TWI622393B - 腫瘤診斷劑 - Google Patents
腫瘤診斷劑 Download PDFInfo
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- TWI622393B TWI622393B TW102102354A TW102102354A TWI622393B TW I622393 B TWI622393 B TW I622393B TW 102102354 A TW102102354 A TW 102102354A TW 102102354 A TW102102354 A TW 102102354A TW I622393 B TWI622393 B TW I622393B
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Abstract
本發明提供不僅可針對受檢者之腫瘤有無進行判定,亦可判別該腫瘤是為惡性腫瘤抑或良性腫瘤而為簡便且副作用或負擔較少且為低成本之腫瘤診斷劑及判定方法。該判定方法為將5-胺基乙醯丙酸(5-aminolevulinic acid)(ALA)或其衍生物或該等之鹽以ALA換算每1kg體重經口投與5~7mg,於投與4~12小時後採取尿試料。對於尿試料中之卟啉類及肌酸(creatine)進行定量,藉由將卟啉類量除以肌酸量之值(nmol/gCre)而判定未具有腫瘤者及具有良性腫瘤者與具有惡性腫瘤者之區別。以ALA換算對每1kg體重投與1~3mg之ALA類時,可明確判定受檢者有無惡性腫瘤。
Description
本發明係有關包含特定投與量之5-胺基乙醯丙酸(5-ALA)或其衍生物或其等之鹽(以下有時將該等合稱為“ALA類”)之腫瘤診斷劑,及藉由投與特定量之ALA類而區別惡性腫瘤與良性腫瘤之判定腫瘤有無之方法,及收集用以區別惡性腫瘤與良性腫瘤而診斷腫瘤有無之資料之方法。
就腫瘤之治療而言,最重要的是早期發現。迄今,腫瘤有無之判定已廣為使用檢測自癌細胞漏出至血中之物質腫瘤標記物之方法。然而腫瘤標記物大部份在正常細胞活動下仍產生少量,故有時於慢性發炎疾病等會顯示擬陽性。即使以陽性率被認為較高之腫瘤胚胎抗原(Carcinoembryonic Antigen:CEA)擬陽性率亦高如20%,以癌症篩檢被判定為陽性的人中以精密檢查後實際發現癌症之概率不過為1.5~4%。且早期癌症其腫瘤標記物大多未顯示高值,檢測感度並不充分。再者,腫瘤標記
物無法適當發現之癌症亦多,並未發現可精度良好地涵蓋所有腫瘤之腫瘤標記物。因此罹患早期癌症而以腫瘤標記物進行癌症檢診被判定為陰性之擬陰性之例亦多,現實狀況對於以腫瘤標記物判定或診斷癌症有無之本身有效性亦有疑問。
另一方面,已知若投與ALA類,則代謝物的原卟啉(proporphyrin)IX累積於腫瘤中而可利用於手術中診斷或治療(例如參考專利文獻1及2)。然而,該等方法中,有必要調製ALA類之同位體,且有必需將採取之體液(體液中所含之細胞)與5-ALA酯體混合,使混合物曝露於光中等之問題。
且以往,為了增加相關的累積卟啉量,認為若增加ALA類之投與量可提高診斷能及治療效率,故於臨床領域及基礎研究領域中,僅投與量之增量受到爭論。因此,已報導為使人類之癌細胞優先進行厭氧代謝,而將投與之ALA類作為血紅素(heme)或細胞色素(cytochrom)之前驅物的原卟啉IX累積於癌細胞(例如參考專利文獻3)。
關於ALA類投與(每1kg體重20mg)後,藉由所採取的試料中之尿卟啉I與尿卟啉III之量及其比,可明確區分腫瘤組織與正常組織,或分析自ALA類投與後之尿等之體內或體外採取之試料中之卟啉類,而診斷腫瘤有無之方法亦已被報導(例如參見專利文獻4)。然而,由於投與高濃度之ALA類而為非常高的成本,即
