TW202421107A - 難治性癌症之預防或治療用之醫藥組合物 - Google Patents
難治性癌症之預防或治療用之醫藥組合物 Download PDFInfo
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Abstract
本發明提供一種含有5-胺基乙醯丙酸(ALA)或其衍生物、或者其等之鹽的用於藉由光動力學療法(PDT)治療或預防耐藥劑性癌症之醫藥組合物、使用該醫藥組合物之耐藥劑性癌症之治療或預防方法。
Description
本發明係關於一種含有5-胺基乙醯丙酸類之用於治療或預防耐藥劑性癌症之醫藥組合物。
5-胺基乙醯丙酸(5-ALA)係具有經口吸收性之物質,當於細胞內線粒體中生合成原血紅素之過程中代謝為原紫質IX(PpIX)。PpIX係具有被稱作索雷譜帶之410 nm附近之吸收帶與被稱作Q帶之500~650 nm附近之吸收帶,藉由照射該等吸收帶波長之光線而產生活性氧種的光敏性物質。因此,可藉由向累積有PpIX之細胞照射吸收帶波長之光線而誘導細胞死亡(非專利文獻1)。應用該殺細胞效果之原理之治療法被稱作光動力學療法(PDT),期待使用5-ALA之PDT之今後的臨床應用(專利文獻1、2)。
根據日本厚生勞動省發佈之「2016年人口動態統計之概況」,日本因惡性贅生物導致之死亡率占死亡總數之28.5%,成為死因排名第1名。針對早期癌症,一般利用手術全部摘除,起效率亦較高。另一方面,於進展期癌症之情形時,一般進行利用抗癌劑之治療。
但是,除了抗癌劑自治療起初開始便不顯示效果之情形以外,多數情況下即便是抗癌劑治療有效之癌症,其效果亦為短暫性,已知於治療中途其效果下降,與此同時出現對於作用機理或結構不同之抗癌劑亦顯示耐性之後天耐性(非專利文獻2、3)。該等耐藥劑性癌細胞(包括癌幹細胞)除了化學療法無效以外,當其再次增殖時會成為轉移及復發之原因。
於當今之癌症治療整體,耐藥劑性癌細胞之存在仍係妨礙其臨床成績提高之較大之原因之一。癌細胞獲得耐藥劑性之機制複雜且多樣,但對於抗癌劑等未顯示充分之敏感性之癌症患者中,利用臨床之各治療演算法明確地進行了患者分類,病情不同於抗癌症劑敏感性癌症,採取不同之治療方針(非專利文獻4)。
上述癌細胞之對於作用機理或結構不同之抗癌劑之後天耐性之交叉於PDT中亦不例外。一般而言,包含5-ALA之PDT中,報告有許多PDT對於具有抗癌劑耐性之癌症無效果之情形,且已知抗癌劑耐性與PDT耐性交叉(非專利文獻5)。據此,不可謂對於抗癌劑具有抗性之癌細胞中,PDT必定發揮殺細胞效果,且無法輕易地想像PDT對於各種抗癌劑抗性癌症之有效性。
進而,如非專利文獻5中所示,對於同一對抗癌劑具有耐性之癌症,既有具有殺細胞效果之光敏性物質,亦有無效果之光敏性物質。因此,就算藉由使用某特定之光敏性物質之PDT能夠對於耐藥劑性癌症獲得效果,但即便是業者亦無法容易地想像藉由同樣地使用其他光敏性物質之PDT是否亦能夠同樣地獲得效果。上述當然不僅限於耐藥劑性癌症,例如雖然使用金絲桃毒或光敏素之PDT顯示抗腫瘤效果,但另一方面,報告有使用TPPS4或5-ALA之PDT未顯示效果之事例(非專利文獻6)。
