TWI673060B - 用於製造供化療癌症患者使用的輔助治療劑的組合物 - Google Patents
用於製造供化療癌症患者使用的輔助治療劑的組合物 Download PDFInfo
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Abstract
本發明提供一種用於製造供化療癌症患者使用的輔助治療劑的組合物。本發明的組合物主要含有發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物。本發明組合物提供抑制大腸息肉發生及癌化、提高化療的效果,包括延長癌症患者存活期,尤其是無惡化存活期及/或減少化療引起副作用的作用。本發明的組合物還提供抗發炎活性,其有效地減少發炎介質如前列腺素E2(PGE 2)、一氧化氮(NO)、腫瘤壞死因子-α(TNF-α)和白細胞介素-6(IL-6)生成。
Description
本案主張2013年9月6日申請之台灣專利申請案第102132310號之優先權,該案以全文引用方式併入本文中。
本發明係關於一種用於製造化療之輔助治療劑的組合物。具體而言,本發明係關於一種用於製造供化療癌症患者使用的輔助治療劑的組合物,其有效抑制大腸息肉增生和癌化、提高化療的效果、提高化療順從性並減少化療副作用。
發酵大豆製品,綠茶,螺旋藻,薑黃,樟芝和葡萄籽都是自然健康寶藏,而且一些生化測試顯示,每種上述物質對人體有健康效應。薑黃中含有的薑黃素的主要藥理活性是抑制腫瘤生長,而樟芝含有大量多醣類可增強免疫功能,並殺死腫瘤細胞。雖然各種市售產品中有單成分配方,但沒有相關研究顯示六成分複方具有減少癌症治療的化療副作用的效果。
以大腸癌為例,大腸癌包括結腸癌和直腸癌,是世界上最常見的惡性腫瘤之一。導致大腸癌原因並不完全清楚,但一般認為,大腸癌
和飲食高度相關。例如,增加攝取精製食品、動物脂肪,和蛋白質豐富的食物,以及富含纖維的食物攝取不足皆會能增加大腸癌發生率,這是現代的疾病。幸運的是,雖然大腸癌的發生率很高,但較容易找到病變,這些病變需要較長時間發展成大腸癌。從息肉發展為最早期的大腸癌階段約5至10年,因此一般來說,只要定期檢查偵測到早期的結腸息肉就能容易控制大腸癌。然而,大腸癌的早期症狀並不明顯且特異性低,因此病人和醫生容易忽略這些症狀,錯過了早期診斷和治療的機會。
一般而言,治療大腸癌有三種最常見的類型:外科手術,放射療法和化學療法。其中,以對腫瘤的理解,目前大腸癌化療主要為以氟尿嘧啶(5-FU)為基礎的聯合化療,以減少復發和腫瘤轉移並延長存活率。
FOLFOX4是目前用於治療二期及三期轉移性大腸癌的化療方案,包括含有氟尿嘧啶(5-FU)、亞葉酸鈣(leucovorin)及雙胺環己烷草酸鉑(oxaliplatin)之藥物。然而,這些藥物有毒性副作用,包括發燒、噁心、嘔吐、腹瀉、骨髓抑制、四肢末梢麻木及血液循環不良。由於藥物引起的副作用的症狀,故患者通常生活品質低甚至有危及生命的併發症。
因此,有必要尋找一種供接受化療的癌症患者使用的輔助治療劑,以減少不適感,提高他們的生活品質。
此外,已知慢性發炎或免疫系統活化與腫瘤的發展有關。若干證據支持了慢性免疫活化參與,例如,使用非類固醇抗炎藥物(NSAID)和降低癌症發展風險之間的關聯。發炎反應的介導物質在腫瘤形成過程中扮演重要角色,並提供用於癌症治療性干預的標的。有需要在接受化療時調節發炎反應。
鑑於上述情況,本發明的目的是提供一種用於製造供接受化療的癌症患者使用的輔助治療劑的組合物。
具體而言,本發明的組合物包括發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物。
根據本發明的具體實施例,所述組合物包含重量比為12-30:4:1-2:1-2:1-2:1-2的發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物。
根據本發明的具體實施例,所述癌症患者是大腸癌患者。
根據本發明的具體實施例,癌症患者是以投予選自5-氟尿嘧啶、亞葉酸鈣、雙胺環己烷草酸鉑及其任意組合的化療藥物進行化療。
根據本發明的具體實施例,本發明的組合物是以口服給藥。
在部分具體實施例中,本發明的組合物能有效地抑制大腸息肉的增生和癌化,提高化療的效果,包括減少腫瘤的大小或延長存活期,特別是無疾病惡化存活期,增加化療順從性和減少化療引起的副作用。
本發明的另一目的是提供抗發炎藥劑的組合物。
