TWI401085B - Contains cytosine derivatives for continuous intravenous administration with anti-tumor agents - Google Patents
Contains cytosine derivatives for continuous intravenous administration with anti-tumor agents Download PDFInfo
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- TWI401085B TWI401085B TW097112411A TW97112411A TWI401085B TW I401085 B TWI401085 B TW I401085B TW 097112411 A TW097112411 A TW 097112411A TW 97112411 A TW97112411 A TW 97112411A TW I401085 B TWI401085 B TW I401085B
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- cancer
- intravenous administration
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- A61K31/706—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom
- A61K31/7064—Compounds having saccharide radicals and heterocyclic rings having nitrogen as a ring hetero atom, e.g. nucleosides, nucleotides containing six-membered rings with nitrogen as a ring hetero atom containing condensed or non-condensed pyrimidines
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- C07H19/02—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing nitrogen
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Description
本發明係關於一種向癌症患者持續靜脈內投與之抗腫瘤劑。
1－(3－C－乙炔基－β－D－核糖五呋喃糖基)胞嘧啶(1－(3－C－ethynyl－β－D－ribopentofuranosyl)cytosine，「ECyd」，參照下述結構式)係將胞苷(胞嘧啶核苷)中的核糖的3'β位取代成乙炔基之新穎的代謝拮抗劑。
ECyd係於日本國所合成之胞苷類似物，Ecyd不同於臨床上通用之嘧啶系抗腫瘤劑(5－FU)或去氧胞苷系衍生物(吉西他濱，gemcitabine)，對DNA的作用較弱，主要具有RNA合成抑制作用。詳細而言，一般認為，其係利用細胞內的尿苷/胞嘧啶激酶將ECyd磷酸化而形成三磷酸化體(ECTP)，該三磷酸化體抑制核糖核酸聚合酶Ⅰ、Ⅱ及Ⅲ的功能，藉此殺死細胞者。
以DNA合成抑制作用為主要作用而在臨床上通用之許多抗腫瘤劑，藉由S期抑制作用而顯示其效果，但不同於動
物試驗中所使用之增殖比較快的腫瘤，已判明臨床上之腫瘤增殖較慢且S期的細胞較少。不同於DNA合成抑制劑，利用ECyd所具有的RNA合成抑制作用之抗腫瘤效果，因於腫瘤的細胞週期中不受影響，故有別於臨床上通用之DNA合成抑制劑，一般認為ECyd可成為臨床上有用的抗腫瘤劑。
ECyd對於廣泛的腫瘤顯示較強的抗腫瘤效果(非專利文獻1、2)，於使用動物模型之抗腫瘤試驗中，亦發現ECy對於許多源自人體之腫瘤株，藉由以急速靜脈內注射每週1次投與2週之投與法，而顯示較強的抗腫瘤效果(非專利文獻3)。又，於動物模型中，在看見抗腫瘤效果之有效劑量下幾乎未觀察到明顯的副作用，從而期持ECyd具有臨床上的有用性。