專利文獻3中揭示有一種含有5-ALA或其鹽之伴隨難治性癌細胞之難治性癌症之預防用或治療用組合物,但其僅揭示了發現於難治性癌細胞中,酪胺酸激酶抑制劑會阻礙參與PpIX之排出之ABCG2,若阻礙ABCG2,則細胞內PpIX之累積升高,可增強5-ALA/PDT對於難治性癌細胞之效果,而關於5-ALA/PDT對於酪胺酸激酶抑制劑耐性之癌症是否有效並未作任何揭示,又,並未提示5-ALA對於其他藥劑之難治性癌症之有效性。
上述專利文獻3中揭示有一種含有5-ALA或其鹽之伴隨難治性癌細胞之難治性癌症之預防用或治療用組合物,專利文獻3中之所謂難治性癌症,係指「較佳為惡性,可為原發性或轉移性、且浸潤性或非浸潤性之癌或肉瘤等,包括腦腫瘤、脊髓腫瘤、上頜竇癌、胰液腺癌、牙齦癌、舌癌、唇癌、咽上部癌、咽中部癌、咽下部癌、喉頭癌、甲狀腺癌、甲狀旁腺癌、肺癌、胸膜腫瘤、癌性腹膜炎、癌性胸膜炎、食道癌、胃癌、大腸癌、膽管癌、膽囊癌、胰腺癌、肝癌、腎癌、膀胱癌、前列腺癌、陰莖癌、睾丸腫瘤、腎上腺癌、子宮頸癌、子宮體癌、陰道癌、外陰癌、卵巢癌、骨腫瘤、乳癌、皮膚癌、黑色素瘤、基底細胞癌、淋巴瘤、霍奇金病、漿細胞瘤、骨肉瘤、軟骨肉瘤、脂肪肉瘤、橫紋肌肉瘤及纖維肉瘤,但並無限定。難治性癌症特佳為腦腫瘤。又,難治性癌症較佳為實體癌」,並未表示5-ALA對實體癌以外之癌症、例如白血病或血液癌疾病中之難治性癌症之有效性。又,專利文獻3實質上僅揭示PDT對於腦腫瘤細胞及子宮頸癌細胞之應用。
來那度胺係用於多發性骨髓瘤等之抗造血器官惡性腫瘤劑。莫加珠單抗係用於T細胞性淋巴瘤等之抗惡性腫瘤劑。維生素A酸(全反式視黃酸(ATRA,All-trans Retinoic Acid))係用於急性前骨髓細胞性白血病等之白血病治療劑。伊馬替尼係用於慢性骨髓性白血病等之抗惡性腫瘤劑。
本說明書中引用之文獻其等全部之揭示藉由明示出處而編入至本說明書中。於編入之揭示包含可能與本說明書之記載矛盾之內容之情形時,本說明書中所記載之內容優先。
[先前技術文獻]
[專利文獻]
[專利文獻1]日本專利特開2005-132766號公報
[專利文獻2]日本專利特表2017-513952號公報
[專利文獻3]國際公開第2015/125732號
[非專利文獻]
[非專利文獻1]T Namikawa et al., World J Gastroenterol. 21(29): 8769-8775, 2015
[非專利文獻2]Ueda K et al., Proc Natl Acad Sci USA, 84: 3004-3008, 1987
[非專利文獻3]Tada Y et al., Int J Cancer, 98: 630-635, 2002
[非專利文獻4]一般社團法人日本血液學會編輯 造血器官腫瘤診療指南
[非專利文獻5]Casas A et al., Curr Med Chem. 18(16): 2486-515, 2011
[非專利文獻6]Luksiene Z et al., Medicina (Kaunas). 2003; 39(7): 677-82.