特別地,本發明的組合物可有效地減少前列腺素E2(PGE2)、一氧化氮(NO),腫瘤壞死因子-α(TNF-α)和白細胞介素-6(IL-6)產生。
本發明的這些和其它方面可以通過以下較佳態樣和圖示的描述更清楚。即使可能有變更或修改,其並不脫離的本發明所揭示的新穎概念的精神和範圍。
前面的概述以及本發明的以下詳細描述結合附圖閱讀時將更易於理解。用於說明本發明的目的,目前較佳態樣顯示於附圖。然而,應當理解,本發明並不限於所示的精確安排和手段。
在附圖中:圖1顯示大鼠結腸中異常腺窩灶(ACF)。(A)相較於C1(1,2-二甲基肼(DMH)對照組)的大鼠,MB-6(B1=17.3毫克/大鼠/天,B2=34.6毫克/大鼠/天,B3=69.2毫克/大鼠/天)治療的大鼠表現出ACF/結腸的總數顯著減少(40.6-51.0%;*p<0.05)。(B)每個ACF的腺窩數分類為1-3腺窩,4-6腺窩和腺窩7。MB-6顯著防止化學誘導ACF的形成,且觀察到腺窩7的組別抑制率最高(81.7%,*p<0.05,對C1組)。
圖2顯示MB-6與亞葉酸鈣/5-氟尿嘧啶化療治療結腸CT-26-VD-荷瘤BALB/c小鼠的存活率。中位存活時間分別為27.5天(單獨腫瘤)、30.5天(NC)、34.5天(PSK)、35天(MB-6-L)、39天(MB-6-M)和39天(MB-6-H)。NC表示陰性對照組;PSK表示多醣;MB-6-L表示0.625克/公斤的MB-6;MB-6-M表示1.25克/公斤的MB-6;MB-6-H表示2.5克/公斤的MB-6。
圖3顯示意圖治療(ITT)族群的次要終點:無惡化存活期(PFS)顯著延長。
除非另外定義,所有本文中使用技術和科學術語具有如本發明所屬技術的通常技術人員所理解的相同的含義。
除非文中另有明確說明,如本文所用,單數形式“一”,“一個”和“該”包括複數個所指對象的“至少一個”。因此,例如,提及“一個成份”包括多個此成份和本領域技術人員已知的等同物。
如本文所使用的,與生物活性藥劑或組合物的施用有關的術語「治療有效量」表示相較於未經治療的對照個體,足以造成經治療個體中欲達成的生物效果的生物活性藥劑或組合物的量或劑量。具體而言,本發明組合物的有效量可以指抑制大腸息肉增生及/或癌化、增進化療有效性,包括延長存活期,特別是無惡化存活期、增加化療順從性及/或減少化療引起的副作用的量。量可以根據給藥途徑和治療的狀況,包括年齡、體重、症狀、治療效果、給藥方法和治療時間調整。例如,在某些具體態樣,用在本發明組合物的口服劑量是每日10至1000毫克/公斤,具體地是每天10至800毫克/公斤,更具體地是每天10至500毫克/公斤,甚至更具體地是每天10至250毫克/公斤,還更具體地是每日10至150毫克/公斤。
如本文所用,術語“個體”或“受試者”包括人類和非人類動物,例如寵物(如狗,貓等),農場動物(如牛,羊,豬,馬等)或實驗動物(例如大鼠,小鼠,豚鼠等)。
根據本發明,本發明組合物可以用作化療的輔助治療劑。在一個具體實施例中,本發明治療有效量的組合物可與藥學上可接受的載劑配製成適當形式的醫藥組合物,以供遞送和吸收為目的。根據給藥方式,本發明的醫藥組合物,較佳含有重量約10%至約100%,或約20%至約100%,或約40%至約100%,或約60%至約100%的活性成分,其中重量百分比是基於組合物整體的重量來計算。
如本文所使用的,術語「載劑」或「藥學上可接受的載劑」是指用於藥物的稀釋劑或賦形劑或類似物,包括製藥工業中普通技術人員所公知者。
本發明提供了一種主要包括發酵大豆萃取物、綠茶、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物的組合物,其可用於製造供接受化療的癌症患者使用的輔助治療劑。
具體來說,本文所用的發酵大豆萃取物是指通過利用至少一種乳酸菌和可視需要的至少一種酵母菌使水溶性大豆萃取物發酵製得的萃取物。在一實施例中,該至少一種乳酸菌是乳桿菌屬且該至少一種酵母菌是酵母菌屬。在某些實施例中,發酵是使用不同種類的乳桿菌屬培養物(例如,5、10、15、20、25或30種乳桿菌屬菌株的培養物)來實施,且較佳地,將至少一種酵母菌添加到不同種類的乳桿菌屬培養物中。