU-68的RR及DCR示於表 156616.doc -27· 201143766 [表6] 非小細胞肺癌患者之太平洋紫杉醇+卡鉑+TSU-68之奏效 率（RR)及病情控制率（DCR) TSU-68投予量(mg/day) η RR(%) DCR(%) 400 3 66.7 100.0 800 34 38.2 79.4 整體 37 40.5 81.1 根據表6之結果確認，將TSU-68併用於太平洋紫杉醇+ 卡鉑併用療法中具有良好之抗腫瘤效果。 為了進行抗腫瘤效果之其他評價，求出無惡化生存時間 (以下稱為「PFS」）。PFS係指自患者之試驗註冊日開始計 算，直至確認如下所示事件之曰中最早之日為止的時間。 1 ·判定最佳綜合效果時確認為PD之日（檢測日）。 2. 由於所有原因而使試驗者死亡之情形（死亡日）。 3. 即便判定最佳綜合效果時未確認為PD，臨床上判斷為 明顯惡化或必須實施後續治療之情形（判斷曰）。 投予400 mg/day或800 mg/day之TSU-68時之非小細胞肺 癌患者之太平洋紫杉醇+卡鉑+TSU-68的PFS示於表7。 [表7] 非小細胞肺癌患者之太平洋紫杉醇+卡鉑+TSU-68的無惡 化生存時間（PFS) TSU-68投予量(mg/day) η PFS中位數(個月） 400 3 4.2 800 34 5.6 整體 37 4.4 156616.doc •28· 201143766 根據表7之結果確認，將TSU_68併用於太平洋紫杉醇+ 卡銘併用療法中具有良好之抗腫瘤效果。 根據以上實施例確認，於太平洋紫杉醇+卡鉑併用療法 中併用TSU-68與太平洋紫杉醇+卡鉑併用療法相比較，不 會增強副作用實現明顯較強之抗腫瘤效果。確認於太平 洋紫杉醇+卡鉑併用療法中併用TSU-68與太平洋紫杉醇+ 卡鉑併用療法中併用TSU-16相比，抗腫瘤效果及副作用之 平衡優異，為非常有用之治療法。又，確認於太平洋紫杉 醇+卡链併用療法中併用TSU-68於癌症治療時於臨床上亦 有用。 1566l6.doc •29-Response to Treatment in Solid Tumor (hereinafter referred to as "recist") (J Natl Cancer lnst 92: 205, 2〇〇〇), by CT (c〇mputed tomography, computed tomography), MRI (magnetic imaging) Imaging) and other imaging diagnostics to determine the tumor diameter, but the item is not specified, but by determining the lowest i-term tumor marker, it is judged as "completely effective" (hereinafter referred to as "CR") when confirming all the lesions of the target lesion. When it was found that the sum of the longest diameter of the target and the longest path of the target lesion was reduced by more than 30%, it was judged as "partial effect" (hereinafter referred to as "PR"), and the minimum recorded since the discovery and treatment began. When the sum of the longest diameter of the target lesion is increased by more than 20%, or when a new lesion occurs, it is judged as "development" (hereinafter referred to as "PD"), and it is judged as In the case of PR, the tumor shrinkage is insufficient, and when it is judged to be PD, the tumor is not sufficiently enlarged when compared with the sum of the smallest and longest diameters since the start of treatment (hereinafter referred to as "stable" (hereinafter referred to as "SD") . RR (%) is the ratio of the number of patients found to be CR or PR to the total number of cases. DCR (%) is the ratio of the number of patients found to be CR, PR or SD to the total number of cases. The RR and DCR of paclitaxel + carboplatin + TSU-68 in patients with non-small cell lung cancer at 400 mg/day or 800 mg/day TSU-68 are shown in Table 156616.doc -27· 201143766 [Table 6] The paclitaxel efficiency (RR) and disease control rate (DCR) of paclitaxel + carboplatin + TSU-68 in patients with non-small cell lung cancer TSU-68 dose (mg/day) η RR (%) DCR (%) 400 3 66.7 100.0 800 34 38.2 79.4 Overall 37 40.5 81.1 According to the results of Table 6, it was confirmed that TSU-68 was used in the combination of paclitaxel + carboplatin and had good antitumor effect. In order to perform other evaluations of the antitumor effect, the deterioration-free survival time (hereinafter referred to as "PFS") was determined. PFS is calculated from the date of the patient's trial registration until the earliest date of the following events is confirmed. 1 • The day when the PD is determined as the best combined effect (test day). 2. The circumstances in which the tester dies for all reasons (day of death). 3. Even if the PD is not confirmed as the best comprehensive effect, it is clinically judged to be significantly worse or the follow-up treatment must be performed (judgment 曰). The PFS of paclitaxel + carboplatin + TSU-68 in non-small cell lung cancer patients at 400 mg/day or 800 mg/day TSU-68 is shown in Table 7. [Table 7] Non-deteriorating survival time (PFS) of paclitaxel + carboplatin + TSU-68 in patients with non-small cell lung cancer TSU-68 dose (mg/day) η PFS median (month) 400 3 4.2 800 34 5.6 Overall 37 4.4 156616.doc •28· 201143766 Based on the results of Table 7, it was confirmed that TSU_68 was used in the combination of Pacific Paclitaxel and Carmen for good antitumor effects. According to the above examples, it was confirmed that the combination of TSU-68 and paclitaxel plus carboplatin in the combination of paclitaxel and carboplatin did not enhance the side effects and achieve a significantly stronger antitumor effect. It is a very useful treatment for the combination of TSU-68 and paclitaxel plus carboplatin in combination with TSU-16 in the combination of TSU-68 and TSU-16. Further, it was confirmed that it is also clinically useful in the treatment of cancer with TSU-68 in combination with paclitaxel + card chain therapy. 1566l6.doc •29-