[發明所欲解決之問題]
本發明之目的在於提供一種用於治療或預防耐藥劑性癌症之醫藥組合物。
[解決問題之技術手段]
本發明者等人對於上述問題反覆進行銳意研究,結果發現藉由使用5-ALA之PDT可有效地治療或預防耐藥劑性癌症,從而完成本發明。
即,本發明係關於:
(1)一種醫藥組合物,其含有下述式(1):
[化1]
(式中,R
1及R
2分別相同或不同,表示氫原子、烷基、醯基、烷氧基羰基、芳基或芳烷基,R
3表示羥基、烷氧基、醯氧基、烷氧基羰氧基、芳氧基、芳烷氧基或胺基)
所示之5-胺基乙醯丙酸(5-ALA)或其衍生物、或者其等之鹽,用於藉由光動力學療法(PDT)治療或預防耐藥劑性癌症,且
上述藥劑係用於減少干擾素調節因子之表現之免疫調節藥、或將CD(Cluster of Differentiation,分化簇)分子、cereblon、mTOR蛋白質、PML-RARα、BCR-Abl酪胺酸激酶及KIT酪胺酸激酶之任一者作為靶之分子靶向治療藥;
(2)一種醫藥組合物,其含有下述式(1):
[化2]
(式中,R
1及R
2分別相同或不同,表示氫原子、烷基、醯基、烷氧基羰基、芳基或芳烷基,R
3表示羥基、烷氧基、醯氧基、烷氧基羰氧基、芳氧基、芳烷氧基或胺基)
所示之5-胺基乙醯丙酸(ALA)或其衍生物、或者其等之鹽,且用於藉由光動力學療法(PDT)治療或預防耐藥劑性白血病。
(3)如(2)之醫藥組合物,其中白血病係成人T細胞白血病;
(4)如(1)至(3)中任一項之醫藥組合物,其中藥劑係來那度胺或莫加珠單抗;
(5)如(1)至(3)中任一項之醫藥組合物,其中藥劑係維生素A酸;
(6)如(1)至(3)中任一項之醫藥組合物,其中藥劑係伊馬替尼;
(7)一種醫藥組合物,其含有下述式(1):
[化3]
(式中,R
1及R
2分別相同或不同,表示氫原子、烷基、醯基、烷氧基羰基、芳基或芳烷基,R
3表示羥基、烷氧基、醯氧基、烷氧基羰氧基、芳氧基、芳烷氧基或胺基)
所示之5-胺基乙醯丙酸(ALA)或其衍生物、或者其等之鹽,用於藉由光動力學療法(PDT)治療或預防癌症,且用於與來那度胺、莫加珠單抗、維生素A酸、及伊馬替尼之至少任一者併用使用;
(8)如(1)至(7)中任一項之醫藥組合物,其中癌症係血液癌;
(9)如(1)至(8)中任一項之醫藥組合物,其中於體外進行PDT之光照射。
[發明之效果]
藉由使用本發明之組合物,能夠治療及預防耐藥劑性癌症。
以下,對本發明具體地進行說明。於某一態樣中,本發明提供一種含有5-胺基乙醯丙酸(5-ALA)或其衍生物、或者其等之鹽(於本說明書中,亦稱為「5-ALA類」)的用於藉由光動力學療法(PDT)治療或預防耐藥劑性癌症之醫藥組合物。
於本說明書中,5-ALA或其衍生物係指下述式(1):
[化4]
(式中,R
1及R
2分別相同或不同,表示氫原子、烷基、醯基、烷氧基羰基、芳基或芳烷基,R
3表示羥基、烷氧基、醯氧基、烷氧基羰氧基、芳氧基、芳烷氧基或胺基)
所示之化合物。
式(1)中,作為R
1及R