發酵中可使用的乳桿菌屬菌株包括,但不限於,嗜酸乳桿菌(Lactobacillus acidophilus)CCRC(食品工業發展研究所之生物資源保存及研究中心,台灣)10695、14026、14064、14065和/或14079;德氏乳桿菌保加利亞亞種(Lactobacillus delbrueckii bulgaricus)CCRC 10696、14007、14009、14010、14069、14071、14098和/或16054;德氏乳桿菌乳亞種(Lactobacillus lactis lactis)CCRC 10791、12267、12306、12312、12315、12323、14016、14015和/或14117;高加索酸奶乳桿菌(Lactobacillus kefir)CCRC 14011和/或馬乳酒樣乳桿菌(Lactobacillus kefiranofaciens)CCRC 16059。發酵中可使用的酵母菌菌株包括,但不限於,釀酒酵母菌(Saccharomyces cerevisiae)CCRC 20577、20578、20581、21494、21550、21797、21805、22138、22234、22337、22731
和/或22728和/或乳酒假絲酵母菌(Candida kefyr)CCRC 21269、21742和/或22057。具體而言,在發酵後進行一個或一個以上步驟,例如滅菌、過濾、濃縮、凍乾或其任何組合。較佳地,在發酵後(例如)通過加熱進行滅菌,且可視需要地進行過濾和濃縮。更佳地,可(例如)經由凍乾來乾燥發酵大豆萃取物,以獲得呈粉末形式的發酵大豆萃取物。在某一實施例中,本發明的發酵大豆萃取物是通過包含以下步驟的製程來製得:(a)利用至少一種乳酸菌與至少一種酵母菌一起使水溶性大豆萃取物發酵,以形成發酵液;(b)對該發酵液進行滅菌;(c)過濾經滅菌發酵液,以收集過濾液;和(d)濃縮過濾液以形成濃縮的發酵大豆萃取物。在特定的實施例中,大豆與蒸餾水混合(例如,以1:10的比例),混合物於約100℃加熱約30分鐘後過濾。得到的大豆萃取水溶液在合適的培養基以至少一乳酸菌和至少一酵母菌發酵,並於36-43℃培養45-50小時,將經發酵萃取物滅菌、過濾及濃縮以得到濃縮形式的發酵大豆萃取物(例如,將過濾液95%的水去除)。在某個實施例中,發酵大豆萃取物為1.136g/ml和71.49%水分、5.15%灰分、0.16%粗脂肪、5.45%粗蛋白質、0.15%粗纖維及碳水化合物。也可含有數種維生素和礦物質:0.004毫克/100克維生素B1、0.12毫克/100克維生素B2、2.17毫克/100克鐵、113.55毫克/100克鈣及379.19毫克/100克磷酸。本文所用的發酵大豆萃取物可如美國專利第6,855,350號和第6,733,801號來製備,所述專利的每一者都以全文引用方式併入本文中。
另外,綠茶萃取物、薑黃萃取物和葡萄籽萃取物係以涉及用水或乙醇萃取的一般標準程序製成。螺旋藻可由收穫螺旋藻後乾燥,然後將其作成粉末或錠劑獲得。此外,可由一般液態發酵,然後乾燥,濃縮和/
或研磨成粉末得到的樟芝菌絲。這些成分可以從市場上購買。
根據本發明的部份具體態樣,如本文所述的組合物,包括發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物,且它們的重量比為12-30:4:1-2:1-2:1-2:1-2,較佳為12-20:4:1-2:1-2:1-2:1-2。根據本發明的特定具體實施例,發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物的重量比是12:4:2:1:1:1。根據本發明另一具體實施例,發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物的重量比是12:4:1:1:2:1。根據上述的重量比,可依不同情況適當地調整該組合物的各成分的重量比例。
本發明組合物可以被製造為各類食品或藥品。食品類的產品可利用常規賦形劑或填料以任何常規技術製造,並且如需要與添加劑混合。另外,藥物可利用治療有效量的本發明組合物和其醫藥上可接受的載劑以一般的藥物技術或方法製造。本發明的組合物的給藥包括口服或注射劑給藥,並且可以進一步包括醫藥上可接受的載劑、稀釋劑和/或賦形劑。上述載劑可以是溶劑、分散介質、包衣、抗菌劑、抗真菌劑、等滲劑和吸收延遲劑等。稀釋劑可以是抑菌性注射用水(BWFI)、磷酸鹽緩衝液、林格溶液或葡萄糖溶液等。賦形劑可以是碳酸鈣、碳酸鈉、磷酸鈣、磷酸鈉、乳糖、澱粉、明膠、藻酸、硬脂酸、硬脂酸鎂等。
在部分特定的具體實施例中,本發明組合物具有抑制大腸息肉增生和/或癌化的作用。具體而言,如實施例中所示,本發明組合物可以抑制由1,2-二甲基肼(DMH)引發的異常腺窩灶(ACF),且還具有防止大
