TWI598096B - Preventive and / or therapeutic agents for side effects of anticancer agents - Google Patents
Preventive and / or therapeutic agents for side effects of anticancer agents Download PDFInfo
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- TWI598096B TWI598096B TW101137456A TW101137456A TWI598096B TW I598096 B TWI598096 B TW I598096B TW 101137456 A TW101137456 A TW 101137456A TW 101137456 A TW101137456 A TW 101137456A TW I598096 B TWI598096 B TW I598096B
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Classifications
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
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Description
本發明係有關一種抗癌劑之副作用的預防劑及/或治療劑。更詳言之,本發明係有關一種包含ALA類之抗癌劑之副作用的預防劑及/或治療劑。
抗癌劑乃為與手術、放射線療法並列的癌症三大治療法之一,常引起嚴重的副作用。一般而言,抗癌劑效果愈強會有愈強的副作用。因此,在抗癌劑的使用選擇上,醫師、患者被迫處於兩難的局面。
基於此種背景,已提出有數個減輕抗癌劑之副作用的方法。例如進行:投予十全大補湯之類的中藥的方法、基於時間生物學控制抗癌劑投予的時間點的方法、投予抗癌劑時進行大量輸液來保護器官的方法等。然而,即便利用此等方法,對抗癌劑之副作用並無多大減輕效果。此外,為進行夜間的點滴、大量輸液等而需住院,在身心或醫療經濟方面其負擔甚大。
此外,作為減輕抗癌劑之副作用的方法,可降低副作用的藥劑的開發亦持續進行。作為此種藥劑,作為腦缺血的治療劑的伊達拉奉(Edaravone)已確認有二氯二胺鉑對腎功能的副作用減輕作用,而極受矚目。然而,該藥劑在開發中被發現有包含因腎衰竭所致之死亡例的嚴重副作用,迄今仍未上市。
原本抗癌劑的作用為何?又,引起抗癌劑之副作用的機制為何?業已存在多種抗癌劑,並已對抗癌劑的作用機制進行研究;多數抗癌劑係藉由阻斷DNA的複製或細胞周期來顯示抗癌作用。此種抗癌劑對生長較快的癌細胞顯示出更強的生長抑制效果。惟,另一方面,由於其對正常細胞亦顯示相同的生長抑制效果,對於正常細胞當中生長較快的髮根、腸道亦顯示出損害-此即為造成抗癌劑之副作用的原因。
此外,某種抗癌劑係藉由產生活性氧物種來抑制、消滅癌症。另一方面,由抗癌劑產生的活性氧多半會對正常細胞造成危害,而此即為造成副作用的原因。作為減輕此種抗癌劑之副作用的方法,可考慮提供抗氧化物質。然而,顯然抗氧化物質會減輕抗癌劑的首要抗癌效果。又,抗氧化物質即使可減輕此種抗癌劑的副作用,但仍無法減輕其他種類抗癌劑的副作用。
如以上所述,抗癌劑效果愈強副作用愈大;反之副作用較少的抗癌劑幾無抗癌效果。又,抑制抗癌劑之副作用的藥劑亦會抑制抗癌劑的抗癌效果。作為突破此兩難的理想抗癌劑,分子標靶藥物便極受歡迎地問世。然而,由艾瑞莎(Iressa)引起的間質性肺炎之實例自不待言,分子標靶藥物亦未能免除其副作用的問題。且,分子標靶藥物也毫無例外地極為昂貴。
基於此種背景,醫師、患者便期望開發出一種實屬有效之抗癌劑之副作用的預防劑及/或治療劑。此外,由於沉重高額醫療費用的負擔故社會上要求迫切開發有效的抗癌劑之副作用的預防劑及/或治療劑。
本發明之課題在於提供一種有效的抗癌劑之副作用的預防劑及/或治療劑。
本說明書中,ALA意指5-胺基乙醯丙酸。ALA亦稱之為δ-胺基乙醯丙酸,為胺基酸的1種。ALA乃活體內的內在物質,已知係作為血紅素的前驅物。ALA已知有各種生理活性,在癌症等的診斷、治療領域中,廣泛使用於光動力學治療(PDT,Photo Dynamic Therapy)、光動力學診斷(PDD,Photo Dynamic Diagnosis)。已知ALA雖為血紅素系化合物的共同前驅物,但在癌細胞中,即使投予ALA亦不會生成血紅素,而是累積作為血紅素系化合物的前驅物的原紫質IX(PPIX)。對累積之PPIX照射光時會產生螢光,由此可進行PDD。此外,在氧存在下對累積之PPIX照射光時則會產生活性氧,由此可進行PDT。亦即,ALA作為PDT的敏化劑僅與抗癌劑有關,而ALA作為抗癌劑之副作用的預防劑及/或治