2所示之烷基之例,可例舉:碳數1~24之直鏈或支鏈之烷基,更具體而言,可例舉:碳數1~18之烷基、碳數1~6之烷基。作為烷基之進而具體之例,可例舉:甲基、乙基、正丙基、異丙基、正丁基、第二丁基等。作為醯基之例,可例舉:碳數1~12之直鏈或支鏈之烷醯基或烯基羰基、芳醯基等,更具體而言,可例舉:碳數1~6之烷醯基。作為醯基之進而具體之例,可例舉:甲醯基、乙醯基、丙醯基、丁醯基等。作為烷氧基羰基之例,可例舉:總碳數2~13之烷氧基羰基,更具體而言,可例舉:總碳數2~7之烷氧基羰基。作為烷氧基羰基之進而具體之例,可例舉:甲氧基羰基、乙氧基羰基、正丙氧基羰基、異丙氧基羰基等。作為芳基之例,可例舉碳數6~16之芳基,例如:苯基、萘基等。作為芳烷基之例,可例舉於碳數6~16之芳基鍵結有碳數1~6之烷基之基,例如:苯基-C
1-6烷基、萘基-C
1-6烷基等。
於某一實施方式中,式(1)中之R
1及R
2為氫原子。於另一實施方式中,R
3為羥基、烷氧基或芳烷氧基,更具體而言為羥基或C
1-12烷氧基。
5-ALA或其衍生物之鹽只要為於藥學上容許之鹽即可,並無特別限定。作為具體之例,可例舉:有機酸或無機酸之酸加成鹽,作為更具體之例,可例舉:鹽酸鹽、氫溴酸鹽、硫酸鹽、磷酸鹽、醋酸鹽、乳酸鹽、檸檬酸鹽、酒石酸鹽、琥珀酸鹽、馬來酸鹽、富馬酸鹽、抗壞血酸鹽等。
該等5-ALA或其衍生物、或者其等之鹽可利用例如日本專利特開平4-9360號公報、日本專利特表平11-501914號公報等中所記載之方法進行製造。
本態樣之醫藥組合物用於治療或預防耐藥劑性癌症。此處,所謂耐藥劑性,係指無法獲得或難以獲得某藥劑之治療或預防效果,包括後天性地獲得耐藥劑性之細胞、及先天性之耐藥劑性細胞。於某一實施方式中,藥劑係免疫調節藥、分子靶向治療藥、或抗癌性抗生素。作為免疫調節藥之例,可例舉減少干擾素調節因子、更具體而言干擾素調節因子4之表現之藥劑。作為分子靶向治療藥之靶之例,可例舉:CD20、CD22、CD33、CD52、CD194(CCR4)等CD分子、cereblon、mTOR蛋白質、PML-RARα、BCR-Abl酪胺酸激酶、KIT酪胺酸激酶等。作為更具體之藥劑之例,可例舉:來那度胺、莫加珠單抗、利妥昔單抗、奧法木單抗、阿侖單抗、吉妥珠單抗、本妥昔單抗、替伊莫單抗、維生素A酸、達沙替尼、博舒替尼、尼洛替尼及伊馬替尼。作為抗癌性抗生素之例,可例舉蒽環系抗癌性抗生素,作為更具體之例,可例舉多柔比星。作為進而具體之藥劑之例,可例舉:來那度胺、莫加珠單抗、維生素A酸及伊馬替尼。又,作為進而具體之藥劑之例,可例舉:來那度胺、莫加珠單抗及維生素A酸。
耐藥劑性癌症之種類無特別限定,例如可例舉:人類、包含人類或不包含人類之哺乳動物之癌症、肉瘤、腺癌、淋巴瘤、白血病、及實體癌及淋巴性癌。作為癌症之更具體之例,可例舉:非小細胞肺癌或NSCLC(Non Small Cell Lung Cancer,非小細胞肺癌)等肺癌、卵巢癌、前列腺癌、結直腸癌、肝癌、腎癌、膀胱癌、乳癌、甲狀腺癌、胸膜癌、胰腺癌、子宮癌、子宮頸癌、睾丸癌、肛門癌、胰腺癌、膽管癌、胃腸道類癌瘤、食道癌、膽囊癌、闌尾癌、小腸癌、胃癌、中樞神經系統之癌症、皮膚癌、絨毛膜癌、頭頸部癌、血液癌、骨源性肉瘤、纖維肉瘤、神經胚細胞瘤、膠質瘤、黑色素瘤、B細胞淋巴瘤、非霍奇金淋巴瘤、伯奇氏淋巴瘤、小細胞淋巴瘤、大細胞淋巴瘤、單核球性白血病、骨髓性白血病、急性淋巴球性白血病、急性骨髓性白血病、及多發性骨髓瘤等。作為癌症之進而具體之例,可例舉血液癌,例如:白血病、淋巴瘤、多發性骨髓瘤、蕈樣肉芽腫、塞紮里氏綜合徵等。作為較佳之例,可例舉慢性骨髓性白血病及成人T細胞白血病,例如成人T細胞白血病。