使經製劑化亦非可膠囊化之量,而必須服用強酸性之呈強酸味之水溶液,且有伴隨嘔吐及光過敏等之病痛之副作用等問題。再者,源自健康者之試料中亦常常見到卟啉類之濃度與腫瘤存在無關地上升之現象,故而雖然簡便但亦會出現擬陽性,而為作為診斷方法有致命問題之顧慮。
〔專利文獻1〕 特開平11-12197號公報
〔專利文獻2〕 特表平11-501914號公報
〔專利文獻3〕 特開2011-016753號公報
〔專利文獻4〕 特開2006-124372號公報
本發明之課題係提供不僅可針對受檢者之腫瘤有無進行判定,亦可判別該腫瘤是為惡性腫瘤抑或良性腫瘤而為簡便且副作用或負擔較少且為低成本之腫瘤診斷劑及判定方法。
本發明人等對使用ALA類以尿為試料進行腫瘤有無之判定中,針對試料採取時間與ALA類之最適投與量之關係重複積極檢討後,完全出乎意料地發現於比以往更為降低投與量進行投與時,可獲得除了腫瘤有無判定
以外亦可提高惡性度判定之預測之較佳結果。亦即,於睡前投與ALA類,於隔天起床後採取第一泡尿,並測定尿中卟啉量及尿中肌酸(creatine)量,使用該等值進行演算分析時,投與以往之大致1/4左右之5-ALA換算每1kg體重6mg之ALA類時,發現可區別未具有腫瘤者、具有良性腫瘤者及具有惡性腫瘤者,進而,投與以往之大致1/12左右之5-ALA換算每1kg體重2mg之ALA類時,確認亦可明確地判定受檢者有無惡性腫瘤。本發明係基於該等見解因而完成本發明。
亦即,本發明係關於[1]一種腫瘤診斷劑,其係包含以通式(1)表示之5-ALA或其衍生物或該等之鹽(以下有時將該等合稱為“本發明之ALA類”)之腫瘤診斷劑:R2R1NCH2COCH2CH2COR3 (1)
〔式中,R1及R2各獨立表示氫原子、碳數1~24之烷基、碳數1~12之醯基、碳數2~13之烷氧基羰基、碳數6~16之芳基或碳數7~22之芳烷基;R3表示羥基、碳數1~24之烷氧基、碳數1~12之醯氧基、碳數2~13之烷氧基羰氧基、碳數6~16之芳氧基、碳數7~22之芳烷氧基或胺基〕,其經口投與量係以5-ALA換算每1kg體重為1~7mg,且藉由測定於經口投與後採取之尿試料中之卟啉類量而用以判定腫瘤之有無及惡性度,及〔2〕如上述〔1〕之腫瘤診斷劑,其中經口投與量係以5-ALA換算每1kg體重為5~7mg。
且作為本發明之實施樣態,係有關〔3〕一
種判定腫瘤之有無及惡性度之方法(以下有時稱為“判定方法〔I〕”)或收集用於該判定之資料之方法,其包含以下(a)~(c)之各步驟:(a)對受檢者以5-ALA換算每1kg體重經口投與5~7mg之以通式(1)表示之5-ALA或其衍生物或該等之鹽(本發明之ALA類)之步驟:R2R1NCH2COCH2CH2COR3 (1)
〔式中,R1及R2各獨立表示氫原子、碳數1~24之烷基、碳數1~12之醯基、碳數2~13之烷氧基羰基、碳數6~16之芳基或碳數7~22之芳烷基;R3表示羥基、碳數1~24之烷氧基、碳數1~12之醯氧基、碳數2~13之烷氧基羰氧基、碳數6~16之芳氧基、碳數7~22之芳烷氧基或胺基〕;(b)於投與4~12小時後採取尿試料之步驟;(c)測定尿試料中卟啉類量之步驟;及〔4〕如上述〔3〕之方法,其進而具備以下之(d)步驟:(d)測定尿試料中之肌酸量,將(c)步驟中測定之卟啉類量除以前述肌酸量而算出卟啉類修正值(nmol/gCre)之步驟;〔5〕如上述〔4〕之方法,其進而具備以下之(e)步驟:(e)基於卟啉類修正值,於5000 nmol/gCre以上時判定受檢者為具有惡性腫瘤者,於2500 nmol/gCre以上、未達5000 nmol/gCre時判定受檢者為具有良性腫瘤者,及於未達2500nmol/gCre時判定受檢者為不具有腫瘤者之步驟。