療劑的使用則完全未思及。
已知ALA可提高醣類、脂質的代謝,但仍無所謂抗癌劑之副作用與醣類、脂質的代謝有關的報導,由既有資訊並無法推知「ALA對於抗癌劑之副作用的預防、治療實屬有效」。
本發明人戮力重複進行研究,確立一種包含ALA類之抗癌劑之副作用的預防劑及/或治療劑,終至完成本發明(惟,ALA類為何對抗癌劑之副作用的減輕有效,對此之縝密機轉的解明乃為今後科學上的課題)。
亦即,本發明係有關一種抗癌劑之副作用的預防劑及/或治療劑,其特徵在於含有以下式(I)表示之化合物或其鹽,R1-NHCH2COCH2CH2COOR2 (I)其中於該式中,R1表示氫原子或醯基,R2表示氫原子、直鏈或分支狀烷基、環烷基、芳基或芳烷基。
本發明之抗癌劑之副作用的預防劑及/或治療劑可進一步含有一種或二種以上的金屬。此種金屬可選自包含鐵、鎂、及鋅的群組。
此外,作為前述抗癌劑的副作用,可為任何抗癌劑之副作用。舉例而言,前述抗癌劑的副作用可為腎臟相關副作用、皮膚症狀相關副作用、全身症狀相關副作用、或消化道系統相關副作用。又前述抗癌劑的副作用可為由所有抗癌劑之副作用排除血液或骨髓相關副作用者。
另外,本發明之抗癌劑之副作用的預防劑及/或治療劑可與抗癌劑併用。
再者,本發明進一步有關一種組合(1)含有以上式(I)表示之化合物的抗癌劑的副作用的預防劑及/或治療劑、與(2)抗癌劑而成的癌治療用醫藥。此等藥劑可同時或不同時投予。
本發明提供一種抗癌劑之副作用的預防劑及/或治療劑。本發明中,「治療」係指不僅完全去除抗癌劑之副作用,還包含改善副作用的症狀。對於「預防」,亦同樣意指「不僅完全不產生副作用的症狀,亦包含使未投予本發明之預防劑可能產生的副作用的症狀更加穩定」。透過使用本發
明之藥劑,可獲得優良抗癌劑之副作用的預防效果及/或治療效果。
此外,藉由投予本發明之抗癌劑之副作用的預防劑及/或治療劑,即使在例如因嚴重的副作用而完全無法對患者投予抗癌劑時、或無法投予標準量的抗癌劑時,亦可對該患者進行標準量的抗癌劑的投予。如此一來,藉由投予本發明之抗癌劑之副作用的預防劑及/或治療劑,便可將抗癌劑原本的效果發揮至最高限度,非但有患者之QOL的提升效果,還可望有患者的延壽效果。
如此,本發明的藥劑對於接受抗癌劑治療的患者不僅有益,還可減輕抗癌劑副作用所產生的社會損失。
第1圖係按每投予條件表示根據5個投予條件對6週大的SD大鼠投予二氯二胺鉑及ALA時的生存率的推移的圖表;第2圖係根據5個投予條件對6週大的SD大鼠投予二氯二胺鉑及ALA時的實驗開始日至第16日之腎臟的HE染色圖像;第3圖係按每投予條件表示根據4個投予條件對6週大的SD大鼠投予二氯二胺鉑及ALA時的體重的推移的圖表;第4圖係按每投予條件表示根據4個投予條件對6週大的SD大鼠投予二氯二胺鉑及ALA時的血清肌酸酐的推移的圖表;第5圖係按每投予條件表示根據4個投予條件對6週大的SD大鼠投予二氯二胺鉑及ALA時的尿素窒素(BUN)的推移的圖表;第6圖係按每投予條件表示根據4個投予條件對6週大的SD大鼠投予二氯二胺鉑及ALA時的尿蛋白值的推移的圖表;第7圖係表示根據4個投予條件對6週大的SD大鼠投予二氯二胺鉑及ALA時的實驗開始日至第16日之腎臟的圖像;第8圖係表示投予二氯二胺鉑及ALA對T24細胞(人體轉移細胞膀胱癌細胞)其T24細胞的生存所造成的影響的圖表;以及第9圖係表示投予二氯二胺鉑及ALA對253J-BV細胞(人體尿路上皮癌細胞)其253J-BV細胞的生存所造成的影響的圖表。
作為本發明之抗癌劑之副作用的預防劑及/或治療劑,只要是含有ALA類之抗癌劑之副作用的預防劑及/或治療劑則未特別限制。本發明的藥劑可依據實施形態,適於在抗癌劑治療前攝取、與抗癌劑治療同時攝取、於抗癌劑治療後攝取、或於抗癌劑副作用產生後攝取。
透過使用本發明之抗癌劑之副作用的預防劑及/或治療劑,抗癌劑的副作用便得以減輕,因此,可視情況而定增加抗癌劑的投予量。
另外,本發明之抗癌劑之副作用的預防劑及/或治療劑可與抗癌劑組合,以例如合劑或套組來使用。
本發明中,抗癌劑並未特別限制。作為此種抗癌劑的非限定實例,可例舉含鉑之抗癌劑(二氯二胺鉑等)。
本發明中,抗癌劑的副作用係指由抗癌劑所導致的身體不適情形全體。抗癌劑的副作用涉及多方面。作為此種副作用的非限定實例,可例舉(1)血紅素的減輕、溶血、貧血等血液或骨髓相關副作用、(2)乏力感、倦怠感、體重減輕等全身症狀相關副作用、(3)掉髮、發疹等皮膚症狀相關副作用、(4)反胃、噁心、便秘、腹瀉等消化道系統相關副作用、(5)腎衰竭等腎臟相關副作用(腎毒性)。
用作本發明之抗癌劑之副作用的預防劑及/或治療劑的化合物係屬ALA類。本說明書中,ALA類係指ALA或者其衍生物或其等之鹽。