本態樣之醫藥組合物之投予方法無特別限定,例如可例舉:經口投予、靜脈內投予、肌內投予、患部局部投予、經皮投予、經直腸投予等。
本態樣之醫藥組合物之劑型無特別限定,例如可例舉:顆粒劑、細粒劑、錠劑等經口投予用劑;液劑、使用時溶解型粉末劑等注射用劑;軟膏、液劑、乳霜劑、凝膠劑等經皮用劑;栓劑等。
本態樣之醫藥組合物亦可除5-ALA或其衍生物、或者其鹽以外,含有藥學上容許之其他原料,例如:藥學上容許之載體、賦形劑、稀釋劑、等張劑、添加劑、崩解劑、結合劑、穩定劑、被覆劑、分散介質、增量劑、pH值緩衝劑、潤滑劑、滑劑、滑澤劑、風味劑、甜味劑、助溶劑、溶劑、凝膠化劑、營養劑等。亦可藉由此種其他原料而對本態樣之醫藥組合物之吸收性或血中濃度產生影響,帶來體內動態之變化。作為其他原料之具體之例,可例舉:水、生理鹽水、動物性油脂、植物性油脂、乳糖、澱粉、明膠、結晶性纖維素、膠質、滑石、硬脂酸鎂、羥丙基纖維素、聚伸烷基二醇、聚乙烯醇、甘油等。
本態樣之醫藥組合物之投予量只要PpIX對於作為對象之耐藥劑性癌細胞之集聚量為PDT中之有效量即可,可由業者適當決定。又,向對象投予之量、時點、投予頻度、投予期間可由業者根據對象之年齡、體重、症狀或狀態、或者欲進行預防或治療之對象內之細胞、組織或器官之狀態或投予之容易程度等適當決定。作為更具體之投予量之例,可例舉:以ALA換算計,體重每1 kg為約1 mg~約1,000 mg、約5 mg~約100 mg、約10 mg~約30 mg、約15 mg~約25 mg等。
本態樣之醫藥組合物之投予頻度無特別限定,例如可例舉一天1次~複數次,例如2、3、4或5次之投予或藉由點滴等之連續投予。本態樣之醫藥組合物之投予期間例如可由業者基於對象之症狀或狀態等各種各樣之臨床學指標等適當決定。
本態樣之醫藥組合物用於光動力學療法(PDT)。PDT係藉由投予對光產生反應之化合物,照射光線而對靶部位進行治療之療法。代表性之例係使用5-ALA類之PDT。
投予本態樣之醫藥組合物後之PDT係藉由照射特定波長之光而實施。所使用之波長可由業者適當決定。作為所使用之波長之例,可例舉:約350 nm~約700 nm、約400 nm~約640 nm、約480 nm~約640 nm、505±10 nm、540±10 nm、580±10 nm、630±10 nm等。
投予本態樣之醫藥組合物後至開始光照射前之時間無特別限定,可由業者根據癌症之種類、投予方法等適當設定。例如,可於投予後約15分鐘~約48小時後、投予後約1~約24小時後開始光照射。
PDT中之照射次數及每1次之照射時間無特別限定,可由業者適當決定。例如,可進行1次或複數次,例如2、3、4或5~約100次之照射。又,可照射相同波長之光,亦可照射不同波長之光。於複數次投予本態樣之醫藥組合物之情形時,亦可於各投予之間,利用1次或複數次之照射進行PDT。
PDT中所照射之光之光量可由業者根據癌症之種類、投予方法、光源等適當設定。作為光量之例,可例舉:約0.01~約200 J/cm
2、約5~約150 J/cm
2、約10~約100 J/cm
2、約30~約100 J/cm
2、約10~約30 J/cm
2、10±10 J/cm
2、30±10 J/cm
2、100±10 J/cm
2等。
又,於作為對象之癌症係血液癌等之情形時,PDT中之光照射可於體外進行。例如,可於投予本態樣之醫藥組合物後,利用血液灌流裝置等令血液體外循環,並向該灌流裝置內之血液進行光照射。
