TWI813331B - β-1腎上腺素受體拮抗劑用於製備減少表皮生長因子受體抑制劑誘導的上皮細胞損傷以及抑制癌細胞的組合物之用途 - Google Patents
β-1腎上腺素受體拮抗劑用於製備減少表皮生長因子受體抑制劑誘導的上皮細胞損傷以及抑制癌細胞的組合物之用途 Download PDFInfo
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Abstract
本發明係關於一種β-1腎上腺素受體拮抗劑用於製備減少或預防表皮生長因子受體抑制劑誘導的正常上皮細胞損傷以及抑制癌細胞的組合物之用途，藉由施用包含β-1腎上腺素受體拮抗劑之組合物以減少表皮生長因子受體抑制劑所誘導的正常上皮細胞損傷，並可與表皮生長因子受體抑制劑一同施用以協同作用抑制癌細胞。
Description
相關申請案的交互參照
本申請主張2020年7月10日提交的美國臨時申請案號63/050,390的優先權之利益。藉由引用將上述申請案的全部內容併入本文中。
本發明係關於一種β-1腎上腺素受體拮抗劑用於製備減少或預防表皮生長因子受體抑制劑誘導的正常上皮細胞損傷以及抑制癌細胞的組合物之用途。
表皮生長因子受體(Epidermal Growth Factor Receptor,EGFR)被視為發展抗腫瘤治療之有效目標物，EGFR標靶治療距離初次登場已經有超過15年的歷史，幫助了無數的癌症病患延長生命。表皮生長因子受體抑制劑(Epidermal Growth Factor Receptor Inhibitor,EGFRI)包含有抗表皮生長因子受體單株抗體(mAb)及表皮生長因子受體酪胺酸激酶抑制劑(EGFR-TKI)。
其中，抗表皮生長因子受體單株抗體作用機轉為專一性地與表皮生長因子受體結合，競爭性的抑制表皮生長因子功能，使得癌細胞無法增生。目前臨床上常用之單株抗體藥物為西妥昔單抗(Cetuximab)、扎魯單抗(Zalutumumab)、尼莫妥單抗(Nimotuzumab)、馬妥珠單抗(Matuzumab)以及帕尼單抗(Panitumumab)。
EGFR-TKI是抑制酪胺酸激酶活性的藥物，由於酪胺酸激酶在細胞內擔任許多訊號傳遞的開關，在細胞生長、增殖及分化中具有重要作用，其突變常常引起癌症。
因此，酪胺酸激酶抑制劑可做為癌症藥物使用，其除了可抑制癌細胞增生之外，還可阻止新的血管生成，阻斷癌細胞養分及氧氣的供給。目前臨床上常用之酪胺酸激酶抑制劑包括有厄洛替尼(Erlotinib)、吉非替尼(Gefitinib)、拉帕替尼(Lapatinib)、阿法替尼(Afatinib)、達克替尼(dacomitinib)、奧希替尼(osimertinib)等。
表皮生長因子受體抑制劑雖然可應用於治療多種癌症，然而在臨床上仍常見以下上皮細胞(epithelial cell)損傷之不良反應，包括：腸上皮毒性、肺部毒性、肝毒性及皮膚上皮細胞損傷。皮膚上皮細胞損傷包含丘疹膿皰皮疹、紫癜性藥疹、皮膚變薄、皮膚炎、紅斑痤瘡、乾燥症、頭髮稀疏、捲髮或皮膚屏障損害等。由於在表皮基底有高表現量的EGFR，使用表皮生長因子受體抑制劑常會出現皮膚藥物不良反應，使正常或是尚未受傷之上皮細胞受損。與正常皮膚相比，表皮生長因子受體抑制劑在皮膚會引起發炎細胞浸潤，尤其是在毛囊中，皮膚的角質層明顯變薄，失去了正常的籃狀編織(basket-weave)結構，並變得更緻密、嗜酸性及角化不全(請見第14圖，摘錄於Herbst,R.S.,et al.,