對於含有ECyd作為有效成分之癌症治療藥，在美國進行了臨床第Ⅰ期試驗，試驗中以急速靜脈內投與方式開始施行3週投與1次、或者每週投與1次投與3週停藥1週之2個方案，從而確保充分的血中濃度，又報告有該癌症治療藥對於先前藥劑中未見治療效果的複數癌種之癌症患者之少數病例，顯示腫瘤增殖抑制作用。
然而，其現狀為，觀察到作為劑量限制毒性之末梢神經毒性，因而難以進一步增加劑量及繼續投藥以進行抗腫瘤劑評價，臨床上之癌症治療效果並不理想(非專利文獻4、5)。
[非專利文獻1]J.Med.Chem.,39,5005－5011,1996
[非專利文獻2]Oncol.Rep.,3,1029－1034,1996
[非專利文獻3]Jpn.J.Cancer Res.,92,343－351,2001
[非專利文獻4]EORTC－NC1－AACR Symposium,Abs.67A,2002
[非專利文獻5]EORTC－NCI－AACR Symposium,Abs.364,2002
本發明提供一種抗腫瘤效果高且表現出末梢神經毒性之危險性低的ECyd之新穎的使用方法。
本發明者對ECyd之使用方法進行了反覆研究，結果發現，於長期持續施行靜脈內投與之情形時，可獲得較高的抗腫瘤效果且可減輕毒性，此方法成為有助於延長患者生存時間之有效方法。
亦即，本發明係關於以下1)至5)之發明者。
1)一種抗腫瘤劑，其特徵在於：其係含有ECyd或其鹽者，且對癌症患者，於2~336小時中持續靜脈內投與以ECyd換算量計每1次為1.30~8.56 mg/m2
之量。
2)如上述1)之抗腫瘤劑，其係於4~72小時中所投與者。
3)如上述1)之抗腫瘤劑，其係於24小時中所投與者。
4)如上述1)至3)中任一項之抗腫瘤劑，其係投與以ECyd換算量計每1次為2.80~8.56 mg/m2
之量。
5)如上述1)至3)中任一項之抗腫瘤劑，其係投以ECyd換
算量計每1次為6.85 mg/m2
之量。
6)一種1－(3－C－乙炔基－β－D－核糖五呋喃糖基)胞嘧啶或其鹽之使用方法，其係用於製造抗腫瘤劑者，該抗腫瘤劑係對癌症患者，於2~336小時中持續靜脈內投與以1－(3－C－乙炔基－β－D－核糖五呋喃糖基)胞嘧啶換算量計每1次為1.30~8.56 mg/m2
之量。
7)一種癌症治療方法，其特徵在於：對癌症患者，於2~336小時中持續靜脈內投與以1－(3－C－乙炔基－β－D－核糖五呋喃糖基)胞嘧啶換算量計每1次為1.30~8.56 mg/m2
量之含有1－(3－C－乙炔基－β－D－核糖五呋喃糖基)胞嘧啶或其鹽之抗腫瘤劑。
藉由本發明之抗腫瘤劑，可減輕表現末梢神經毒性之危險性，而且可發揮高抗腫瘤效果。亦即，由於副作用所造成之治療中斷的危險性少，且可獲得如確實延長患者生存時間之高治療效果。
作為本發明之抗腫瘤劑有效成分之ECyd，係以1－(3－C－乙炔基－β－D－核糖五呋喃糖基)胞嘧啶所表示之公知化合物，已知有ECyd經由RNA合成抑制作用而對許多癌種發揮抗腫瘤效果。再者，未報告有，可藉由持續靜脈內投與ECyd，而一面抑制副作用的發生一面有效地治療癌症。
作為ECyd之鹽，若係藥學上容許之鹽則無特別限制，例如可舉出：鹽酸鹽、氫溴酸鹽、硫酸鹽、硝酸鹽、磷酸
鹽等之無機酸鹽；乙酸鹽、丙酸鹽、酒石酸鹽、富馬酸鹽、馬來酸鹽、蘋果酸鹽、檸檬酸鹽、甲磺酸鹽、對甲苯磺酸鹽、三氟乙酸鹽等之有機酸鹽。
本發明之ECyd或其鹽，可藉由公知方法例如日本專利第3142874號公報中所記載方法而製造。
本發明之抗腫瘤劑係靜脈內投與者，其投與形態為注射劑。該注射劑，可為液狀注射劑，亦可為使用時將其溶解後使用之冷凍乾燥注射劑或粉末注射劑等固體狀注射劑。
本發明之抗腫瘤劑，可藉由將藥理學上容許之載體添加於ECyd或其鹽中且依常法而製備。該載體，係使用作為製劑原材料而慣用之各種有機或無機載體物質，於固體狀注射劑中可調配入賦形劑、潤滑劑、黏合劑、崩散劑等，於液狀注射劑中可調配入稀釋劑、助溶解劑、懸浮劑、等張化劑、pH調整劑、緩衝劑、穩定化劑、止痛劑等。又，根據需要，亦可使用防腐劑、抗氧化劑、著色劑等之製劑添加物。