於某一實施方式中,本態樣之醫藥組合物亦可與抗癌劑等其他藥劑組合使用。本態樣之醫藥組合物中可含有其他藥劑,亦可製成本態樣之醫藥組合物與藥劑之組合物。又,可於投予藥劑後投予本態樣之醫藥組合物進行PDT,亦可於投予本態樣之醫藥組合物進行PDT後,再投予藥劑。又,於投予本態樣之醫藥組合物後,可於進行PDT之前、或實施複數次之PDT之間投予藥劑。作為其他藥劑之例,可例舉:酪胺酸激酶抑制劑、免疫調節藥、及分子靶向治療藥等抗癌劑。又,亦可例如向預定進行、進行了或持續進行利用來那度胺、莫加珠單抗、維生素A酸、伊馬替尼或多柔比星等之治療之對象,與來那度胺、莫加珠單抗、維生素A酸、伊馬替尼或多柔比星併用地進行使用本態樣之醫藥組合物之PDT。於更具體之實施方式中,併用之藥劑係來那度胺、莫加珠單抗、維生素A酸或伊馬替尼。於進而更具體之實施方式中,併用之藥劑係來那度胺、莫加珠單抗或維生素A酸。於某一實施方式中,其他藥劑不包含酪胺酸激酶抑制劑。又,於另一實施方式中,其他藥劑不包含ABCG2抑制劑。
於另一態樣中,本發明係關於一種含有5-ALA類之用於藉由PDT治療或預防耐藥劑性癌症之套組。又,於另一態樣中,本發明係關於一種藉由使用5-ALA類之PDT治療或預防藥劑抗性癌症之方法。又,於另一態樣中,本發明係關於一種用於使用PDT之耐藥劑性癌症之治療或預防的5-ALA類。又,於進一步之態樣中,本發明係關於一種5-ALA類之用途,其係用於製造用以使用PDT治療或預防耐藥劑性癌症之醫藥組合物。該等態樣之更具體之實施方式乃如醫藥組合物之態樣中所記載。
再者,於本說明書中,例如於記載有「1~5次」等數值範圍之情形時,應理解該記載表示其範圍內之任意之數值,例如1、2、3、4、5之各值。又,於本說明書中,所謂「約」之用語,意指±10%、較佳為±5%之範圍。又,其範圍之邊界值之數值視為記載於本說明書中。
以下,茲記載實施例對本發明更加詳細地說明,但本發明未必受此等實施例限定。
[實施例]
實施例1:成人T細胞白血病(ATL)細胞株中之殺細胞效果之確認
使用ATN-1、C8166、TL-Om1、Hut102、MT-1作為ATL細胞株。該等之中,來那度胺敏感性株係Hut102,耐性株係C8166。ATN-1、TL-Om1、MT-1對於來那度胺之敏感性不明。另一方面,維生素A酸敏感性株係C8166,耐性株係Hut102。ATN-1、TL-Om1、MT-1對於維生素A酸之敏感性不明。又,莫加珠單抗敏感性株係ATN-1、TL-Om1、MT-1,耐性株係Hut102。C8166對於莫加珠單抗之敏感性不明。對該等細胞進行繼代、培養。為了實驗,以於實驗開始時密度成為1×10
6細胞/ml之方式製備細胞。
於上述細胞懸濁液中以濃度成為0、0.0625、0.125、0.25、0.5 mM之方式添加5-ALA,進行4小時負載。將5-ALA負載後之細胞洗淨,進行中心波長630 nm之光線照射(0、10、30及100 J/cm
2),利用細胞計數套組-8(Cell Counting Kit-8)算出細胞存活率(%)。
將結果示於圖1。如圖1所示,使用5-ALA之PDT殺傷作為那度胺耐性株之C8166細胞株、作為莫加珠單抗耐性株及維生素A酸耐性株之HuT102細胞株,表示對於該等耐藥劑性癌細胞亦有效。