進而本發明之實施樣態,係提供〔6〕一種
判定腫瘤之有無及惡性度之方法(以下亦有時稱為“判定方法(II)”)或收集用於該判定之資料之方法,其包含以下(f)~(h)之各步驟:(f)對受檢者以5-ALA換算每1kg體重經口投與1~3mg之以通式(1)表示之5-ALA或其衍生物或該等之鹽(本發明之ALA類)之步驟:R2R1NCH2COCH2CH2COR3 (1)
〔式中,R1及R2各獨立表示氫原子、碳數1~24之烷基、碳數1~12之醯基、碳數2~13之烷氧基羰基、碳數6~16之芳基或碳數7~22之芳烷基;R3表示羥基、碳數1~24之烷氧基、碳數1~12之醯氧基、碳數2~13之烷氧基羰氧基、碳數6~16之芳氧基、碳數7~22之芳烷氧基或胺基〕;(g)於投與4~12小時後採取尿試料之步驟;(h)測定尿試料中卟啉類量之步驟;及〔7〕如上述〔6〕之方法,其進而具備以下之(i)步驟:(i)測定尿試料中之肌酸量,將(h)步驟中測定之卟啉類量除以前述肌酸量而算出卟啉類修正值(nmol/gCre)之步驟;及〔8〕如上述〔7〕之方法,其進而具備以下之(j)步驟:(j)於卟啉類修正值為2000 nmol/gCre以上時判定受檢者為具有惡性腫瘤者,於未達2000 nmol/gCre時判定受檢者為不具有惡性腫瘤者之步驟。
且,本發明之判定方法為輔助醫師診斷之方法,不包含醫師之診斷行為。
投與本發明之特定投與量的腫瘤診斷劑時,由於在正常細胞中ALA類會迅速代謝為血紅素及細胞色素,故漏出於尿中之卟啉類相較於腫瘤細胞會侷限於低濃度。因此,使用本發明之腫瘤診斷劑時,投與量比以往更為減少反而擬陽性亦減少,而可針對受檢者之腫瘤有無區別惡性腫瘤與良性腫瘤並加以診斷,而可容易地進行腫瘤之早期發現、治療效果之追蹤、預後之診斷,且自副作用之觀點而言,亦可減輕受檢者之負擔。再者,由於僅在就寢前服用,採取起床時自然排尿之尿即可準備試料,故判定所需之拘束時間少,而可減輕受檢者之負擔而診斷腫瘤之有無。
圖1為表示自以5-ALA換算投與100mg或300mg之本發明腫瘤診斷劑之受檢者中採取之尿中的卟啉類修正值的圖表。
圖2為表示自以5-ALA換算投與1g之本發明腫瘤診斷劑之受檢者中採取之尿中的卟啉類修正值的圖表。
本發明之腫瘤診斷劑只要係藉由測定經口投與後所採取之尿試料中之卟啉類量而用以判定腫瘤之有無及惡性度之腫瘤診斷劑,且包含以通式(1)表示之ALA或其衍生物或該等之鹽(本發明之ALA類),
R2R1NCH2COCH2CH2COR3 (1)
〔式中,R1及R2各獨立表示氫原子、碳數1~24之烷基、碳數1~12之醯基、碳數2~13之烷氧基羰基、碳數6~16之芳基或碳數7~22之芳烷基;R3表示羥基、碳數1~24之烷氧基、碳數1~12之醯氧基、碳數2~13之烷氧基羰氧基、碳數6~16之芳氧基、碳數7~22之芳烷氧基或胺基〕,且經口投與量係以5-ALA換算每1kg體重為1~7mg之腫瘤診斷劑,則並無特別限制,但較好經口投與量以5-ALA換算每1kg體重為5~7mg或1~3mg,更好為5~7mg。
至於上述碳數1~24之烷基,可舉例為碳數1~24之直鏈或分支鏈之烷基,較好為碳數1~18之烷基,最好為碳數1~6之烷基。碳數1~6之烷基具體例可舉例為甲基、乙基、正丙基、異丙基、正丁基、第二丁基、第三丁基、正戊基、正己基等。