至於賦形劑，例如可舉出：乳糖、蔗糖、氯化鈉、葡萄糖、麥芽糖、甘露醇、赤藻糖醇、木糖醇、麥芽糖醇、肌醇、葡聚糖、山梨糖醇、白蛋白、尿素、澱粉、碳酸鈣、高嶺土、結晶纖維素、矽酸、甲基纖維素、甘油、海藻酸鈉、阿拉伯膠以及該等之混合物等。至於潤滑劑，例如可舉出：精製滑石、硬脂酸鹽、硼砂、聚乙二醇以及該等之混合物等。至於黏合劑，例如可舉出：單糖漿、葡萄糖液、澱粉液、明膠溶液、聚乙烯醇、聚乙烯醚、聚乙烯吡
咯烷酮、羧甲基纖維素、蟲膠、甲基纖維素、乙基纖維素、水、乙醇、磷酸鉀以及該等之混合物等。至於崩散劑，例如可舉出：乾燥澱粉、海藻酸鈉、瓊脂粉、昆布糖粉、碳酸氫鈉、碳酸鈣、聚氧乙烯山梨糖醇酐脂肪酸酯類、十二烷基硫酸鈉、硬脂酸單甘油酯、澱粉、乳糖以及該等之混合物等。至於稀釋劑，例如可舉出：水、乙醇、聚乙二醇、丙二醇、乙氧基化異硬脂醇、聚氧化異硬脂醇、聚氧乙烯山梨糖醇酐脂肪酸酯類以及該等之混合物等。至於穩定化劑，例如可舉出：焦亞硫酸鈉、乙二胺四乙酸、硫代乙醇酸、硫代乳酸以及該等之混合物等。至於等張化劑，例如可舉出：氯化鈉、硼酸、葡萄糖、甘油以及該等之混合物等。至於pH值調整劑及緩衝劑，例如可舉出：檸檬酸鈉、檸檬酸、乙酸鈉、磷酸鈉以及該等之混合物等。至於止痛劑，例如可舉出：鹽酸普魯卡因、鹽酸利多卡因以及該等之混合物等。
本發明之抗腫瘤劑之投與量，就發生副作用的危險性與抗腫瘤效果之關係而言，每1次以ECyd換算量計，較好的是1.30~8.56 mg/m2
，更好的是2.80~8.56 mg/m2
，尤其好的是6..85 mg/m2
。
又，本發明之抗腫瘤劑係於2~336小時中向癌症患者持續靜脈內投與者，就發生副作用的危險性與抗腫瘤效果之關係而言，更好的是於4~72小時中進行投與，尤其好的是於24小時中進行投與。
藉由該長時間之持續靜脈內投與，可一面抑制末梢神經
毒性等副作用之發生一面有效率地治療癌症。
又，本發明之抗腫瘤劑，就一面減輕末梢神經毒性一面發揮更高的抗腫瘤效果之方面而言，較好的是以連續投與方案作為1個療程而反覆施行持續靜脈內投與；作為該投與方案，較好的是1~3週投與1次之持續靜脈內投與，尤其好的是3週投與1次之持續靜脈內投與。
作為本發明之抗腫瘤劑之投與方案，較好的是，以3週1次於24小時中持續靜脈內投與以ECyd換算量計為1.30~8.56 mg/m2
之抗腫瘤劑作為1個療程，而施行1次或重複多次；或者4週內，以1週1次於4小時中持續靜脈內投與以ECyd換算量計為1.30~8.56 mg/m2
之抗腫瘤劑、反覆施行3次作為1療程，而施行1次或重複多次；更好的是，以3週1次於24小時中持續靜脈內投與以ECyd換算量計為6.85 mg/m2
之抗腫瘤劑作為1個療程，而施行1次或重複多次；或者4週內，以1週1次於4小時中持續靜脈內投與以ECyd換算量計為1.30 mg/m2
之抗腫瘤劑、反覆施行3次作為1療程，而施行1次或重複多次。
作為應用本發明之抗腫瘤劑之癌症，並無特別限制，例如可舉出：頭頸部癌、食道癌、胃癌、結腸/直腸癌、肝癌、膽囊/膽管癌、胰臟癌、肺癌、乳癌、卵巢癌、膀胱癌、前列腺癌、睾丸腫瘤、骨/軟部肉瘤、惡性淋巴瘤、白血病、子宮頸癌、皮膚癌、腦腫瘤等，尤其好的是頭頸部癌、肺癌、胃癌、結腸/直腸癌、胰臟癌、乳癌。
又，作為本發明之抗腫瘤劑投與對象之癌症患者，可為
未曾接受癌症治療的患者，亦可為目前正接受治療的患者，亦可為已接受治療的患者。
本發明之抗腫瘤劑，亦可與其他抗腫瘤劑或放射線併用，至於可併用之抗腫瘤劑，例如可舉出：5－氟尿嘧啶(5－FU)、喃氟啶(tegafur)－尿嘧啶製劑、喃氟啶－吉莫斯特(gimeracil)－氧嗪酸鉀(oteracil potassium)製劑、阿黴素(doxorubicin)、泛艾黴素(epirubicin)、鹽酸伊立替康(irinotecan)、依託泊苷(etoposide)、多烯紫衫醇(docetaxel)、紫杉醇(paclitaxel)、順鉑(cisplatin)、卡鉑(carboplatin)、奧沙利鉑(oxaliplatin)、雲芝多醣、香菇多醣、必醫你舒(picibanil)等。
以下，舉出實施例更詳細地說明本發明，但本發明並不限定於該等。
實施例1