關於對來那度胺之耐性,將作為耐性株之C8166與作為來那度胺敏感性株之Hut102的與每單位照射能量密度之細胞存活率(%)對應之5-ALA之各EC
50值與其95%置信區間示於表1。
[表1]
EC 50(mmol/L) (95%置信區間) | ||
來那度胺耐性株:C8166 | 來那度胺敏感性 株 : Hut102 | |
10 J/cm 2 | 0.113 (0.100-0.128) | 0.441 (0.329-0.612) |
30 J/cm 2 | 0.087 (0.078-0.097) | 0.277 (0.200-0.396) |
100 J/cm 2 | 0.077 (0.069-0.086) | 0.173 (0.144-0.208) |
根據各EC
50值之結果顯示:來那度胺耐性株C8166之使用5-ALA之PDT之殺細胞效果與來那度胺敏感性株Hut102相比,為相同程度。因此,提示使用5-ALA之PDT於來那度胺非敏感性之患者細胞中亦發揮非常優異之殺細胞效果,又,同時顯示來那度胺與使用5-ALA之PDT之併用使用亦有效之可能性。
關於對維生素A酸之耐性,將作為耐性株之Hut102與作為維生素A酸敏感性株之C8166的與每單位照射能量密度之細胞存活率(%)對應之5-ALA之各EC
50值與其95%置信區間示於表2。
[表2]
EC 50(mmol/L) (95%置信區間) | ||
維 生素 A 酸耐性株: Hut102 | 維生素A酸敏感性株:C8166 | |
10 J/cm 2 | 0.441 (0.329-0.612) | 0.113 (0.100-0.128) |
30 J/cm 2 | 0.277 (0.200-0.396) | 0.087 (0.078-0.097) |
100 J/cm 2 | 0.173 (0.144-0.208) | 0.077 (0.069-0.086) |
根據各EC
50值之結果顯示:維生素A酸耐性株C8166之使用5-ALA之PDT之殺細胞效果與維生素A酸敏感性株Hut102相比,為相同程度。因此,提示使用5-ALA之PDT於維生素A酸非敏感性之患者細胞中亦發揮非常優異之殺細胞效果,又,同時顯示維生素A酸與使用5-ALA之PDT之併用使用亦有效之可能性。
關於對莫加珠單抗之耐性,將作為耐性株之Hut102與作為敏感性株之ATN-1、TL-Om1、MT-1的與每單位照射能量密度之細胞存活率(%)對應之5-ALA之各EC
50值與其95%置信區間示於表3。
[表3]
EC 50(mmol/L) (95%置信區間) | ||||
莫加珠 單 抗敏感性株: ATN-1 | 莫加珠 單 抗敏感性株: TL-Om1 | 莫加珠單抗耐性株: HuT102 | 莫加珠 單 抗敏感性株: MT-1 | |
10 J/cm 2 | 0.113 (0.105-0.121) | 0.269 (0.236-0.306) | 0.441 (0.329-0.612) | > 0.5 |
30 J/cm 2 | 0.087 (0.083-0.093) | 0.141 (0.128-0.155) | 0.277 (0.200-0.396) | 0.202 (0.184-0.221) |