Dermatologic side effects associated with gefitinib therapy：clinical experience and management.Clin Lung Cancer,2003.4(6)：p.366-9)。目前針對皮生長因子受體抑制劑引起之皮膚藥物不良反應的處置為減少劑量或是停止表皮生長因子受體抑制劑治療。因此對於減少或是預防表皮生長因子受體抑制劑所引起的上皮細胞損傷的需求仍然存在；本發明解決此需求以及其他需求。
有鑑於上述問題，本發明之目的係在於提供一種β-1腎上腺素受體拮抗劑用於製備減少或預防表皮生長因子受體抑制劑誘導的正常上皮細胞損傷的組合物之用途。
為解決表皮生長因子受體抑制劑(EGFRI)治療癌症時所引起的正常(或尚未受傷)上皮細胞損傷，藉由將包含β-1腎上腺素受體拮抗劑的組合物施用於有需要之個體或患者，以減少或預防因施用EGFRI治療癌症時所造成之正常上皮細胞損傷。
在一實施例中，所述之正常上皮細胞為尚未有表皮生長因子受體抑制劑引起損傷或毒性之上皮細胞。
在一實施例中，所述β-1腎上腺素受體拮抗劑可在表皮生長因子受體抑制劑之前、之後或與其同時投予。在一實施例中，所述β-1腎上腺素受體拮抗劑可在表皮生長因子受體抑制劑之前投予。
本發明之一些具體實例係針對抑制一個體因表皮生長因子受體抑制劑(EGFRI)治療癌症時所引起的正常(或尚未受傷)上皮細胞損傷之方
法，其包含向有需要之個體投予有效量之至少一種β-1腎上腺素受體拮抗劑，藉此減輕或預防該個體上皮細胞損傷之症狀及/或徵象。
本發明之一些具體實例係在於提供一種β-1腎上腺素受體拮抗劑用於製備抑制癌細胞的組合物之用途。該等組成物包含至少一種β-1腎上腺素受體拮抗劑與至少一種皮生長因子受體抑制劑之組合。β-1腎上腺素受體拮抗劑與至少一種皮生長因子受體抑制劑可產生累加或協同作用。
本發明之一些具體實例係針對抑制個體中癌症生長之方法，其包含向有需要之個體投予有效量之至少一種β-1腎上腺素受體拮抗劑與至少一種皮生長因子受體抑制劑之組合，藉此減輕該個體之癌症之症狀及/或徵象。
本發明組成物及方法可用於治療或抑制任何類型之癌症生長。在一些具體實例中，待治療癌症或待抑制之癌症生長為實體腫瘤或血液腫瘤，諸如肝癌、膽管癌、乳癌、肺癌、胃癌、胰臟癌、結腸直腸癌、子宮癌、子宮頸癌、白血病及淋巴瘤。
在一實施例中，所述表皮生長因子受體抑制劑為表皮生長因子受體酪胺酸激酶抑制劑(EGFR-Tyrosine Kinase Inhibitor,EGFR-TKI)。表皮生長因子受體酪胺酸激酶抑制劑之非限制性實例包括吉非替尼、厄洛替尼、阿法替尼、達克替尼、奧希替尼、拉帕替尼或其組合。
在一實施例中，所述上皮細胞係指皮膚上皮細胞，腸上皮細胞或角膜上皮細胞。
在一實施例中，所述β-1腎上腺素受體拮抗劑之非限制性實例包括阿替洛爾(atenolol)、倍他洛爾(betaxolol)、比索洛爾(bisoprolol)、艾司
洛爾(esmolol)、醋丁洛爾(acebutolol)、美托洛爾(metoprolol)、奈比洛爾(nebivolol)或其組合。
在一實施例中，所述表皮生長因子受體抑制劑(EGFRI)引起之皮膚上皮細胞毒性包括下述至少一種：丘疹膿皰皮疹、紫癜性藥疹、皮膚變薄、皮膚炎、紅斑痤瘡、乾燥症、頭髮稀疏、捲髮或皮膚屏障損害。
在一實施例中，所述表皮生長因子受體抑制劑(EGFRI)引起之腸上皮細胞毒性包括下述至少一種：口腔黏膜炎、生殖器黏膜炎或腹瀉。