作為ALA衍生物,可例示以下式(I)表示之化合物。式(I)中,R1表示氫原子或醯基,R2表示氫原子、直鏈或分支狀烷基、環烷基、芳基或芳烷基。此外,式(I)中,ALA係相當於R1及R2為氫原子的情況。
R1-NHCH2COCH2CH2COOR2 (I)
ALA類只要在活體內,以式(I)之ALA或其衍生物的狀態作為有效成分而發揮作用即可,亦能以由活體內的酵素分解之前驅藥(前驅物,prodrug)的形式進行投予。
作為式(I)之R1之醯基,可例舉甲醯基、乙醯基、丙醯基、丁醯基、異丁醯基、戊醯基、異戊醯基、三甲基乙醯基、己醯基、辛醯基、苯甲羰基等直鏈或分支狀之碳數1~8之烷醯基、或苯甲醯基、1-萘甲醯
基、2-萘甲醯基等碳數7~14之芳醯基。
作為式(I)之R2之烷基,可例舉甲基、乙基、丙基、異丙基、丁基、異丁基、二級丁基、三級丁基、戊基、異戊基、新戊基、己基、庚基、辛基等直鏈或分支狀之碳數1~8之烷基。
作為式(I)之R2之環烷基,可例舉環丙基、環丁基、環戊基、環己基、環庚基、環辛基、環十二基、1-環己烯基等可存在飽和、或一部分不飽和鍵的碳數3~8之環烷基。
作為式(I)之R2之芳基,可例舉苯基、萘基、蒽基、菲基等碳數6~14之芳基。
作為式(I)之R2之芳烷基,芳基部分可例示與上述芳基相同者,烷基部分亦可例示與上述烷基相同者,具體可例舉苯甲基、苯乙基、苯丙基、苯丁基、二苯甲基、三苯甲基、萘甲基、萘乙基等碳數7~15之芳烷基。
作為較佳之ALA衍生物,可例舉R1為甲醯基、乙醯基、丙醯基、丁醯基等的化合物。又作為較佳之ALA衍生物,可例舉上述R2為甲基、乙基、丙基、丁基、戊基等的化合物。此外,作為較佳之ALA衍生物,可例舉上述R1與R2的組合為(甲醯基與甲基)、(乙醯基與甲基)、(丙醯基與甲基)、(丁醯基與甲基)、(甲醯基與乙基)、(乙醯基與乙基)、(丙醯基與乙基)、(丁醯基與乙基)之各組合的化合物。
ALA類當中,作為ALA或其衍生物之鹽,可例舉藥理學上允許之酸加成鹽、金屬鹽、銨鹽、有機胺加成鹽等。作為酸加成鹽,可例示如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、磷酸鹽、硝酸鹽、硫酸鹽等各無機酸鹽、甲酸鹽、乙酸鹽、丙酸鹽、甲苯磺酸鹽、琥珀酸鹽、草酸鹽、乳酸鹽、酒石酸鹽、乙醇酸鹽、甲磺酸鹽、丁酸鹽、戊酸鹽、檸檬酸鹽、富馬酸鹽、馬來酸鹽、蘋果酸鹽等各有機酸加成鹽。作為金屬鹽,可例示鋰鹽、鈉鹽、鉀鹽等各鹼金屬鹽、鎂、鈣鹽等各鹼土金屬鹽、鋁、鋅等各金屬鹽。作為銨鹽,可例示銨鹽、四甲基銨鹽等烷基銨鹽等。作為有機胺鹽,則可例示三乙胺鹽、哌啶鹽、嗎福啉鹽、甲苯胺鹽等各鹽。此外,此等鹽在使用時亦能以溶液形式使用。
以上之ALA類當中,最佳者為ALA、及、ALA甲基酯、ALA乙基
酯、ALA丙基酯、ALA丁基酯、ALA戊基酯等各種酯類、以及此等之鹽酸鹽、磷酸鹽、硫酸鹽。特別是,ALA鹽酸鹽、ALA磷酸鹽可例示為特佳者。
上述ALA類可透過例如化學合成、利用微生物生產、利用酵素生產等周知方法來製造。此外,上述ALA類可形成水合物或溶劑合物,亦可單獨或適當組合2種以上來使用ALA類。
本發明之抗癌劑之副作用的預防劑及/或治療劑係以在不發生過多症的範圍,進一步含有含金屬為佳;作為所述金屬,只要未對本發明之效果造成損害,則可有利地使用金屬化合物。作為本發明中的金屬,可例舉鐵、鎂、鋅、鎳、釩、鈷、銅、鉻、鉬,惟較佳為鐵、鎂、鋅。
作為鐵化合物,可例舉檸檬酸亞鐵、檸檬酸亞鐵鈉、檸檬酸鐵鈉、檸檬酸鐵銨、焦磷酸鐵、血質鐵(heme iron)、聚葡萄糖鐵、乳酸鐵、葡萄糖酸亞鐵、二伸乙三胺五乙酸鐵鈉、二伸乙三胺五乙酸鐵銨、乙二胺四乙酸鐵鈉、乙二胺五乙酸鐵銨、三伸乙四胺鐵、二羧甲基麩胺酸鐵鈉、二羧甲基麩胺酸鐵銨、乳鐵蛋白鐵、運鐵蛋白鐵、氯化鐵、三氧化二鐵、鐵葉綠酸鈉、鐵蛋白鐵、富馬酸亞鐵、焦磷酸亞鐵、含糖氧化鐵、乙酸鐵、草酸鐵、琥珀酸亞鐵、琥珀酸檸檬酸鐵鈉、硫酸鐵、硫酸三甘胺酸鐵等。此等當中,較佳為檸檬酸亞鐵、檸檬酸亞鐵鈉。
作為鋅化合物,可例舉氯化鋅、氧化鋅、硝酸鋅、碳酸鋅、硫酸鋅、二伸乙三胺五乙酸鋅二銨、乙二胺四乙酸鋅二鈉、鋅原紫質、鋅酵母、葡萄糖酸鋅。
上述金屬可分別使用1種或2種以上,作為金屬的投予量,相對於ALA類的投予量,以莫耳比計可例舉0.01~10倍量,較佳為0.1~5倍量,更佳為0.2~2倍量。
本發明所含有抗癌劑之副作用的預防劑及/或治療劑之ALA類及金屬,可作成包含ALA類及金屬的組成物來投予、或各自單獨投予,惟在各自單獨投予時亦以同時投予為佳。然,嚴格說來,即便為非同時,為使ALA類及金屬的投予能夠發揮相加效果或相乘效果,亦可於兩者間未隔開相當時候之下來進行。
作為本發明抗癌劑之副作用的預防劑及/或治療劑的投予路徑,可例