就以下情形之神經毒性之發生頻率及治療效果進行研究：以3週1次於24小時中向癌症患者持續靜脈內投與以ECyd換算量計為2.80~8.56 mg/m2
之抗腫瘤劑作為1療程，而反覆施行；以及，以3週1次向癌症患者急速靜脈內投與以ECyd換算量計為2.81~9.46 mg/m2
之抗腫瘤劑作為1療程，而反覆施行。
本試驗，係以標準治療法無效或者無治療法之各種固體癌症(例如，消化器官腫瘤、頭頸部腫瘤、乳癌等)患者作為對象而施行，主要是評價安全性，相當於臨床第Ⅰ期試
驗，該臨床第Ⅰ期試驗係用來決定分別對各癌症實施的臨床第Ⅱ期試驗中不產生副作用可安全投與之最佳投與量(RD)。此時，於能夠進行評價之情形時，亦就對腫瘤之治療效果進行評價。對腫瘤之治療效果，係以RECIST之評價法(Journal of the National Cancer Institute，2000，Vol.92，No.3，205~216)作為參考，且以目標病變(能夠根據CT等的切片寬度進行測定的尺寸以上之病變)與非目標病變(目標病變以外之所有病變)之綜合性評價，來判定對腫瘤之縮小效果。於該試驗中，所謂PR(部分奏效)，係指各目標病變之長徑的總和顯示有投與前的總和30%以上的縮小，且於一定期間(通常4週)內維持其效果，其間未看見非目標病變的惡化之情形。所謂PD(進行)，係指與試驗開始以後所記錄的最小長徑和相比較，目標病變之長徑和增加20%以上，或者看見已有的非目標病變有明顯惡化或有新病變之情形。所謂SD(穩定)，係指成為PR中腫瘤的縮小並不充分，但成為PD卻並不充分，腫瘤停止發展，未看見惡化之情形。又，所謂MR(微效)，係指腫瘤之縮小未達30%，但維持與其相近的效果(15%左右的縮小)，或者暫時地顯示相當於PR的治療效果之症例。結果示於圖1。
於圖1中，表示將ECyd製劑(注射劑)施行3週1次急速靜脈內投與2.80~9.46 mg/m2
及24小時持續靜脈內投與之結果，於施行急速靜脈內投與之情形時，自2.81 mg/m2
之投與量起，3例中有2例(66%)看見末梢神經毒性，並未確認治療效果；於6.31 mg/m2
之投與量中，3例中有2例看見末
梢神經毒性，3例中有2例顯示有效性(SD以上)。另一方面，於施行持續靜脈內投與之情形時，於2.80 mg/m2
~5.48 mg/m2
之投與量中，並未看見末梢神經毒性，有效性(SD以上)為20~50%。
因此，提示向對標準治療無效或無治療法之各種固形癌(例如，消化器官癌、頭頸部腫瘤、乳癌等)患者持續靜脈內投與ECyd，係抑制末梢神經毒性的發生而且發揮高有效性之投與方法。
實施例2
研究以下情形之神經毒性之發生頻率及治療效果：於4週內，以重複3次1週1次於4小時中持續靜脈內投與以ECyd換算量計為1.30 mg/m2
之抗腫瘤劑作為1療程，而反覆施行；以及，於4週內，以重複3次1週1次急速靜脈內投與以ECyd換算量計為1.32 mg/m2
之抗腫瘤劑作為1療程，而反覆施行。再者，本試驗之對象患者、評價方法及評價標準與實施例1之試驗相同。
作為本試驗之結果，於施行急速靜脈內投與之情形時，3例中有1例(33%)看見末梢神經毒性，未確認有效性(SD以上)。另一方面，於施行持續靜脈內投與之情形時，3例中有1例(33%)看見末梢神經毒性，但有效性(SD以上)為66%。
因此，提示向標準治療無效或者無治療方法的各種固形癌(例如，消化器官癌、頭頸部腫瘤、乳癌等)患者持續靜脈內投與ECyd，係抑制末梢神經毒性的發生而且發揮高有
效性之投與方法。
實施例3
研究源自神經塉之大白鼠腎上腺髓質嗜鉻細胞瘤PC12株之ECyd接觸方案對細胞增殖抑制之影響。
於將AUC(接觸時間與ECyd濃度之積)設為同等，且維持與顯示接觸ECyd達100小時時IC80(0.08 μM)的效力之ECyd濃度為同等之AUC的各方案中，對播種於培養皿上的PC12株進行處理，然後交換細胞培養液。用結晶紫(crystal violet)測定其後之細胞增殖，結果示於圖2。
於接觸0.5小時中，PC12株之細胞增殖即使於6日後亦幾乎未恢復，將接觸時間設為25小時至100小時中，PC12株之細胞增殖顯示恢復，接觸時間愈長則細胞增殖的恢復愈快，因此判明神經細胞PC12株之細胞增殖抑制易受Cmax的影響，長時間接觸低濃度的ECyd，與短時間接觸高濃度的ECyd相比，細胞增殖抑制為輕度。