在一實施例中，所述包含β-1腎上腺素受體拮抗劑的組合物可進一步包含前文所述的表皮生長因子受體抑制劑(EGFRI)，用於抑制癌細胞生長時減少EGFRI所引起的上皮細胞損傷。
本案中使用的術語「發明」、「該發明」、「此發明」及「本發明」旨在廣泛指稱本案的發明標的和下述申請專利範圍的全部。包含這些術語的陳述應理解為不限制本文所述之發明標的或下述申請專利範圍的含義或其涵蓋範圍。本案涵蓋之發明實施例由下述申請專利範圍所定義，而非由本發明內容所定義。本發明內容是本發明各方面之高層次概述，並介紹了在以下實施方式中進一步描述的部分概念。本發明內容非旨在識別出所要求保護之發明標的的關鍵或必要特徵，也非旨在單獨用以判定所要求保護之發明標的。發明標的應藉由參考整份說明書、任何或所有圖式以及每項申請專利範圍之適當部分來理解。
搭配所附圖式以及以下之詳細描述閱讀，將使本發明變得更加明顯易懂。
第1圖係為施用不同濃度之表皮生長因子受體酪胺酸激酶抑制劑至正常上皮細胞，其上皮細胞的存活率示意圖；第2圖係為施用不同濃度之β-1腎上腺素受體拮抗劑倍他洛爾(betaxolol)至正常上皮細胞，其上皮細胞的存活率示意圖；第3圖係為先施用β-1腎上腺素受體拮抗劑倍他洛爾(betaxolol)至正常上皮細胞，經1小時後再施用表皮生長因子受體酪胺酸激酶抑制劑，其上皮細胞的存活率示意圖；第4圖係為同時施用表皮生長因子受體酪胺酸激酶抑制劑與β-1腎上腺素受體拮抗劑至正常上皮細胞，其上皮細胞的存活率示意圖；第5圖係為施用表皮生長因子受體酪胺酸激酶抑制劑至A549癌細胞，其癌細胞的存活率示意圖；第6圖係為單獨施用表皮生長因子受體酪胺酸激酶抑制劑以及同時施用表皮生長因子受體酪胺酸激酶抑制劑與β-1腎上腺素受體拮抗劑至A549癌細胞，其癌細胞的存活率示意圖；第7圖係為單獨施用表皮生長因子受體酪胺酸激酶抑制劑以及同時施用表皮生長因子受體酪胺酸激酶抑制劑與β-1腎上腺素受體拮抗劑至PC9癌細胞，其癌細胞的存活率示意圖；第8圖係為先施用非選擇性β腎上腺素受體拮抗劑至正常上皮細胞，經1小時後再施用表皮生長因子受體酪胺酸激酶抑制劑，其上皮細胞的存活率示意圖；
第9圖係為同時施用表皮生長因子受體酪胺酸激酶抑制劑與非選擇性β腎上腺素受體拮抗劑至A549癌細胞，其癌細胞的存活率示意圖；第10圖至第12圖係為β-1腎上腺素受體拮抗劑對表皮生長因子受體酪胺酸激酶抑制劑誘導之紅斑痤瘡影響示意圖；第13圖係為β-1腎上腺素受體拮抗劑對抗表皮生長因子受體單株抗體誘導之丘疹膿皰皮疹影響示意圖；第14圖係為正常皮膚細胞(A)與表皮生長因子受體抑制劑治療後(B)之皮膚細胞伊紅染色影像圖(摘錄於Herbst,R.S,et al.,Dermatologic side effects associated with gefitinib therapy clinical experience and management.Clin Lung Cancer,2003.4(6)：p.366-9)；第15圖係為先施用β-1腎上腺素受體拮抗劑比索洛爾(Bisoprolol)至正常上皮細胞，經1小時後再施用表皮生長因子受體酪胺酸激酶抑制劑，其上皮細胞的存活率示意圖；第16圖係為先施用β-1腎上腺素受體拮抗劑醋丁洛爾(acebutolol)至正常上皮細胞，經1小時後再施用表皮生長因子受體酪胺酸激酶抑制劑，其上皮細胞的存活率示意圖。