舉亦包含舌下投予的經口投予、或者吸入投予、包含點滴的靜脈內投予、使用泥罨劑等的經皮投予、坐劑、或利用鼻胃管、鼻腸管、胃造口管(gastrostomy tube)或是腸造口管之強制性腸道營養法(enteral nutrition)所進行的投予等非經口投予等,惟一般為經口投予。
於此,投予的對象典型上為人類,惟寵物、實驗動物、家畜等非人類動物的情況亦包含在內。
作為本發明抗癌劑之副作用的預防劑及/或治療劑的劑型,可根據上述路徑投予來適當決定,可例舉注射劑、點滴劑、錠劑、膠囊劑、細粒劑、散劑、液劑、溶於糖漿等的水劑、泥罨劑、坐劑等。
為調製本發明抗癌劑之副作用的預防劑及/或治療劑,可視需求添加藥理學上可允許之擔體、賦形劑、稀釋劑、添加劑、崩解佐劑、結合劑、被覆劑、潤滑劑、滑走劑、滑劑、風味劑、甘味劑、溶解化劑、溶劑、凝膠劑、營養劑等,具體可例示水、生理食鹽水、動物性脂肪及油、植物油、乳糖、澱粉、明膠、結晶性纖維素、橡膠、滑石、硬脂酸鎂、羥丙基纖維素、聚烯烴二醇、聚乙烯醇、甘油。此外,以水溶液形式調製本發明之抗癌劑之副作用的預防劑及/或治療劑時,為防止ALA類的分解,需留意勿使水溶液呈鹼性,若其呈鹼性時,亦可藉由去除氧氣來防止分解。
作為本發明抗癌劑之副作用的預防劑及/或治療劑的量、頻率、時間,係依欲利用本發明之抗癌劑之副作用的預防劑及/或治療劑者的年齡、體重、症狀等而異,惟作為較佳投予量之實例,可例舉成人每人4μmol~13100μmol,較佳為7μmol~4400μmmol,更佳為13μmol~3100μmol,再更佳為20μmol~880μmol。再者,上述較佳投予量之範圍僅為例示,並非予以限定。
作為本發明抗癌劑之副作用的預防劑及/或治療劑的投予的時間點,最佳的是,由開始投予抗癌劑的至少3日以上前連續投予本發明的藥劑,在使用抗癌劑的持續治療中亦持續投予本發明的藥劑。惟,開始投予抗癌劑之時起開始投予本發明的藥劑,接著在使用抗癌劑的持續治療中亦持續投予本發明的藥劑,亦可獲得一定的效果。更且,僅於開始投予抗癌劑之前的期間投予本發明的藥劑,也可獲得一定的效果。
此外,藉由投予本發明抗癌劑之副作用的預防劑及/或治療劑,即使在例如因嚴重的副作用而完全無法對患者投予抗癌劑時、或無法投予標準量的抗癌劑時,亦可對該患者進行標準量的抗癌劑的投予。如此一來,藉由投予本發明之抗癌劑之副作用的預防劑及/或治療劑,便可將抗癌劑原本的效果發揮至最高限度,非但有患者之QOL的提升效果,還可望有患者的延壽效果。
本發明抗癌劑之副作用的預防劑及/或治療劑還可與其他既有抗癌劑之副作用的預防劑及/或治療劑組合使用。作為既有抗癌劑之副作用的預防劑及/或治療劑的實例,可例舉利用點滴之電解質的大量投予、十全大補湯等中藥等。茲認為此等藥劑與ALA之抗癌劑之副作用的預防劑及/或治療劑相關之機制於根本上各自相異,因而可望有相加效果,且視情況而定,有相乘效果。
本說明書中所使用之用語,除非特別定義,否則係用以說明特定之實施形態,並非用來限定本發明。
又,本說明書中所使用之用語「包含(含有)」,除脈絡上應做明顯相異之理解的情況以外,係意圖指出「記述之事項(構件、步驟、要素、數字等)存在」,且未排除「除此之外之事項(構件、步驟、要素、數字等)存在」。
只要沒有不同之定義,此處所使用之所有用語(含技術用語及科學用語)係具有與從事本發明所屬之技術的該行業人士所廣泛理解的意思相同者。此處所使用之用語,只要沒有明示相異定義,否則應作為具有與本說明書及相關技術領域中的意義之整合的意義來解釋,不應就理想化或過度形式化的意義來解釋。
以下根據實施例對本發明更具體進行說明,惟本發明之技術範圍並未限定於此等例示。
為確認針對由投予抗癌劑所生成之副作用,投予ALA類所產生的副作用降低效果,係對大鼠投予二氯二胺鉑及ALA,並確認其對大鼠的
影響。
大鼠係由日本SLC股份有限公司購入44隻6週大的SD大鼠(公)。購入後,予以馴養7日後使用於實驗。
實驗期間共定為16日,並將實驗群根據ALA之投予條件分成下述之I~V之5群。除陰性對照群(negative control,I群)之外,係於所有實驗群中,在實驗開始起第6日投予二氯二胺鉑(CDDP)。CDDP的投予量係定為8.0mg/kg體重,並投予至各大鼠的腹腔內。此外,作為陰性對照群,係對I群投予生理食鹽水來代替二氯二胺鉑。又對於III群、VI群、V群,係按照下述排程投予ALA。另一方面,未對陽性對照群(positive control,II群)投予ALA。再者,III群、IV群、V群的ALA的投予係藉由按每日一次經口投予ALA鹽酸鹽10mg/kg體重+檸檬酸亞鐵鈉15.7mg/kg體重(溶解於蒸餾水、重碳酸鈉)來進行。
I群(陰性對照群):在實驗開始起到第6日投予生理食鹽水。除此之外,進行一般的飼養。n=4