至於上述碳數1~12之醯基,可舉例為碳數1~12之直鏈或分支鏈之烷醯基、碳數3~12之直鏈或分支鏈烯基羰基、碳數5~12之單環式或多環式芳醯基或碳數5~12之單環式或多環式芳氧基羰基,最好為碳數1~6之烷醯基,具體可舉例為甲醯基、乙醯基、丙醯基、丁醯基、戊醯基等。且,上述碳數1~12之醯基中之碳數係包含羰基之碳。
至於上述碳數2~13之烷氧基羰基,較好為碳數2~7之烷氧基羰基,具體可舉例為甲氧基羰基、乙氧基
羰基、正丙氧基羰基、異丙氧基羰基、丁氧基羰基、戊氧基羰基、己氧基羰基、庚氧基羰基、辛氧基羰基、壬氧基羰基、癸氧基羰基、十一烷氧基羰基、十二烷氧基羰基。且,上述碳數2~13之烷氧基羰基中之碳數係包含羰基之碳。
至於上述碳數6~16之芳基可舉例為單環式或多環式芳基,具體可舉例為苯基、萘基、蒽基、菲基、芘基等。
至於上述碳數7~22之芳烷基可舉例為由上述碳數6~16之芳基與上述碳數1~6之烷基所成之基,具體可舉例為苄基、苯乙基等。
至於上述碳數1~24之烷氧基可舉例為碳數1~24之直鏈或分支鏈之烷氧基,較好為碳數1~16之烷氧基,最好為碳數1~12之烷氧基。具體可舉例為甲氧基、乙氧基、正丙氧基、異丙氧基、正丁氧基、戊氧基、己氧基、辛氧基、癸氧基、十二烷氧基等。
至於上述碳數1~12之醯氧基可舉例為碳數1~12之直鏈或分支鏈之烷醯氧基,較好為碳數1~6之烷醯氧基。具體可舉例為乙醯氧基、丙醯氧基、丁醯氧基、戊醯氧基等。
至於上述碳數2~13之烷氧基羰氧基較好為碳數2~7之烷氧基羰氧基,具體可舉例為甲氧基羰氧基、乙氧基羰氧基、正丙氧基羰氧基、異丙氧基羰氧基、丁氧基羰氧基、戊氧基羰氧基、己氧基羰氧基等。又,上述碳數
2~13之烷氧基羰氧基中之碳數係包含羰基之碳。
至於上述碳數6~16之芳氧基可舉例為單環式或多環式芳氧基,具體可舉例為苯氧基、萘氧基、蒽氧基、菲氧基、芘氧基等。至於碳數7~22之芳烷氧基較好為具有前述芳烷基者,具體可舉例為苄氧基、苯乙氧基等。
通式(1)中,作為R1及R2較好為氫原子。作為R3較好為羥基、烷氧基或芳烷氧基,更好為羥基或碳數1~12之烷氧基,最好為甲氧基或己氧基。
通式(1)中,R1及R2為氫原子,R3為羥基之化合物為5-ALA,為最佳之例舉。5-ALA以外之5-ALA衍生物之較佳例可舉例為5-ALA甲酯、5-ALA乙酯、5-ALA丙酯、5-ALA丁酯、5-ALA戊酯、5-ALA己酯等之5-ALA酯,最好可例舉5-ALA甲酯或5-ALA己酯。又,5-ALA之酯體顯示與5-ALA同樣之生理效果則揭示於例如特表平11-501914號公報。
至於5-ALA或5-ALA衍生物之藥理學上容許之鹽,可舉例為藥理學上容許之酸加成鹽、金屬鹽、銨鹽、有機胺加成鹽等。作為酸加成鹽可舉例為例如鹽酸鹽、氫溴酸鹽、氫碘酸鹽、磷酸鹽、硝酸鹽、硫酸鹽等之各種無機鹽,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、甲烷磺酸鹽、丁酸鹽、戊酸鹽、檸檬酸鹽、富馬酸鹽、馬來酸鹽、蘋果酸鹽等之各種有機酸加成鹽。作為金屬鹽,可舉
例為鋰鹽、鈉鹽、鉀鹽等之各鹼金屬鹽,鎂、鈣等之各鹼土金屬鹽,鋁、鋅等之各金屬鹽。作為銨鹽,可舉例為銨鹽、四甲基銨鹽等之烷基銨鹽等。作為有機胺鹽,可舉例為三乙胺鹽、哌啶鹽、嗎啉鹽、甲苯胺鹽等之各鹽。
5-ALA或5-ALA衍生物亦可利用化學合成、利用微生物之生產、利用酵素之生產之任一方法製造。例如5-ALA衍生物之胺基中之醯基或羧基中之酯基等,可利用化學合成之一般方法,藉由使胺基之醯化或羧基之酯化等而製造。且取得5-ALA或5-ALA衍生物之鹽時,於通式(1)所示之化合物以鹽之形態獲得時,只要直接純化即可,且以游離形態獲得時,只要藉由溶解或懸浮於適當有機溶劑中,並添加酸或鹼之通常方法形成鹽即可。本發明之ALA類有時亦以與水或各種溶劑之加成物形態存在,該等加成物亦可使用作為本發明之腫瘤診斷劑。