以下內容將搭配圖式，藉由特定的具體實施例說明本發明之技術內容，熟悉此技術之人士可由本說明書所揭示之內容輕易地了解本發明之其他優點與功效。本發明亦可藉由其他不同的具體實施例加以施行或應用。本說明
書中的各項細節亦可基於不同觀點與應用，在不背離本發明之精神下，進行各種修飾與變更。
用語「個體(subject)」和「患者(patient)」可交互使用，且是指被診斷出有EGFRI所造成之上皮細胞損傷及/或癌症，或疑似有EGFRI造成之上皮細胞損傷及/或癌症的哺乳動物。個體包括靈長類動物，較佳為人類。
「有效量」的拮抗劑是指能產生所需效果之一定量的抑制劑，例如與未受治療之個體相比，減少上皮細胞損傷率及/或癌細胞抑制率至少約1%、5%、10%、20%、30%、40%、50%、60%、70%、80%、90%、95%。
本文所用之專有術語「治療」包括預防性(例如防治性)、緩解性及治癒性用途或結果。需要治療或預防的個體或患者意指包含已經有或疑似有EGFRI造成之上皮細胞損傷；已經有或疑似有癌症的個體或患者，或尚未產生EGFRI造成正常上皮細胞損傷的患者。
本文中所有數字可被理解為以「約」修飾。如用於本文中，術語「約」意指包含正負10%的變化。
另外，本領域技術人員可依據例如上皮細胞損傷的嚴重程度和類型、患者年齡、體重、性別、併發症以及施予患者的其它藥物，快速地判定針對特定類型的上皮細胞損傷施予的β-1腎上腺素受體拮抗劑的合適劑量和劑量數；本領域技術人員將了解到，較佳的劑量為對有需求之患者產生治療效果，例如加速上皮細胞修復的劑量。
β-1腎上腺素受體拮抗劑可以任何有效量投予。在一些具體實例中，其可以約0.01% w/w至約10% w/w、約0.05% w/w至約5% w/w、約0.1% w/w至約1% w/w範圍內之劑量投予。
藉由比較本文提供之組成物的試管內活性與動物模型中之活體內活性來測定本文提供之組成物的適用劑量。此項技術中已知將小鼠及其他動物中之有效劑量外推成人類有效劑量之方法；例如參看美國專利第4,938,949號，其以引用的方式併入本文中。
組成物以有效抑制上皮細胞損傷或或減少癌細胞生長之量投予。所投予醫藥組成物之劑量將視所治療病狀之嚴重程度、特定調配物及其他臨床因素(諸如接受者之體重及一般狀態及投藥途徑)而定。在一實施例中，單一劑量在給定數量的天數(即1天、7天、14天、21天、1個月等)中一天施予一次。
在又一實施例中，可在一天內(每2小時、4小時、6小時或12小時等)施予多劑量，以每天多次劑量地施予多天。
根據本文提供之方法，藉由多種途徑中之任一者傳遞組成物，包括(但不限於)注射(例如皮下、肌肉內、靜脈內、動脈內、腹膜內、皮內)；皮膚；真皮；經皮；經口(例如錠劑、藥丸、藥液、可食用膜帶)；植入滲透泵；栓劑；氣溶膠噴霧；局部；關節內；經眼；鼻吸入；肺吸入；壓入皮膚及陰道中。
在一實施例中，組合物被配製成下列形式之一以進行局部遞送：軟膏、乳霜、溶液、凝膠、懸浮液、噴霧或洗劑；在另一實施例中，組合物被配製成用於緩慢或持續釋放。
實施例1
針對表皮生長因子受體酪胺酸激酶抑制劑對上皮細胞的影響進行MTT試驗(即細胞存活率分析)，其實驗流程如下：