II群(陽性對照群):在實驗開始起到第6日投予CDDP。除此之外,進行一般的飼養。n=10
III群(「前投予群」):在實驗開始日起到第5日止共計5日間投予ALA。且於第6日投予CDDP。除此之外,進行一般的飼養。n=10
IV群(「後投予群」):在實驗開始起到第6日投予ALA,其後投予CDDP。且於第6日~第15日止的10日間投予ALA。除此之外,進行一般的飼養。n=9
V群(「全投予群」):在實驗開始日起至第15日止的15日間投予ALA。且於第6日投予ALA,其後投予CDDP。n=9
在實驗開始日起至第15日止的15日間,按2日1次進行抽血。此外,實施對大鼠的毛色鮮豔度、排便狀態、活動度的觀察。又在第16日進行各大鼠的解剖,摘出腎臟。摘出後作成腎臟切片,進行HE染色後,於顯微鏡下進行觀察。
本實驗期間內的各實驗群之大鼠的生存率係示於第1圖。如第1圖所示,在陽性對照群(II群)中,因抗癌劑的副作用,實驗開始日起第
9日可看出生存率下降。與此相對,在投予ALA的群(III群、IV群、V群)中,因抗癌劑之副作用導致生存率下降的開始時間延遲。此外,在投予ALA的群(III群、IV群、V群)中,顯示出可將第16日以前的生存率下降加以抑制。在整個實驗期間投予ALA的「全投予群」(V群)其生存率最高。惟,在「前投予群」(III群)、「後投予群」(IV群)中,亦顯示出對抗癌劑之副作用的一定的抑制效果。因此,關於抗癌劑之副作用所導致的生存率下降,透過投予ALA可顯示確實的治療效果及預防效果。
將在第16日利用解剖由各大鼠所摘出的腎臟以福馬林固定後,作成切片,並以HE染色來確認腎臟的狀態。腎臟的HE染色影像係示於第2圖。如第2圖所示,投予ALA可減輕由抗癌劑之副作用引起對腎臟的損害。在整個實驗期間投予ALA的「全投予群」(V群)最為有效。惟,在「前投予群」(III群)及「後投予群」(IV群)中亦顯示出一定的效果。因此,關於抗癌劑之副作用對腎臟的損害,係顯示確實的治療效果及預防效果。
再者,I群~V群中之各大鼠的毛色鮮豔度、排便狀態及活動度的相關評定係示於下述表1。此外,在實驗開始日起的第9日至第13日止觀察到強烈的副作用。因此,將第9日、第11日、第13日的狀態由計分表示來進行評定。於此,毛色鮮豔度係評定皮膚症狀相關的副作用;排便狀態係評定消化道系統相關的副作用;活動度則評定全身症狀相關的副作用,尤其評定倦怠感相關的副作用。
此外,就各項目,對每隻小鼠依下述基準進行評定,將加總第9日、第11日、第13日此3日分所得之數值除以評定對象的小鼠數目。
5:極佳;4:一般狀態;3:略差;2:差;1:死亡
5:一般排便;4:排便少;3:略有腹瀉;2:腹瀉;1:死亡
5:一般狀態;4:動作微弱;3:幾乎不動;2:不動;1:死亡
5:極佳;4:一般狀態;3:略差;2:差;1:死亡
由表1可明瞭,其顯示出投予ALA對由抗癌劑所產生的各種副作用有減輕作用。在整個實驗期間投予ALA的「全投予群」(V群)係顯示出最良好的結果。惟,在「前投予群」(III群)、「後投予群」(IV群)中,亦顯示出一定的效果。因此,關於抗癌劑之副作用,透過投予ALA可顯示確實的治療效果及預防效果。
為確認針對投予抗癌劑之對腎臟之副作用(腎毒性),投予ALA類所產生的副作用降低效果,係對投予大鼠二氯二胺鉑及ALA,並確認其對大鼠的血清肌酸酐、血尿素氮值(BUN)、尿蛋白的影響。此外,血清肌酸酐及血尿素氮值(BUN)係由血液樣本測定。而尿蛋白則由尿樣本來測定。
再者,亦同時觀察作為對全身症狀的副作用、及消化道系統相關副作用的體重減輕。
大鼠係由日本SLC股份有限公司購入46隻6週大的SD大鼠(公)。購入後,予以馴養7日。於馴養時間結束之時點,進行各大鼠的體重測定、抽血及採尿。此外,自其翌日起以44隻開始進行實驗。再者,對於馴養後的測定,係由實驗排除血清肌酸酐、血尿素氮值(BUN)、及尿蛋白值較差的2個體。
於本實驗中,根據ALA的投予條件,將實驗群分成下述之I~IV之4群。除此之外,利用與實施例1同樣的方法來進行。
I群(陰性對照群):在實驗開始起到第6日投予生理食鹽水。除此
之外,進行一般的飼養。n=8
II群(陽性對照群):在實驗開始起到第6日投予CDDP。除此之外,進行一般的飼養。n=14
III群(「後投予群」):在實驗開始起到第6日投予ALA,其後投予CDDP。且於第6日~第15日止的10日間投予ALA。除此之外,進行一般的飼養。n=10
IV群(「全投予群」):在實驗開始日起至第15日止的15日間投予ALA。且於第6日投予ALA,其後投予CDDP,n=11
在實驗開始日、第6日、第7日、第9日、第11日、第13日、及第15日測定各大鼠的體重,並實施抽血及採尿。所抽取之血液樣本係使用於血清肌酸酐、血尿素氮值(BUN)的測定。此外,所採取之尿樣本則使用於尿蛋白的測定。又於第16日進行各大鼠的解剖,摘出腎臟進行觀察。