腸息肉增生和/或癌化的作用。
在部分特定的具體實施例中,本發明組合物具有增強化療有效性的效果,其包括延長癌症患者存活期,特別是無惡化存活期。如實施例中所示,接受本發明組合物及化療的受試者相較於接受化療但未接受本發明組合物的受試者顯示較長的存活期,特別是較長的無惡化存活期。
在部分特定的具體實施例中,本發明的組合物具有增加化療順從性的效果。如實施例所示,接受本發明組合物及化療的受試者相較於接受化療但未接受本發明組合物的受試者顯示出顯著較高的化療順從性。
在部分特定的具體態樣中,本發明的組合物具有降低化療引起副作用的效果。如實施例所示,在癌症化療過程中投予本發明組合物時,發現該組合物可降低化療的副作用,尤其是減少腎損傷和改善嗜中性白血球低下。
此外,根據本發明,所述組合物如本文所述可作為抗發炎劑。具體而言,本發明的組合物可有效地減少發炎細胞,如巨噬細胞中的前列腺素E2(PGE2),一氧化氮(NO),腫瘤壞死因子-α(TNF-α)和白細胞介素-6(IL-6)的產生。
本發明適用於治療癌症,包括前列腺癌、乳腺癌、子宮癌、血液癌、卵巢癌、子宮內膜癌、子宮頸癌、結腸直腸癌、睾丸癌、淋巴瘤、橫紋肌肉瘤、神經母細胞瘤、胰腺癌、肺癌、腦癌、皮膚癌、胃癌、口腔癌、肝癌、喉癌、膽癌、甲狀腺癌、肝癌、腎癌及鼻咽癌。根據本發明的一個具體態樣,所述患者是大腸癌患者。根據本發明的具體態樣,化療使用藥物包括5-氟尿嘧啶,亞葉酸鈣和雙胺環己烷草酸鉑。
以下面實施例提供了用於示範而不是限制的目的,進一步說明本發明。本領域的技術人員按目前揭露應理解所揭露的特定具體態樣可進行許多變化而仍得到類似的結果而不脫離本發明的精神和範圍。
實施例
實施例1:抑制1,2-二甲基肼(DMH)誘導形成的異常腺窩灶(ACF)
1.1 材料與方法
動物研究是由國立台灣大學實驗動物管理和使用委員會批准,所有動物都按照照顧和使用實驗動物的標準指引處理。約6週齡的F344雄性大鼠係購自國立台灣大學醫學院實驗動物中心。
將雄性F344大鼠隨機依重量分組,每組8隻大鼠。大鼠於適應後第一週餵食含重量百分比17.7%的蛋白質、64.9%的碳水化合物及5.2%的脂肪的哈倫AIN-76純化糧囓齒動物飼料(Harlan AIN-76 purified rodent diet,美國印第安納州印第安納波利斯哈倫實驗室)(哈倫AIN-76純化糧囓齒動物飼料資料頁,http://www.harlan.com/download.axd/1131a6e16 17348b9a99 c8d2af933f796.pdf?d=170481)。大鼠被關在不銹鋼籠子裡,可自由取得食物和蒸餾水。動物室保持在23±1℃,50±10%濕度和12小時光照/黑暗週期。食物攝入量和體重每週記錄。
本發明的組合物(MB-6)包括六種成分,即發酵大豆萃取物(以在美國專利號6,855,350和6,733,801中所述的方法製備)、綠茶萃取物(Camellia sinensis O.)、螺旋藻(Arthrospira platensis)、薑黃萃取物(Curcuma longa L.)、樟芝菌絲體及葡萄籽萃取物(Vitis vinifera)。表1顯示
於特定實施例中MB-6的成分,其重量比為12:4:2:1:1:1。
將動物分組如下:C1,注射1,2-二甲基肼(DMH)對照組;C2,注射生理鹽水對照組;B1,接受低劑量本發明的六成分配方實驗組(17.3毫克/大鼠/天);B2,接受中劑量本發明的六成分配方實驗組(34.6毫克/大鼠/天);B3,接受高劑量本發明的六成分配方實驗組(69.2毫克/大鼠/天)。DMH溶解於鹽水(0.9%NaCl溶液中)形成2%的溶液,將pH調至6.7,然後分裝並儲存於-20℃直到需要。DMH以每週20毫克/公斤腹膜內(IP)注射,共4週(相當於注射每公斤體重1毫升的2%的溶液)。對照組給予生理食鹽水注射液(每公斤體重1毫升生理食鹽水)。參照表2和表3。
第15週時動物禁食1夜,第二天吸入二氧化碳安樂死。之後取出結腸,測量長度和重量並計算異常腺窩灶(ACF)數量和腺窩組成每個ACF的病灶數量。簡言之,結腸沿縱軸剪開並使粘膜層朝上展開,切成三段,近端,中間和後面。每段置於2張濾紙間且存放在含有10%福馬林緩衝液的培養皿中,並固定24小時以上。為定量ACF,固定結腸組織用0.2%亞甲基藍(用PBS作為溶劑)染色,ACF數量在光學顯微鏡下以40-100倍放大進行評估。為了確定腺窩的多樣性,每個ACF的腺窩數量進一步劃分為1-3個腺窩,4-6個腺窩和7個腺窩。