因此，可明瞭持續投與ECyd對神經細胞之細胞增殖的影響輕微。
實施例4
研究人類肺癌腫瘤A549株之ECyd接觸方案對細胞增殖抑制之影響。
於將AUC(接觸時間與ECyd濃度之積)設為同等，且維持與顯示接觸ECyd達100小時時之IC80(0.08 μM)的效力之ECyd濃度為相等的AUC之各方案中，對播種於培養皿上的A549株進行處理，然後交換細胞培養液。用結晶紫
(crystal violet)測定其後之細胞增殖，結果示於圖3。
於接觸0.5小時至接觸100小時中，A549株之細胞增殖即使於6日後亦幾乎未恢復。判明腫瘤細胞之細胞增殖抑制不受Cmax的影響。
因此，揭示ECyd之持續投與可發揮與急速投與同等的細胞增殖抑制效果。
由以上揭示，本發明之ECyd之持續投與，係不在發生末梢神經毒性下顯示高細胞增殖抑制效果之有效的癌症治療法。
圖1係對以3週1次急速靜脈內投與ECyd製劑之情形與持續靜脈內投與ECyd製劑之情形的癌症中作為劑量限制毒性之神經毒性的表現及治療效果進行比較之圖(PR：部分奏效，SD：穩定)。橫軸表示神經毒性發生或治療效果之頻率(%)。
圖2係表示源自神經塉之大白鼠腎上腺髓質嗜鉻細胞瘤PC12株之ECyd接觸方案對細胞增殖抑制的影響之圖。
圖3係表示人類肺癌腫瘤A549株之ECyd接觸方案對細胞增殖抑制的影響之圖。
Claims (6)
- 一種用於製備抗腫瘤劑之用途，該抗腫瘤劑係含有1-(3-C-乙炔基-β-D-核糖五呋喃糖基)胞嘧啶或其鹽者，且對癌症患者於2~336小時中持續靜脈內投與以1-(3-C-乙炔基-β-D-核糖五呋喃糖基)胞嘧啶換算量計每1次為1.30~8.56 mg/m2 之量。
- 如請求項1之用於製備抗腫瘤劑之用途，其係於4~72小時中所投與者。
- 如請求項1之用於製備抗腫瘤劑之用途，其係於24小時中所投與者。
- 如請求項1至3中任一項之用於製備抗腫瘤劑之用途，其係投與以1-(3-C-乙炔基-β-D-核糖五呋喃糖基)胞嘧啶換算量計每1次為2.80~8.56 mg/m2 之量。
- 如請求項1至3中任一項之用於製備抗腫瘤劑之用途，其係投與以1-(3-C-乙炔基-β-D-核糖五呋喃糖基)胞嘧啶換算量計每1次為6.85 mg/m2 之量。
- 一種1-(3-C-乙炔基-β-D-核糖五呋喃糖基)胞嘧啶或其鹽之用途，其係用於製造抗腫瘤劑者，該抗腫瘤劑係對癌症患者於2~336小時中持續靜脈內投與以1-(3-C-乙炔基-β-D-核糖五呋喃糖基)胞嘧啶換算量計每1次為1.30~8.56 mg/m2 量。
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| WO1996018636A1 (en) | 1994-12-13 | 1996-06-20 | Taiho Pharmaceutical Co., Ltd. | 3'-substituted nucleoside derivatives |
| RU2185172C2 (ru) * | 2000-04-10 | 2002-07-20 | Научно-исследовательский институт клинической иммунологии СО РАМН | Способ коррекции показателей крови и увеличения продолжительности жизни больных т-лимфолейкозом животных |
| JP3748536B2 (ja) * | 2001-02-09 | 2006-02-22 | 三共株式会社 | ピリミジンヌクレオシド誘導体の結晶 |
-
2007
- 2007-04-06 JP JP2007100676A patent/JP5066737B2/ja not_active Expired - Fee Related
-
2008
- 2008-04-03 TW TW097112411A patent/TWI401085B/zh not_active IP Right Cessation
- 2008-04-04 ES ES08738486T patent/ES2402954T3/es active Active