作為本發明之腫瘤診斷劑,可適當組合2種以上之本發明之ALA類使用。例如單獨使用或組合2種以上使用5-ALA、5-ALA甲酯、5-ALA乙酯、5-ALA丙酯、5-ALA丁酯、5-ALA戊酯等之各種5-ALA酯類,以及該等之鹽酸鹽、磷酸鹽、硫酸鹽等。
本發明之ALA類可利用一般方法作成適當製劑。至於製劑之劑型,宜為散劑、顆粒劑等之固體製劑,但基於使用簡便之觀點,較好成為溶液劑、乳劑、懸浮劑等之液劑。前述液劑之製造方法,可較好地例示為例如將本發明之ALA類與溶劑混合之方法,進而例示為混合懸
浮劑或乳化劑之方法。如以上,將本發明之ALA類作成製劑時,依據製劑化之需要,可調配適當擔體例如賦型劑、結合劑、溶劑、溶解助劑、懸浮劑、乳化劑、等張劑、緩衝劑、安定化劑、無痛化劑、防腐劑、抗氧化劑、著色劑、滑澤劑、崩解劑、濕潤劑、吸附劑、甜味劑、稀釋劑等之任意成分。
本發明之腫瘤有無及惡性度之判定方法中,上述判定方法〔I〕係具有對受檢者以5-ALA換算每1kg體重5~7mg經口投與本發明之ALA類,而判定腫瘤之有無及惡性度方面之特徵,上述判定方法〔II〕係具有對受檢者以5-ALA換算每1kg體重1~3mg經口投與本發明之ALA類,而判定惡性腫瘤之有無方面之特徵。
判定方法〔I〕中之步驟(a)為對受檢者以5-ALA換算每1kg體重經口投與5~7mg之本發明之ALA類之步驟,至於投與時期,基於可在起床時採取尿而對受檢者負擔較小方面而言,期望在就寢前投與。
判定方法〔I〕中之步驟(b)為於本發明之ALA類投與4~12小時後採取尿試料之步驟,至於上述4~12小時後之尿試料,可舉例在本發明之ALA類投與後4~12小時之任意時間採尿之“自然排尿試料”或“以導管等採尿之試料”。上述採取之次數可為一次,亦可為複數次採取,基於對受檢者之負擔較少方面,較好在就寢前投與本發明之ALA類,並在起床時採取自然排尿之尿試料。由於尿中之卟啉類會因光及溫度而受到影響,故較好採取
後立即測定卟啉類量。採取後未立即測定卟啉類時,較好在遮光條件下進行保存,至於保存溫度較好為1~25℃,更好為2~10℃,其中最好為4℃。且,較好同時測定卟啉類量及肌酸量。
判定方法〔I〕中之步驟(c)為測定尿試料中卟啉類量之步驟,至於本發明中被測定之卟啉(類)可舉例為例如原卟啉IX、尿卟啉I、尿卟啉III、輔卟啉(coporphyrin)I、輔卟啉III、七羧基卟啉I、七羧基卟啉III、六羧基卟啉I、六羧基卟啉III、五羧基卟啉I、五羧基卟啉III、異輔原卟啉(isocoproporphyrin)、副卟啉(harderoporphyrin)、異副卟啉、介卟啉(mesoporphyrin)IX、次卟啉(deuteroporphyrin)IX、pemptoporphyrin,其中可較好舉例為原卟啉IX、尿卟啉I、尿卟啉III、輔卟啉I、輔卟啉III。
作為測定上述卟啉類量之方法,若為可對卟啉類定量之方法,則未特別限制,可依據目的或簡便性適當選擇,可利用HPLC(高速液體層析法)、TLC(薄層層析法)、使用螢光檢測器之螢光HPLC檢測法、免疫分析法等之生物學檢測法等而測定,但較好為螢光HPLC檢測法。
上述螢光HPLC檢測法中,卟啉類可以激發波長為350~500 nm且螢光波長為550~750nm,較好激發波長為380~440nm且螢光波長為590~690nm,更好為激發波長為400~410nm且螢光波長為610~640nm進行檢
測。具體而言,可例示下述方法:於受檢尿試料200μL中添加碘-乙酸混合溶液(1/1,v/v),以渦流混合後,以10000rpm離心10分鐘後,將採取之上清液20μL注入HPLC儀器中,以流速1.0mL/min、管柱溫度40℃進行測定,使用螢光檢測器,算出卟啉類濃度之方法。