實驗數據採用SAS軟體進行單因子變異數分析,以學生t檢定比較組間差異。p<0.05表示顯著差異。
1.2 結果
共50隻F344大鼠隨機分配到C1組(DMH控制組),C2組(正常控制組),B 1組(MB-6-L),B2組(MB-6-M)和B3組(MB-6-H)。這5
組的體重隨著時間沒有顯著差異。每結腸ACF的數量示於圖1A。與C1組(DMH控制組)的大鼠相比,服用MB-6的大鼠表現出顯著降低ACF/結腸的總數(40.6-51.0%,P<0.05)。每ACF病灶數量被分為1-3個腺窩(小),4-6個腺窩(中),和7病個腺窩(大)。MB-6顯著防止化學誘導ACF的形成,7個腺窩的組別(81.7%,圖1B)抑制率最高。亦可參閱表4和表5。
動物實驗顯示本發明六成分配方有效減少1,2-二甲基肼引發的異常腺窩灶數量,且特別是減少大異常腺窩灶發生。
實施例2:抑制1,2-二甲基肼的形成(DMH)引起的大腸癌
2.1 材料與方法
購買來的約6週齡的F344雄性大鼠適應1週後隨機分成數組。每組有30隻。將動物分組如下:C1組:注射1,2-二甲基肼(DMH)對照組;C2組:注射生理鹽水對照組;B2組:服用中劑量本發明六成分配方(34.6毫克/大鼠/天)實驗組。DMH溶解於鹽水(0.9%NaCl溶液)形成2%的溶液,將pH調至6.7,然後分裝並儲存於-20℃直到需要。DMH係每週以30毫克/公斤劑量腹膜內(IP)注射共8週(相當於注射每公斤體重1.5毫升的2%溶液)。對照組注射生理鹽水(每公斤體重1.5毫升鹽水)。見表6和表7。
在32週實驗期間的到期日,試驗動物禁食過夜,然後用乙醚麻醉殺死,第二天解剖。除去動物結腸,測量長度和重量,然後保存為下列腫瘤的分析。
取出結腸,盲腸,小腸和胃並沿著這些器官的縱軸完全切開。用磷酸鹽緩衝鹽水後,將器官被平放在濾紙上,粘膜面朝上。檢查在樣品上的腫瘤,並記錄腫瘤的位置、數量和大小。各腫瘤的長度(L),寬度(W)和深度(D)以游標尺測量,且每個腫瘤的體積(V)以公式:V=(L * W* D * π)/6進行計算。樣品拍照並保存。
實驗數據採用SAS軟體進行單因子變異數分析,以學生t檢定比較組間差異。p<0.05表示顯著差異。
2.2 結果
如表8所示數據,在腫瘤數目方面,本發明的六成分配方可有效地抑制由1,2-二甲基肼誘發的腫瘤的形成達抑制率38.4%,並有顯著統計差異(P<0.05)。
此外,腫瘤以體積分成三組,分別為0-100mm3(小型),100-500mm3(中型),以及超過500mm3(大型),如表9所示。本發明六成分配方可以抑制由1,2-二甲基肼引發的腫瘤,尤其是顯著抑制小尺寸的腫瘤(0-100mm3)達49.7%的抑制率(p<0.001)。
實施例3:減少小鼠大腸癌的體積和延長動物存活
3.1 材料與方法
雄性BALB/c小鼠係購自在台灣的從國家實驗動物中心,並21±2℃維持在12小時的光/暗週期。AIN-76純化飼料和蒸餾水由小鼠自由採食。
將小鼠隨機分成7組,每組12隻小鼠和每籠3隻小鼠。小鼠結腸癌細胞系CT-26-VD是在含有10%胎牛血清的完整經杜爾貝科改良伊格爾培養基(Dulbecco's Modified Eagle Medium(DMEM);GIBCO,目錄號11995)於37℃在含5%二氧化碳的培養箱中培養。建立小鼠結腸癌模型已如前所述
(威特克M等,Int J Radiat Oncol Biol Phys 2014;88:1188-95)。簡言之,將小鼠稱重並基於體重以適當劑量戊巴比妥鈉(Somnotol,加拿大,10微升/克,6.5毫克/毫升)麻醉。將100微升的CT-26-VD細胞懸浮液(2×105個細胞/毫升,2×104細胞/小鼠)注入小鼠脾臟(第0天),並保護動物免受低溫直到恢復。處理過的小鼠口服管餵3種不同劑量的MB-6(0.625克/公斤(MB-6-L),1.25克/公斤(MB-6-M)和2.5克/公斤(MB-6-H))。注射腫瘤細胞後的第三和第六天隨後小鼠以LV/5-FU(亞葉酸鈣/5-氟尿嘧啶)治療。陰性對照組(negative control(NC))和陽性組小鼠分別給予無菌Milli-Q水和PSK(多醣K,0.325克/公斤),以替代測試物質的MB-6。該分組的摘要示於表10。