在多孔盤(24孔)中每孔種入固定數量(7×104cell/dish)的HaCaT細胞(人類皮膚角質細胞)，於培養24小時後，將不同濃度之阿法替尼(0、1、2.5、5、10、20、50μM)與0.1%的DMSO加入細胞中並培養24小時；加入MTT(3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide，溴化-3-(4,5-二甲基-2-噻唑)-2,5-二苯基四氮唑)300λ，經1小時後抽掉上清液再加入DMSO並震盪，抽取200λ/well液體加入另一多孔盤(96孔)中，並用ELISA測量吸光值(OD570，optical density 570nm)，計算出細胞存活率，實驗共進行3次，其吸光值與細胞存活率之數據如下表1所示。
參照第1圖，第1圖係為施用不同濃度之表皮生長因子受體酪胺酸激酶抑制劑至正常上皮細胞，其上皮細胞的存活率示意圖；由圖中可知，隨著阿法替尼的濃度提高，HaCaT細胞的存活率逐漸下降，當濃度提高至5μM時，細胞存活率僅剩34.8%；由此可知，表皮生長因子受體酪胺酸激酶抑制劑會增加正常上皮細胞的凋亡。
實施例2
針對β-1腎上腺素受體拮抗劑對上皮細胞的影響進行MTT試驗，其實驗流程與實施例1相似，僅將阿法替尼置換為倍他洛爾，於此不再贅述；實驗共進行4次，其吸光值與細胞存活率之數據如下表2所示。
參照第2圖，第2圖係為施用不同濃度之β-1腎上腺素受體拮抗劑倍他洛爾至正常上皮細胞，其上皮細胞的存活率示意圖；由圖中可知，隨著倍他洛爾的濃度提高，HaCaT細胞的存活率至少為90%以上，當濃度提高至100μM之高濃度時，細胞存活率才下降至88.1%；由此可知，基本上倍他洛爾不影響正常上皮細胞的存活率。
實施例3
針對先後施用β-1腎上腺素受體拮抗劑與表皮生長因子受體酪胺酸激酶抑制劑對上皮細胞的影響進行MTT試驗，其實驗流程與實施例1相似，將HaCaT細胞先施用之倍他洛爾，經1小時後再施用阿法替尼並培養24小時，觀察HaCaT細胞之存活率。
參照第3、15及16圖，係為先施用β-1腎上腺素受體拮抗劑至正常上皮細胞，經1小時後再施用表皮生長因子受體酪胺酸激酶抑制劑，其上皮細胞的存活率示意圖；由第3、15及16圖中可知，僅施用β-1腎上腺素受體拮抗劑時，HaCaT細胞的存活率為100%，僅施用阿法替尼時，隨著濃度提高時，HaCaT細胞的存活率逐漸下降；但先施用β-1腎上腺素受體拮抗劑後再施用阿法替尼時，HaCaT細胞的存活率相較於僅施用阿法替尼時提高不少，且於阿法替尼濃度越高時，可看出HaCaT細胞凋亡明顯減少；由此可知，β-1腎上腺素受體拮抗劑確實可降低表皮生長因子受體酪胺酸激酶抑制劑所造成之上皮細胞損傷。
實施例4
針對同時施用β-1腎上腺素受體拮抗劑與表皮生長因子受體酪胺酸激酶抑制劑對上皮細胞的影響進行MTT試驗，其實驗流程與實施例1相似，將HaCaT細胞同時施用倍他洛爾及阿法替尼並培養24小時，觀察HaCaT細胞之存活率。
參照第4圖，第4圖係為同時施用表皮生長因子受體酪胺酸激酶抑制劑與β-1腎上腺素受體拮抗劑至正常上皮細胞，其上皮細胞的存活率示意圖；由圖中可知，僅施用倍他洛爾時，HaCaT細胞的存活率為100%，僅施用阿法替尼時，隨著濃度提高時，HaCaT細胞的存活率逐漸下降；但同時施用倍他洛爾及阿法替尼時，HaCaT細胞的存活率相較於僅施用阿法替尼時提高不少；由此可知，β-1腎上腺素受體拮抗劑確實可降低表皮生長因子受體酪胺酸激酶抑制劑所造成之上皮細胞損傷。
實施例5
由前述實施例中，可發現同時施用β-1腎上腺素受體拮抗劑及表皮生長因子受體酪胺酸激酶抑制劑於正常上皮細胞時，可提高正常上皮細胞之存活率；接著，針對癌細胞，分別測試僅施用表皮生長因子受體酪胺酸激酶抑制劑以及同時施用β-1腎上腺素受體拮抗劑及表皮生長因子受體酪胺酸激酶抑制劑對癌細胞之抑制效果，其實驗流程與實施例1相似，於此不再贅述。