本實驗期間內的各實驗群之大鼠的體重變動係示於第3圖。如第3圖所示,在陽性對照群(II群)中,因抗癌劑之副作用,於第1日以後可看出體重減輕。與此相對,在投予ALA的群(III群、IV群)中,因抗癌劑之副作用導致體重減輕的情況得以抑制。更者,在投予ALA的群(III群、IV群)中,經確認第5日以後體重再度上升。在整個實驗期間投予ALA的「全投予群」(IV群)最為有效,惟在「後投予群」(III群)中亦顯示出一定的效果。因此,關於作為抗癌劑之副作用的體重減輕,透過投予ALA可顯示確實的治療效果及預防效果。
本實驗期間內的各實驗群之大鼠的血清肌酸酐值的變動係示於第4圖。如第4圖所示,在陽性對照群(II群)中,因抗癌劑之副作用,於第3日以後可看出血清肌酸酐量劇烈增加。另一方面,在投予ALA的群(III群、IV群)中,受抗癌劑之副作用影響的血清肌酸酐值於第5日雖可看出些微上升,但維持幾近與陰性對照群相同的值。
本實驗期間內的各實驗群之大鼠的血尿素氮值(BUN)的變動係示於第5圖。如第5圖所示,在陽性對照群(II群)中,因抗癌劑之副作用,於第3日以後可看出血尿素氮值(BUN)劇烈增加。另一方面,在投予ALA的群(III群、IV群)中,受抗癌劑之副作用影響的血尿素氮
值於第5日雖可看出些微上升,但顯示出維持幾近與陰性對照群相同的值。
本實驗期間內的各實驗群之大鼠的尿蛋白值的變動係示於第6圖。如第6圖所示,在陽性對照群(II群)中,因抗癌劑之副作用,於第1日以後可看出尿蛋白值劇烈增加。另一方面,在投予ALA的群(III群、IV群)中,受抗癌劑之副作用影響的尿蛋白值相較於陰性對照群(I群),於第3日雖可看出些微上升,但顯示出維持大致上與陰性對照群相同的值。
由第4圖~第6圖可明瞭,ALA可減輕抗癌劑之副作用對腎臟的損害。
在整個實驗期間投予ALA的「全投予群」(IV群)最為有效,惟在「後投予群」(III群)中亦顯示出一定的效果。因此,關於抗癌劑對腎臟之副作用,透過投予ALA可顯示確實的治療效果及預防效果。
於第16日所摘出之各大鼠的腎臟的照片圖像顯示於第7圖。由血清肌酸酐值、尿素毒素值(BUN)、及尿蛋白值可判斷在實驗期間中腎功能發生損害的個體的腎臟係呈泛黃浮腫。於第7圖中,茲以箭號表示呈泛黃浮腫的腎臟。
茲驗證ALA的投予是否對針對癌細胞之抗癌劑的細胞毒性(抗癌效果)造成影響。
本實驗中係使用以下癌細胞,亦即T24細胞(人體轉移細胞膀胱癌細胞)及253J-BV細胞(人體尿路上皮癌細胞)。又作為抗癌劑係使用二氯二胺鉑;作為ALA則使用ALA鹽酸鹽。再者,在ALA的投予中係一併投予檸檬酸亞鐵鈉。
ALA與檸檬酸亞鐵鈉的濃度係設為比實施例1及實施例2中可得到抗癌劑之副作用減輕效果的濃度(ALA鹽酸鹽:10mg/kg體重(約59.67μM)、檸檬酸亞鐵鈉:15.7mg/kg體重(約29.85μM))高約3.35倍的濃度(ALA鹽酸鹽:200μM、檸檬酸亞鐵鈉:100μM)。此外,具體而言,實施例3之每1kg體重的ALA與檸檬酸亞鐵鈉的濃度量係以達實施例1及實施例2中之每1升容積的ALA與檸檬酸亞鐵鈉的量的約3.35
倍的方式來計算(此外,對於以下二氯二胺鉑的約1.5倍亦同樣地計算)。
另一方面,二氯二胺鉑的濃度係設為以實施例1及實施例2中所使用之濃度(8mg/kg體重(約26.66μM))的約1.5倍的40μM為最大值的稀釋2倍系列(40μM、20μM、10μM、5μM、2.5μM、1.25μM、0μM)。
於下述I群~IV群中比較各濃度的細胞毒性。
I群:「無添加群」,即未投予任何ALA的群
II群:「前投予群」,即僅於「前培養時」投予ALA的群
III群:「同時投予群」,即僅於「投予二氯二胺鉑時」投予ALA的群
IV群:「全投予群」,即於「前培養時」與「投予二氯二胺鉑時」投予ALA的群
再者,以下將更明確說明各群之意義。
具體而言,本實驗係以下述方式進行。
(1)將T24細胞(人體轉移細胞膀胱癌細胞)或253J-BV細胞(人體尿路上皮癌細胞)利用10cm培養皿,以含有10%FBS的DMEM培養基培養至適度混雜的狀態。其後,藉由胰蛋白處理回收之。
(2)於I群(無添加群)及III群(同時投予群)之試驗群中,係將(1)中回收的細胞,以在含有10%FBS的DMEM培養基中形成50000cells/ml之密度的方式懸浮。此外,於II群(前投予群)及IV群(全投予群)之試驗群中,則將(1)中回收的細胞,以在含有200μM之ALA鹽酸鹽、100μM之檸檬酸亞鐵鈉、及10%FBS的DMEM培養基中形成50000cells/ml之密度的方式懸濁。
(3)接著,將(2)中所得之各懸濁液,於96-well之微板(microplate)上按每1well各分注100μl,於37℃進行前培養24小時。