每週一次監測每隻小鼠體重。在第15天的小鼠注射螢光素(150毫克/公斤,IP),吸入3%異氟烷麻醉,並與非侵入性的IVIS成像系統100系列(Xenogen,CA)放置在暗箱中。使用該系統的軟體進行生物發光定量以測定腫瘤生長。每隻小鼠的壽命被記錄到第55天。研究結束後,所有動物以吸入二氧化碳方式安樂死。
3.2 結果
相較於LV/5-FU化療組,MB-6不影響CT-26-VD-荷瘤BALB/c小鼠的飼料攝取量和體重。生物發光量化結果顯示,投予1.25或2.5克/公斤的MB-6顯著增加LV/5-FU化療的治療功效(數據未顯示)。中位存活時間分別為27.5天(單獨腫瘤)、30.5天(NC)、34.5天(PSK)、35天(MB-6-L)、39天(MB-6-M)和39天(MB-6-H)(圖2)。投予0.625至2.5克/公斤的MB-6顯著延長接受化療的荷瘤小鼠壽命,其中相較於NC組,MB-6-M延長超過30%以上的壽命。
實施例4:人體臨床試驗
4.1材料與方法
4.1.1病人資格
本試驗為雙臂、多中心、平行、雙盲、隨機、安慰劑對照的臨床試驗,其評估轉移性大腸直腸癌患者以MB-6結合FOLFOX4(5-FU+LV+雙胺環己烷草酸鉑)對比安慰劑的療效和安全性。此臨床試驗經過參與試驗的6家醫院的人體試驗委員會核准,且所有患者提供受試者同意書。
受試者納入條件有年滿20年或以上、有病理證實的CRC和/或轉移的臨床證據、至少有1個電腦斷層掃描(CT)或核磁共振攝影(MRI)可測量的病灶、美國東岸癌症臨床研究合作組織(Eastern Cooperative Oncology Group)(ECOG)體能狀態2,擁有充足的骨髓儲備(血紅蛋白9克/分升,絕對嗜中性白血球數1.5×109/升,血小板100×109/升)和肝腎功能(總膽紅素1.25×,肌酸酐1.25,肝臟轉胺酶(ALT)和天冬胺酸轉胺酶(AST)<2.5×正常上限)。
受試者排除條件有懷孕或哺乳期、未採取適當的避孕措施、顯示中樞神經系統轉移的跡象、需要全身抗生素治療的主動感染、目前有慢性腹瀉和其他嚴重合併症(如心絞痛,心肌梗死,充血性心臟衰竭,癲癇症,或其他經醫師判斷的顯著醫學狀態)、具有第二原發惡性腫瘤病史(除了充分治療的基底細胞皮膚癌或子宮頸原位癌)或正以任何其他抗癌藥劑同時治療,或在過去的4個星期內以其他研究藥物治療。
4.1.2 治療方案
患者以MB-6和伴隨的FOLFOX4治療(de Gramont A et al.,J Clin Oncol 2000;18:2938-47;Goldberg RM et al.,J Clin Oncol 2004;22:23-30)。MB-6劑量為每天3次隨餐服用每個320毫克的6粒膠囊。安慰劑組投予只含非活性成分的相同數量膠囊。FOLFOX4化療方案為在第一天靜脈注射LV(200毫克/米2)和雙胺環己烷草酸鉑(85毫克/米2)2個小時,隨後快速輸注400毫克/米25-FU及靜脈注射600毫克/米2 22小時,在第二天靜脈注射LV(200毫克/米2)2個小時,隨後快速輸注400毫克/米25-FU及靜脈注射600毫克/米2 22小時。FOLFOX4方案每2週重複一次共計16週。
4.1.3 追蹤評估
隨機分組前和每2週測量生命徵象和體重。每4週測血清癌胚抗原(CEA)含量及血液學和生化參數(紅血球細胞(RBC)計數,血容比,白血球細胞(WBC)計數,血小板計數,絕對嗜中性白血球計數,分類計數,總膽紅素,肌酸酐,ALT和AST)測試。每8週執行腫瘤評估。服藥順從性在每個考察訪問記錄。
4.1.4 主要指標
如前所述(艾森豪爾EA等人,Eur J Cancer 2009;45:228-47),本研究的主要療效終點係以計算MB-6最佳總體反應(以RECIST1.1標準的完全緩解(CR)+部分緩解(PR))評估,並將結果與接受安慰劑的患者進行比較。
4.1.5 次要指標
無惡化存活期(PFS)被評定為從隨機分組日期至觀察到疾病惡化日期的期間。任何原因引起的死亡被認為是惡化事件。在最後一次客觀腫瘤評估當天檢查無經記錄疾病進展的患者或生存追蹤。如無基線後腫瘤評估或生存追蹤,則疾病惡化係於試驗藥物治療(MB-6或安慰劑)起始當天檢查。
試驗藥物治療起始或之後的不良反應(AE)的表現是按照MedDRA編碼字典(Program CTE。Common terminology criteria for adverse events(CTCAE)3.0版,美國國家癌症研究所2006年)的全身器官分類和較佳術語分類。對不良反應的持續的時間,嚴重程度,與研究藥物關係,採取的行動和結果進行記錄。該事件是否被列為嚴重不良反應(SAE)也被