參照第5圖至第7圖，第5圖係為施用表皮生長因子受體酪胺酸激酶抑制劑至A549癌細胞，其癌細胞的存活率示意圖；第6圖係為單獨施用表皮生長因子受體酪胺酸激酶抑制劑以及同時施用表皮生長因子受體酪胺酸激酶抑制劑與β-1腎上腺素受體拮抗劑至A549癌細胞，其癌細胞的存活率示意圖；以及第7圖係為單獨施用表皮生長因子受體酪胺酸激酶抑制劑以及同時施用表皮生長因子受體酪胺酸激酶抑制劑與β-1腎上腺素受體拮抗劑至PC9癌細胞，其癌細胞的存活率示意圖。
由第5圖可知，阿法替尼施用於A549癌細胞(EGFR突變的肺癌細胞)時，隨著濃度越高，A549癌細胞的存活率逐漸下降，於濃度為50μM時，A549癌細胞之存活率下降至26.4%；由此可知，表皮生長因子受體酪胺酸激酶抑制劑可顯著增加癌細胞的凋亡；其實驗共進行3次，其吸光值與細胞存活率之數據如下表3所示。
由第6圖可知，僅施用倍他洛爾時，A549癌細胞的存活率為100%，當阿法替尼與倍他洛爾同時施用時，對於A549癌細胞的抑制效果相較於單獨施用阿法替尼，可增加細胞毒性作用；由此可知，β-1腎上腺素受體拮抗劑可提高表皮生長因子受體酪胺酸激酶抑制劑的抗癌效果。
由第7圖可知，將阿法替尼與倍他洛爾同時施用另一PC9癌細胞(EGFR突變的癌細胞)時，對於PC9癌細胞的抑制效果相較於單獨施用阿法替尼，可增加細胞毒性作用；由此可知，EGFR所誘導的相關癌細胞，同時施用β-1腎上腺素受體拮抗劑及表皮生長因子受體酪胺酸激酶抑制劑，可提高抗癌效果。
實施例6
為驗證是否僅有β-1腎上腺素受體拮抗劑可減少表皮生長因子受體酪胺酸激酶抑制劑所引起的上皮細胞損傷，且具有增加抑制癌細胞之效果，另找了非選擇性β腎上腺素受體拮抗劑，如噻嗎洛爾(Timolol)，但不限於此，與表皮生長因子受體酪胺酸激酶抑制劑共同施用；觀察其對於HaCaT細胞以及A549癌細胞之作用，其實驗流程與實施例1相似，於此不再贅述。
參照第8圖及第9圖，第8圖係為先施用非選擇性β腎上腺素受體拮抗劑至正常上皮細胞，經1小時後再施用表皮生長因子受體酪胺酸激酶抑制劑，其上皮細胞的存活率示意圖；第9圖係為同時施用表皮生長因子受體酪胺酸激酶抑制劑與非選擇性β腎上腺素受體拮抗劑至A549癌細胞，其癌細胞的存活率示意圖。
由第8圖可知，固定阿法替尼的濃度，改變施用的噻嗎洛爾的濃度時，HaCaT細胞的存活率相較於單獨施用阿法替尼顯著下降，且於同時施用濃度10μM的噻嗎洛爾時，即下降至37%以下；由此可知，非選擇性β腎上腺素受體拮抗劑與阿法替尼明顯降低了HaCaT細胞的存活率，非選擇性β腎上腺素受體拮抗劑無法預防或減少因表皮生長因子受體抑制劑(EGFRI)治療癌症時所引起的正常(或尚未受傷)上皮細胞損傷。
由第9圖可知，同時施用噻嗎洛爾及阿法替尼於A549癌細胞時，A549癌細胞的存活率並沒有顯著改變，而當噻嗎洛爾的濃度提高至50μM時，A549癌細胞的存活率反而相對提高；由此可知，同時施用非選擇性β腎上腺素受體拮抗劑及表皮生長因子受體酪胺酸激酶抑制劑，並無法提高抗癌效果。
實施例7
尋找因表皮生長因子受體酪胺酸激酶抑制劑或抗表皮生長因子受體單株抗體引起的上皮細胞損傷的患者，例如，患有紅斑痤瘡或丘疹膿皰皮疹之患者，將包含有β-1腎上腺素受體拮抗劑的組合物配置成局部施用之外用藥，施用於患者觀察其治療效果。