上述判定方法〔I〕較好進而具備測定尿試料中之肌酸量,將(c)步驟中測定之卟啉類量除以前述肌酸量而算出卟啉類修正值(nmol/gCre)之上述步驟(d)。尿中之水分濃度由於會受食物攝取之有無、水分攝取之多寡、出汗之多寡等生理變動因素之影響而變動幅度較大,且由於卟啉類量之評價中僅依成分濃度而評價亦有過小或過大評價之可能性,故有必要進行濃度修正,作為該修正方法,已知有與尿中成分同時測定尿量,算出1天排泄量而進行修正之方法,或與尿中成分同時定量尿中量變動較少之成為基準的物質,而修正目的成分濃度之方法,但使用成為基準之物質時,已廣泛使用自腎臟排出過程中被腎小管再吸收較少、不易受生理變動因素影響之較多量存在、依成人其產生量每kg體重大致為一定之肌酸。具體而言,藉由測定本發明中使用之尿試料中之肌酸量,將(c)步驟中測定之卟啉類量除以肌酸量,進行所謂之“肌酸修正”,以卟啉類修正量(nmol/gCre)進行判定。且作為尿試料中肌酸量之測定方法,可使用已確立之傑夫(Jaffe)法或酵素法(肌酸酶-肌胺酸氧化酶-POD法)等,但一般係使用檢測感度高之套組而被多數銷售之
酵素法。
上述判定方法〔I〕較好進而具備基於上述步驟(d)中算出之卟啉類修正值,進行腫瘤有無及惡性度之判定之步驟(e),於與不具有腫瘤者之陰性對照尿試料中之卟啉類修正值比較時,於受檢者之卟啉類修正值顯著有意義較高時,可判定受檢者為具有惡性腫瘤者,於有意義較高時可判定受檢者為具有良性腫瘤者,於無有意義差時,可判定受檢者為不具有腫瘤者。具體而言,基於卟啉類修正值,於5000nmol/gCre以上時可判定受檢者為具有惡性腫瘤者,於2500nmol/gCre以上、未達5000 nmol/gCre時可判定受檢者為具有良性腫瘤者,及於未達2500nmol/gCre時可判定受檢者為不具有腫瘤者。
判定方法〔II〕中,步驟(f)中,除了對受檢者以5-ALA換算每1kg體重經口投與1~3mg之本發明之ALA類以外,接續步驟(f)進行之步驟(g)~(i)係分別與前述判定方法〔I〕之步驟(b)~(d)對應,可基於該等進行。
上述判定方法〔II〕較好進而具備基於上述步驟(i)中算出之卟啉類修正值,進行腫瘤有無及惡性度之判定之步驟(j),於與不具有腫瘤者之陰性對照尿試料中之卟啉類修正值比較時,於受檢者之卟啉類修正值有意義較高時,可判定受檢者為具有惡性腫瘤者,於無有意義差時,可判定受檢者並非距有惡性腫瘤者而為不具有腫瘤者。具體而言,基於卟啉類修正值,於2000
nmol/gCre以上時可判定受檢者為具有惡性腫瘤者,於未達2000 nmol/gCre時可判定受檢者判定為具有良性腫瘤者或不具有惡性腫瘤者。
判定方法〔II〕中,在上述步驟(j)中被判定為不具有惡性腫瘤者之受檢者,可進而使用上述判定方法〔I〕進行判定。亦即,以ALA換算每1kg體重經口投與5~7mg之ALA類,投與4~12小時後採取尿試料,基於尿試料中之卟啉類修正值,可判定受檢者為具有腫瘤者或為不具有腫瘤者。
至於本發明之收集用以判定腫瘤之有無及惡性度之資料的方法,可例示為包含以下(1)~(4)之各步驟之方法:1)對受檢者以5-ALA換算每1kg體重經口投與5~7mg或1~3mg之上述腫瘤診斷劑之步驟;2)於投與4~12小時後採取尿試料之步驟;3)測定尿試料中卟啉類量之步驟;4)測定尿試料中之肌酸量,將步驟3)中測定之卟啉類量除以前述肌酸量而算出卟啉類修正值(nmol/gCre)之步驟。