記錄下來。
4.2 結果
4.2.1 病人的人口統計
共招募72例轉移性大腸癌患者。研究對象被隨機雙盲的方式以1:1的比例採用塊狀排列隨機分派投予MB-6或安慰劑。34例患者被隨機分配到的MB-6組,38例至安慰劑組。共有60名患者(29例MB-6組,31例安慰劑組)完成了為期16週的試驗(83.3%)。所有72名患者納入了ITT(意向性治療)的群體。2組之間病人的人口統計學和基線特徵無明顯差異(p<0.05)。
4.2.2 主要結果
最好的總體反應率分別為MB-6組的41.2%和安慰劑組的39.5%,無顯著差異(p=1.000)。經RECIST1.1標準最後一次測量腫瘤緩解率(CR+PR)為MB-6組的61.8%,和安慰劑組的63.2%。
4.2.3 次要終點
無一例MB-6組患者在16週的研究期間病情惡化,而6例安慰劑組病情惡化。MB-6組患者相較於安慰劑組患者有顯著降低的疾病惡化率(0.0%對15.8%,p=.026)。在16週的研究期間MB-6組無死亡病例,而安慰劑組有2例。此外,在停藥後8週,經本發明六成分配方治療的病患的無惡化存活期顯著延長(p=0.0056)。參見表11。
此外,MB-6組中體重沒有從基線顯著下降,而安慰劑組在試驗的第4,6及8週顯示顯著體重下降(p<0.05)。然而,在試驗結束時兩組間體重變化無顯著差異(P=0.114)。此外,在8週FOLFOX4化療顯著降低血清CEA含量,且在MB-6存在下有類似的降低效果。
另外,MB-6的順從性為93.8±11.6%,安慰劑順從性為94.1±11.4%(p=0.919)。非可預期地,安慰劑組相比,MB-6組對FOLFOX4化療呈現顯著較高順從性(94.4±7.8%對89.0±13.2%,p=0.037)。請參閱表12。
如表12所示,本發明的組合物(MB-6)能提升受試者對化療的容忍度(p值=0.0370)。
4.2.4 安全性和副作用減少
AE不良反應的嚴重性根據CTCAE3.0分級,其中1=輕度,2=中度,3=重度,4=危及生命的和5=死亡。一般來說,相較於MB-6組,安慰劑組中4級的不良反應有顯著較高的發生率(28.9%對2.9%,P=0.004)。總共有19名患者(6例在MB-6組和13例在安慰劑組)被通報28起嚴重不良反應(SAE)。具體而言,相較於MB-6組,安慰劑組也有顯著更高的血清肌酸酐增加發生率(29%對5.9%,p=0.014),這表示MB-6組減少化療對腎臟造成的不良反應。請參閱表13。
此外,本發明的六成分配方(MB-6)能改善化療引起的嗜中性白血球低下,特別是針對具有較高等級不良反應的嚴重情形(程度4,p值=0.0302)。請參閱表14。
實施例5:抗發炎研究
巨噬細胞在發炎反應扮演中心角色。經LPS活化後,即導致包括NF-κB途徑和MAP激酶途徑的下游信息傳導途徑活化。這些信息傳導途徑誘導多種發炎介質,其包括一氧化氮、前列腺素和前發炎性細胞激素的表現。因此,RAW264.7鼠的類巨噬細胞細胞為我們提供了抗炎活性篩選的優良模型。
5.1 方法
5.1.1 細胞培養和樣品處理
含5%二氧化碳潮濕氣體中,於37℃下在補充10%FBS的DMEM培養基中培養RAW264.7細胞。以密度為0.1-1x105細胞/孔將RAW264.7細胞鋪在在96-孔盤中。然後將細胞以0.0625-1毫克/毫升濃度的試藥(MB-6)或陽性對照(地塞米松或西樂葆)培養,然後用100ng/mL的LPS活化18小時。在培養期結束時,用比色MTT測定法測定細胞存活率。保存並在-20℃冷凍細胞培養上清液供分析亞硝酸鹽、PGE 2、TNF-α和IL-6含量。
5.1.2 亞硝酸鹽測定
用Griess試劑系統(Promega公司,麥迪遜,WI,USA)測定培養基中的亞硝酸鹽含量,並可用以推定為反映NO含量。簡言之,將50μL細胞培養基和50μL磺胺溶液混合,並在室溫下培養10分鐘,然後加入用50μL NED溶液中溶液,在室溫再培養10分鐘。使用微板讀數器(BioTek的,威努斯基,VT,USA)在520nm測量吸光度。在所有實驗中的新鮮培養基被用作空白試劑。樣品中亞硝酸鹽的含量由標準的亞硝酸鈉曲線讀出。
5.1.3 PGE2,TNF-α和IL-6的測定法
用EIA套組(R&D系統,明尼阿波利斯,明尼蘇達。USA)定量PGE 2和TNF-α和IL-6在培養基中含量。
5.2 結果