參照第10圖至第12圖，第10圖至第12圖係為β-1腎上腺素受體拮抗劑對表皮生長因子受體抑制劑誘導之紅斑痤瘡影響示意圖；其中，第10圖係使用0.25%(w/w)倍他洛爾對因阿法替尼所誘導引起的紅斑痤瘡進行治療，於治療至第14天時，紅斑痤瘡相較於第1天具有明顯的改善。第11圖係使用0.25%(w/w)倍他洛爾對因奧希替尼所誘導引起的紅斑痤瘡進行治療，於治療至第4天時，紅斑痤瘡即具有明顯的改善。第12圖係使用0.25%(w/w)倍他洛爾對紅斑痤瘡進行治療，於治療至第7天時，紅斑痤瘡即具有明顯的改善。
參照第13圖，第13圖係為β-1腎上腺素受體拮抗劑對抗表皮生長因子受體單株抗體誘導之丘疹膿皰皮疹影響示意圖；使用0.25%(w/w)倍他洛爾對因西妥昔單抗所誘導引起的丘疹膿皰皮疹進行治療，於治療至第30天時，丘疹膿皰(箭頭處)有明顯的改善。
綜上所述，β-1腎上腺素受體拮抗劑確實可減少或預防表皮生長因子受體酪胺酸激酶抑制劑(EGFR-TKI)以及抗表皮生長因子受體單株抗體(mAb)誘導的正常上皮細胞損傷，減少表皮生長因子受體酪胺酸激酶抑制劑(EGFR-TKI)以及抗表皮生長因子受體單株抗體(mAb)誘導的上皮細胞損傷，並可提高EGFR-TKI對於癌細胞的抑制效果；另使用非選擇性β腎上腺素受體拮抗劑作為對比，可知非選擇性β腎上腺素受體拮抗劑並無法減少或預防EGFR-TKI誘導的正常上皮細胞損傷，且也無法提高EGFR-TKI對於癌細胞的抑制效果。
因此，使用β-1腎上腺素受體拮抗劑對於減少EGFR-TKI誘導的上皮細胞損傷，也一併提高EGFR-TKI對於癌細胞的抑制效果，非所屬技術領域具通常知識者參考先前技術而可得知，故具有無法預期之功效。
上述實施例僅例示性說明本發明之原理及功效，而非用於限制本發明。任何熟習此項技術之人士均可在不違背本發明之精神及範疇下，對上述實施例進行修飾與改變。因此，本發明之權利保護範圍，應如本發明申請專利範圍所列。
Claims (4)
- 一種包含表皮生長因子受體酪胺酸激酶抑制劑(EGFR-TKI)及β-1腎上腺素受體拮抗劑的組合物用於製備抑制個體癌細胞的藥物之用途，其包括向該個體施用包含有效量的表皮生長因子受體酪胺酸激酶抑制劑(EGFRI-TKI)及β-1腎上腺素受體拮抗劑的組合物的步驟。
- 如請求項1所述之用途，其中該β-1腎上腺素受體拮抗劑係選自阿替洛爾、倍他洛爾、比索洛爾、艾司洛爾、醋丁洛爾、美托洛爾、耐比洛爾及其組合所組成之群。
- 如請求項1所述之用途，其中該EGFRI-TKI係選自吉非替尼、厄洛替尼、阿法替尼、達克替尼、奧希替尼、拉帕替尼或其組合。
- 如請求項1所述之用途，其中該個體癌細胞選自肝癌、膽管癌、乳癌、肺癌、胃癌、胰臟癌、結腸直腸癌、子宮癌、子宮頸癌、白血病及/或淋巴瘤之癌細胞。
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| US20160175485A1 (en) * | 2013-08-27 | 2016-06-23 | The Regents Of The University Of California | Combination therapy to promote wound healing |
| KR101938036B1 (ko) * | 2015-04-16 | 2019-01-14 | 서울대학교산학협력단 | 고혈압 치료제를 이용한 흡연 및 비흡연자의 폐암 억제 방법 |