(1)於前培養後,由各個Well移除培養基。其後,於I群(無添加群)及II群(前投予群)中添加包含各種濃度(40、20、10、5、2.5、1.25、0μM)之二氯二胺鉑與10%FBS的DMEM培養基,在37℃之CO2培養箱(incubator)中進行培養。此外,於III群(同時投予群)及IV群(全
投予群)中添加含有各種濃度(40、20、10、5、2.5、1.25、0μM)之二氯二胺鉑、200μM之ALA鹽酸鹽、100μM之檸檬酸亞鐵鈉、與10%FBS的DMEM培養基,在37℃之CO2培養箱中進行培養。
(2)在二氯二胺鉑存在下培養48小時後,於各Well中添加I0μl之作為Cell Counting Kit-8之基質的WST-8(同仁化學研究所),於37℃進行發色反應2小時。其後,對各Well藉由測定450nm的吸光度來測定生存率。
此外,在不含二氯二胺鉑的培養基中進行培養時的吸光度係設為生存率100%。又,在不含細胞的培養基中添加WST-8使其發色時的吸光度則設為生存率0%。由此,對各Well計算「細胞的生存率(%)」。其後,依下式計算「細胞的死亡率(%)」。
「細胞的死亡率(%)」=100-「細胞的生存率(%)」
I~IV群之細胞的死亡率顯示於第8圖及第9圖。此外,細胞的死亡係因二氯二胺鉑妨害細胞的生存,因此在第8圖及第9圖中,係將「細胞的死亡率(%)」記載為「妨害率(%)」。
第8圖係表示投予二氯二胺鉑所致之T24細胞(人體轉移細胞膀胱癌細胞)的死亡率(%)。此外,I群~IV群中的T24細胞的50%妨害濃度(50%死亡濃度)(μM)分別為5.73μM(I群)、5.21μM(II群)、4.87μM(III群)、5.56μM(IV群)。
第9圖係表示投予二氯二胺鉑所致之253J-BV細胞(人體尿路上皮癌細胞)的死亡率(%)。此外,I群~IV群中的253J-BV細胞的50%妨害濃度(50%死亡濃度)(μM)分別為3.92μM(I群)、3.92μM(II群)、2.80μM(III群)、2.89μM(IV群)。
如第8圖及第9圖所示,對於二氯二胺鉑的抗癌效果,ALA的投予與其投予時期及投予期間無關,顯示出幾乎未減弱抗癌劑之效果。
對因進行期的大腸癌引起腸阻塞的女性,於2009年8月19日(於該時間點為61歲)進行緊急手術。根據手術時所見,存有拳頭大的大腸癌,即使摘出腫瘤、消除腸阻塞,但仍可見多數腹膜腔轉移,經診斷為剩餘壽命3個月。
手術後,作為抗癌劑治療,除FOLFOX(5-FU、Isovorin、Elplat此3劑併用)及FOLFIRI(5-FU、Isovorin、Campto此3劑併用)外亦併用Avastin等分子標靶藥物。其後,與此抗癌劑治療同時進行,按每日經口攝取50mg之胺基酮戊酸(aminolevulinic acid)磷酸鹽與57.4mg之檸檬酸亞鐵鈉。
其結果,手術後1年可以持續進行抗癌劑治療。1年後,雖因副作用而已放棄抗癌劑的投予,但仍持續經口攝取50mg之胺基酮戊酸磷酸鹽與57.4mg之檸檬酸亞鐵鈉,而大幅超過所宣告的剩餘壽命3個月,在1年半期間,能夠以副作用經改善的狀態生存。
患者其副作用係呈現強烈的貧血症狀,因此作為副作用改善的指標便選擇貧血改善效果作為比較對象。(i)即將手術前的2009年8月19日、及(ii)開始攝取胺基酮戊酸磷酸鹽與檸檬酸亞鐵鈉經過約1年5個月後的2011年1月28日的紅血球數、血紅素值、白血球數顯示於以下表2。
如上表可理解,於即將手術前雖可看出因癌性貧血導致紅血球與血紅素減少、及炎症導致白血球增加,但在(ii)之攝取開始起約1年5個月後的時間點,可知透過投予胺基酮戊酸磷酸鹽與檸檬酸亞鐵鈉,紅血球數與血紅素增加,由投予抗癌劑所致之副作用的貧血既已改善;另一方面,白血球數平穩地回復至正常值。如考量到抗癌劑所產生的強烈副作用出現,則認為亦會對造血系統造成強烈的損傷,但所謂「貧血已改善」的結果是極為驚人,縱然罹患腹膜腔轉移,在大幅超過醫師所宣告的剩餘壽命3個月的1年半後仍可過著生活品質(QOL)經改善的生活。
本發明之藥劑能夠作為抗癌劑之副作用的預防劑及/或治療劑而有利地利用。
Claims (3)
- 一種下式(I)表示之化合物或其鹽用於製備抗癌劑之副作用的預防劑及/或治療劑之用途,R1-NHCH2COCH2CH2COOR2 (I)其中於該式中,R1表示氫原子或醯基,R2表示氫原子、直鏈或分支狀烷基、環烷基、芳基或芳烷基,前述抗癌劑係DNA複製阻斷劑或細胞周期阻斷劑,前述抗癌劑之副作用係為選自包含腎臟相關副作用、皮膚症狀相關副作用、全身症狀相關副作用、消化道系統相關副作用、以及血液或骨髓相關副作用之群組的至少一個副作用,前述預防劑及/或治療劑進一步含有一種或二種以上的金屬化合物。