5.2.1 MB-6對LPS誘導的NO和PGE2產生和細胞存活的效果
取得培養基,並測定亞硝酸鹽和PGE2含量以評估MB-6對RAW 264.7細胞中LPS誘導NO和PGE2生成的效果。MB-6依劑量顯著抑制LPS誘導的NO生成。此外,MB-6的治療也減少LPS誘導的PGE2生成。西樂葆(Celebrex),一種COX-2抑製劑,被用來作為PGE2生成的陽性對照。此外,以MTT測定法評估MB-6對RAW 264.7細胞的細胞毒性作用,MB-6於使用濃度(0.0625-1毫克/毫升)並不影響細胞存活。
5.2.2 MB-6對LPS誘導的TNF-α和IL-6釋放的效果
通過酶免疫測定法(ELISA)進一步評估MB-6對LPS誘導的細胞介質釋放,如TNF-α和IL-6,的效果。發現,MB-6預處理的細胞顯著減少IL-6和TNF-α的生成。
結果如表15所示
結論
本研究結果證實MB-6增加了大腸癌患者的化療效力。體內臨床前試驗顯示,MB-6能夠延長經LV/5-FU治療的罹結腸癌Balb/c小鼠壽命。臨床試驗的結果顯示,在16週的試驗期間,相較於安慰劑組,投予MB-6的患者有顯著較長的PES,在第8週觀察到MB-6和安慰劑組血清CEA含量有類似的降低,這表示添加MB-6不減低FOLFOX4效果。此外,在MB-6組觀察到對FOLFOX4顯著較好的順從性,這表示較好的耐受性,MB-6組對於大於等於4級的不良反應有顯著較低的發生率。
MB-6組患者有顯著較高的中位PFS和較慢的疾病惡化,這表示MB-6提高了接受FOLFOX4治療的轉移性結直腸癌患者的整體生存品質。這些數據與顯示MB-6延長經化療的荷瘤小鼠30%以上的壽命的前臨床前試驗一致。
雖然MB-6組和安慰劑組在最佳總反應率(CR+PR)的無顯著差異,我們的數據與先前顯示FOLFOX4整體腫瘤反應率為58.5%的研究(Tournigand C等人,J Clin Oncol 2006;24:394-400)一致。這表示MB-6沒有削弱FOLFOX4對轉移性結直腸癌患者的效果。注意到,在研究結束時兩組間的CEA含量和免疫功能沒有顯著差異,確認MB-6對化療方案沒有負面影響。換句話說,MB-6不干擾FOLFOX4在這些轉移性結直腸癌(mCRC)患者的細胞毒性作用。我們的數據還顯示,MB-6能夠提供抗發炎活性,其支持以MB-6治療癌症進展較慢的結果。
總結,體內前臨床試驗顯示MB-6能夠延長經LV/5-FU治療的
罹結腸癌Balb/c小鼠壽命。臨床試驗結果顯示在16週的試驗期間,相較於安慰劑組,投予MB-6的患者有顯著較長的PFS,且他們在大於等於4級的不良反應有顯著較低的發生率。
本發明所屬領域具有普通知識者基於本文描述可利用本發明至其最大範圍而無需進一步說明。因此,所提供的本發明說明、實施例和請求項應理解為示範的目的,而不是以任何方式限制對本發明的範圍。
Claims (8)
- 一種組合物用於製造在個體以化療治療癌症的化療輔助治療劑的用途,其中該組合物係包括發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物,以及該化療輔助治療劑係有效於減少化療引起的副作用,其中所述之減少化療引起的副作用包括減少腎損傷和改善嗜中性白血球低下。
- 如請求項1的用途,其中該發酵大豆萃取物是由水性大豆萃取物與至少一種乳酸桿菌及視需要至少一種酵母菌發酵而製得。
- 如請求項1的用途,其中該發酵大豆萃取物是通過包含以下步驟的方法而製得:(a)以至少一種乳酸菌與至少一種酵母菌使水溶性大豆萃取物發酵,以形成發酵液;(b)對該發酵液進行滅菌;(c)過濾經滅菌的發酵液,以形成過濾液;和(d)濃縮過濾液,以形成濃縮的發酵大豆萃取物。
- 如請求項1的用途,其中該發酵大豆萃取物、綠茶萃取物、螺旋藻、薑黃萃取物、樟芝菌絲體和葡萄籽萃取物係以重量比12-30:4:1-2:1-2:1-2:1-2存在於該組合物中。
- 如請求項1的用途,其中該化療係以投予5-氟尿嘧啶及亞葉酸鈣,或5-氟尿嘧啶及亞葉酸鈣連同雙胺環己烷草酸鉑的化療藥物施行。
- 如請求項5的用途,其中該化療輔助治療劑係在以該化療治療癌症之個體中,有效於增加化療順從性、提高化療的治療效果、及/或延長存活期。
- 如請求項6的用途,其中該存活期是無惡化存活期。
- 如請求項6或7的用途,其中該癌症為大腸癌。
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