成為本發明之腫瘤診斷劑或判定方法或收集用於判定之資料之方法的對象之腫瘤,可大致分為惡性腫瘤及良性腫瘤。以浸潤來看,作為已轉移腫瘤的惡性腫瘤可舉例為惡性黑色素瘤(melanoma)、皮膚癌、肺癌、氣管及支氣管癌、口腔上皮癌、食道癌、胃癌、結腸癌、直腸癌、大腸癌、肝臟及肝內膽管癌、腎癌、胰臟癌、前列腺癌、乳癌、子宮頸癌、卵巢癌、腦腫瘤等之上皮細胞等
惡化性之癌,亦即惡性腫瘤、骨肉瘤(osteosarcoma)、肌肉瘤等之支持組織構成細胞惡性化之癌,此外,作為自律地增生但僅於發生部位增生之腫瘤的良性腫瘤可例示乳頭瘤、腺瘤、囊腺瘤等之由上皮性細胞發生者,與纖維瘤、黏液瘤、脂肪瘤、軟骨瘤、骨瘤、橫紋肌瘤、平滑肌瘤、血管瘤等之自非上皮性細胞發生者。至於惡性腫瘤或良性腫瘤存在之組織並未特別限定,但可舉例為腦、眼球、鼻道、鼻腔、氣管、支氣管、口腔、咽喉、食道、胃、乳房、結直腸、肺、卵巢、中樞神經系統、肝臟、膀胱、尿道、輸尿管、胰臟、頸管、腹腔、肛門、子宮頸、生殖器、腎臟、前列腺、肌肉、骨、造血細胞。
以下,藉由實施例更具體說明本發明,但本發明之技術範圍並不限定於該等例示者。
針對特別是以健康診斷未見到異常之健康人受試者7名、由醫師診斷為癌之具有惡性腫瘤之受試者1名合計8名進行調查。各人之平均體重為50kg。於就寢前服用於膠囊中封入有100mg之5-ALA者1膠囊,指示於起床時採取第一泡尿。且於他日,於就寢前服用100mg之5-ALA膠囊3膠囊,指示於起床時採取第一泡尿。
於所採取之尿試料200μL中,添加200μL之0.08%碘-乙酸混合溶液(1/1,v/v),以渦流混合後,於4℃以10000rpm離心10分鐘。採取經離心溶液之上清液,將各20μL注入HPLC儀器(Shimadzu LC-10A VP)
中。作為管柱,係使用CAPCELL PAK C18 AG120(4.6mm×250mm,5μm(島津JLC(股)製))。作為移動相,使用設定為A:12.5%乙腈、1M乙酸銨(pH5.15)與B:80%乙腈、50mM乙酸銨(pH5.15),梯度:第0~5分鐘為等強度(isocratic)A100%;第5~30分鐘為線性梯度A100%-0%、B0-100%;第30~40分鐘為等強度B100%;第40~41分鐘為線性梯度A0-100%、B100-0%;第41-50分鐘為等強度A100%之系統;測定係以流速1.0mL/min、管柱溫度40℃進行。檢測波長設為激發波長(Ex)404nm,螢光波長(Em)620nm。
使用另外準備之標準溶液,藉內部標準法作成校正線及算出定量結果等之資料處理係使用LC-solution(版本1.21 SP1)(島津股份有限公司)進行,自標準溶液之波峰面積算出各試料之各卟啉濃度,卟啉類量係以尿中之尿卟啉I、III、輔原卟啉I、III之量之合計值求得。
試料係使用CicaLiquid-S CRE(關東化學股份有限公司製),測定儀器係使用自動分析裝置JCA-BM12(日本電子股份有限公司製),以酵素法亦使用同一尿試料測定肌酸量,算出卟啉類修正值。又,測定未投與5-ALA時之各人尿試料中之卟啉量及肌酸量,算出卟啉類修正值作為對照組。結果示於圖1。
(結果)
將圖1之X軸為服用之5-ALA投與量,Y軸為所測定之卟啉類量除以肌酸量之值設為尿中卟啉類修正值(nmol/gCre)進行作圖。上述8名中,投與300mg之5-ALA時,具有惡性腫瘤者之尿中卟啉濃度值超過5000 nmol/gCre。健康人受試者6名之尿中卟啉濃度值未達2500 nmol/gCre,但健康受試者中之剩餘1名之尿中卟啉濃度值為3500 nmol/gCre左右。本檢查實施後,該受檢者經醫師診察接受精密儀器檢查後,發現子宮肌瘤,明確為具有良性腫瘤者。