- 如申請專利範圍第1項所述之用途,其中,前述金屬化合物係選自包含鐵、鎂、及鋅之化合物的群組。
- 如申請專利範圍第1項所述之抗癌劑之用途,其中,前述預防劑及/或治療劑係與抗癌劑併用。
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CN102438653B (zh) * | 2008-11-25 | 2019-04-23 | 奥尔德生物制药公司 | 预防或治疗恶病质、虚弱、疲劳和/或发烧il-6拮抗剂 |
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CN101870726B (zh) * | 2010-06-04 | 2013-02-13 | 臧林泉 | 一种多肽-顺铂偶合物及其制备方法与应用 |
WO2012127466A1 (en) * | 2011-03-24 | 2012-09-27 | Bar Ilan University | 5-aminolevulinic acid derivatives, methods for their preparation and uses thereof |
EP2767280B1 (en) | 2011-10-12 | 2024-05-22 | SBI Pharmaceuticals Co., Ltd. | Anemia of cancer improving / prophylactic agent |
JP5818905B2 (ja) | 2011-10-12 | 2015-11-18 | Sbiファーマ株式会社 | エリスロポエチン産生促進剤 |
CN103974701A (zh) | 2011-10-12 | 2014-08-06 | 思佰益药业股份有限公司 | 慢性肾脏病的改善、预防剂 |
US9707196B2 (en) | 2011-10-12 | 2017-07-18 | Sbi Pharmaceuticals Co., Ltd. | Treatment agent and/or prophylactic agent for side effects of cancer drugs |
-
2012
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- 2012-10-05 ES ES12839452T patent/ES2704848T3/es active Active
- 2012-10-05 CN CN201280060637.9A patent/CN104066428A/zh active Pending
- 2012-10-05 EP EP12839452.5A patent/EP2767277B1/en active Active
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- 2012-10-05 CN CN201910614509.8A patent/CN110339207B/zh active Active
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2015
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HK1201730A1 (zh) | 2015-09-11 |
JP2016006121A (ja) | 2016-01-14 |
CN110339207A (zh) | 2019-10-18 |
CN110339207B (zh) | 2022-08-05 |
JPWO2013054756A1 (ja) | 2015-03-30 |
WO2013054756A1 (ja) | 2013-04-18 |
EP2767277A1 (en) | 2014-08-20 |
JP5818906B2 (ja) | 2015-11-18 |
EP2767277B1 (en) | 2018-11-28 |
US9707196B2 (en) | 2017-07-18 |
EP2767277A4 (en) | 2015-04-08 |
ES2704848T3 (es) | 2019-03-20 |
TW201322976A (zh) | 2013-06-16 |
US20140302173A1 (en) | 2014-10-09 |
CN104066428A (zh) | 2014-09-24 |
JP6051283B2 (ja) | 2016-12-27 |
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