- 2008-04-04 RU RU2009140983/15A patent/RU2471486C2/ru not_active IP Right Cessation
- 2008-04-04 US US12/594,823 patent/US8642572B2/en not_active Expired - Fee Related
- 2008-04-04 JP JP2009508910A patent/JPWO2008126398A1/ja active Pending
- 2008-04-04 EP EP08738486A patent/EP2145625B1/en not_active Not-in-force
- 2008-04-04 WO PCT/JP2008/000874 patent/WO2008126398A1/ja not_active Ceased
Non-Patent Citations (3)
| Title |
|---|
| Hideshi Hattori et al., "Nucleosides and nucleotides. 158. 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)-cytosine, 1-(3-C-ethynyl-β-D-ribo-pentofuranosyl)uracil, and their nucleobase analogues as new potential multifunctional antitumor nucleosides with a broad spectrum of activity", J. Med. Chem., 1996, 39:5005-5011 * |
| Kazuo Ota, "Recent cancer chemotherapy" ,The journal of the Japanese society of internal medicine/the 84th meeting, 1987, 76(11):1658-1662 * |
| U.S. FDA, CDER, "Guidance for Industry, Estimating the maximum safe starting dose in initial clinical trials for therapeutics in adult healthy volunteers", July 2005 * |
Also Published As
| Publication number | Publication date |
|---|---|
| US20100120709A1 (en) | 2010-05-13 |
| US8642572B2 (en) | 2014-02-04 |
| EP2145625A1 (en) | 2010-01-20 |
| AU2008238724A1 (en) | 2008-10-23 |
| TW200846013A (en) | 2008-12-01 |
| JP2010024140A (ja) | 2010-02-04 |
| RU2471486C2 (ru) | 2013-01-10 |
| JPWO2008126398A1 (ja) | 2010-07-22 |
| ES2402954T3 (es) | 2013-05-10 |
| EP2145625A4 (en) | 2011-08-17 |
| JP5066737B2 (ja) | 2012-11-07 |
| RU2009140983A (ru) | 2011-05-20 |
| EP2145625B1 (en) | 2013-02-27 |
| WO2008126398A1 (ja) | 2008-10-23 |
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| MM4A | Annulment or lapse of patent due to non-payment of fees |