100 J/cm 2 | 0.084 (0.081-0.088) | 0.092 (0.085-0.100) | 0.173 (0.144-0.208) | 0.115 (0.107-0.123) |
根據各EC
50值之結果顯示:莫加珠單抗耐性株Hut102之使用5-ALA之PDT之殺細胞效果與其他莫加珠單抗敏感性株相比,至少同等。因此,提示使用5-ALA之PDT於莫加珠單抗非敏感性之患者細胞中亦發揮非常優異之殺細胞效果,又,同時顯示莫加珠單抗與使用5-ALA之PDT之併用使用亦有效之可能性。
實施例2:慢性骨髓性白血病(CML)細胞株中之殺細胞效果之確認
使用LAMA84-r作為伊馬替尼耐性CML細胞株,使用原細胞株LAMA84-s(伊馬替尼敏感性)作為比較對照。又,使用K562/ADR作為多柔比星耐性CML細胞株,使用原細胞株K562(多柔比星敏感性)作為比較對照。對該等細胞進行繼代、培養。為了實驗,以於實驗開始時密度成為1×10
6細胞/ml之方式製備細胞。
於上述細胞懸濁液中以濃度成為0、0.0625、0.125、0.25、0.5 mM之方式添加5-ALA,進行4小時負載。將5-ALA負載後之細胞洗淨,進行中心波長630 nm之光線照射(0、10、30及100 J/cm
2),利用細胞計數套組-8算出細胞存活率(%)。
將結果示於圖2。如圖2所示,使用5-ALA之PDT殺傷作為伊馬替尼耐性株之LAMA84-r細胞株及作為多柔比星耐性株之K562/ADR細胞株。該等殺細胞效果與各敏感性原細胞株相比,為相同程度,由此提示使用5-ALA之PDT於伊馬替尼及多柔比星非敏感性之患者細胞中亦有效。
[產業上之可利用性]
根據本發明,能夠藉由使用5-ALA等之PDT預防或治療耐藥劑性癌症。本發明可用於醫療領域等。
相關申請
該申請主張2019年4月26日以日本特許廳作為受理官廳提出申請之國際申請編號PCT/JP2019/17995之優先權之利益。優先權基礎申請之整體藉由明示出處而作為本說明書之一部分。
圖1係表示來那度胺耐性株以及莫加珠單抗及維生素A酸耐性株之細胞存活率之曲線圖。
圖2係表示伊馬替尼耐性株及多柔比星耐性株之細胞存活率之曲線圖。
Claims (1)
- 一種下述式(1)所示之化合物、或者其等之鹽之用途,其係用於製造藉由光動力學療法(PDT)治療或預防對於選自由將CD分子作為靶之分子靶向治療藥、將cereblon作為靶之分子靶向治療藥、將mTOR蛋白質作為靶之分子靶向治療藥、將PML-RARα作為靶之分子靶向治療藥、將BCR-Abl酪胺酸激酶作為靶之分子靶向治療藥、將KIT酪胺酸激酶作為靶之分子靶向治療藥及蒽環系抗癌性抗生素所組成之群中之至少一個治療藥具有耐性之對象之血液癌之醫藥, (式中,R 1及R 2分別相同或不同,表示氫原子、碳數1~24之烷基、碳數1~12之醯基、總碳數2~13之烷氧基羰基、碳數6~16之芳基或於碳數6~16之芳基鍵結有碳數1~6之烷基之基,R 3表示羥基或C 1-12烷氧基), 血液癌係選自由白血病、淋巴瘤、多發性骨髓瘤、蕈樣肉芽腫、塞紮里氏綜合徵、B細胞淋巴瘤、非霍奇金淋巴瘤、伯奇氏淋巴瘤、小細胞淋巴瘤、大細胞淋巴瘤、單核球性白血病、骨髓性白血病、急性淋巴球性白血病、急性骨髓性白血病、慢性骨髓性白血病及成人T細胞白血病所組成之群,且 於體外進行PDT之光照射。
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