| AU2017275492A1 (en) * | 2016-06-01 | 2018-12-20 | Harold Richard Hellstrom | Treatment of dry eye disease with parasympathetic and anti-sympathetic agents |
| US11154518B2 (en) * | 2018-12-28 | 2021-10-26 | Chang Gung Memorial Hospital, Linkou | Methods and apparatus for treating a wound |
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2021
- 2021-07-08 JP JP2022577113A patent/JP2023533911A/ja active Pending
- 2021-07-08 TW TW110125065A patent/TWI776584B/zh active
- 2021-07-08 EP EP21837895.8A patent/EP4180033A4/en active Pending
- 2021-07-08 CN CN202180048775.4A patent/CN116056693A/zh active Pending
- 2021-07-08 WO PCT/CN2021/105167 patent/WO2022007878A1/zh not_active Ceased
- 2021-07-08 TW TW111121714A patent/TWI813331B/zh active
- 2021-07-08 US US18/015,147 patent/US20230248671A1/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 期刊 Hu P, et al. "β2-adrenergic receptor activation promotes the proliferation of A549 lung cancer cells via the ERK1/2/CREB pathway" Oncology Reports 36(3): 2016; 1757-1763 |
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| Publication number | Publication date |
|---|---|
| WO2022007878A1 (zh) | 2022-01-13 |
| EP4180033A4 (en) | 2024-09-25 |
| TWI776584B (zh) | 2022-09-01 |
| CN116056693A (zh) | 2023-05-02 |
| EP4180033A1 (en) | 2023-05-17 |
| TW202202144A (zh) | 2022-01-16 |
| TW202237123A (zh) | 2022-10-01 |
| US20230248671A1 (en) | 2023-08-10 |
| JP2023533911A (ja) | 2023-08-07 |
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