另一方面,投與100mg之5-ALA時,具有惡性腫瘤者之尿中卟啉濃度之值,相較於健康人受試者7名之值,有意義較高為超過3000 nmol/gCre。因此,確認藉由每1kg體重投與2mg/kg之5-ALA,可明確區別具有惡性腫瘤者與具有惡性腫瘤者以外者。
由以上結果,顯示藉由投與300mg,可區別腫瘤之有無以及區別惡性腫瘤與良性腫瘤。且,顯示藉由投與100mg之5-ALA,可檢出惡性腫瘤。且,投與5-ALA所有人中,並未見到胃部不舒適感及作嘔。
針對特別是以健康診斷未見到異常之健康人受試者5名、與由醫師診斷為癌之具有惡性腫瘤之受試者5名合計10名,使其等服用1g之5-ALA,服用後0小時、4小時、8小時採取隨時尿,對各者算出卟啉修正值
(nmol/gCre),將服用後0小時、4小時、8小時之隨時尿之尿卟啉I、III、輔原卟啉I、III之量合計之量作為每個人之卟啉類修正量。結果示於圖2。其結果,無法明確區別不具有腫瘤者(H1~H5)與具有惡性腫瘤者(C1~C5)。本資料為服用如以往一般所用之1g之高濃度5-ALA時,顯示出現擬陽性之結果,為證明本發明中投與量之最適化優異之結果。且,有數名見到胃部不舒適感及作嘔。
Claims (7)
- 一種製造以通式(1)表示之5-胺基乙醯丙酸或其衍生物或該等之鹽的腫瘤診斷劑之用途,R2R1NCH2COCH2CH2COR3 (1)〔式中,R1及R2各獨立表示氫原子、碳數1~24之烷基、碳數1~12之醯基、碳數2~13之烷氧基羰基、碳數6~16之芳基或碳數7~22之芳烷基;R3表示羥基、碳數1~24之烷氧基、碳數1~12之醯氧基、碳數2~13之烷氧基羰氧基、碳數6~16之芳氧基、碳數7~22之芳烷氧基或胺基〕,其係藉由測定尿試料中之卟啉類量而判定腫瘤之有無及惡性度。
- 如請求項1之製造以通式(1)表示之5-胺基乙醯丙酸或其衍生物或該等之鹽的腫瘤診斷劑之用途,該腫瘤診斷劑之經口投與量係以5-胺基乙醯丙酸換算每1kg體重為1~7mg,且藉由測定於經口投與後採取之尿試料中之卟啉類量而判定腫瘤之有無及惡性度。
- 如請求項1或2之製造以通式(1)表示之5-胺基乙醯丙酸或其衍生物或該等之鹽的腫瘤診斷劑之用途,其中經口投與量係以5-胺基乙醯丙酸換算每1kg體重為5~7mg。
- 一種腫瘤之檢出方法或收集用於判定腫瘤之有無及惡性度之資料之方法,其包含以下(a)~(c)之各步驟:(a)對受檢者以5-胺基乙醯丙酸換算每1kg體重經口投與5~7mg之以通式(1)表示之5-胺基乙醯丙酸或其衍生物或該等之鹽之步驟:R2R1NCH2COCH2CH2COR3 (1)〔式中,R1及R2各獨立表示氫原子、碳數1~24之烷基、碳數1~12之醯基、碳數2~13之烷氧基羰基、碳數6~16之芳基或碳數7~22之芳烷基;R3表示羥基、碳數1~24之烷氧基、碳數1~12之醯氧基、碳數2~13之烷氧基羰氧基、碳數6~16之芳氧基、碳數7~22之芳烷氧基或胺基〕;(b)於投與4~12小時後採取尿試料之步驟;(c)測定尿試料中卟啉類量之步驟。
- 如請求項4之方法,其進而具備以下之(d)步驟:(d)測定尿試料中之肌酸(creatine)量,將(c)步驟中測定之卟啉類量除以前述肌酸量而算出卟啉類修正值(nmol/gCre)之步驟。
- 一種腫瘤之檢出方法或收集用於判定腫瘤之有無及惡性度之資料之方法,其包含以下(f)~(h)之各步驟:(f)對受檢者以5-胺基乙醯丙酸換算每1kg體重經口投與1~3mg之以通式(1)表示之5-胺基乙醯丙酸或其衍生物或該等之鹽之步驟:R2R1NCH2COCH2CH2COR3 (1)〔式中,R1及R2各獨立表示氫原子、碳數1~24之烷基、碳數1~12之醯基、碳數2~13之烷氧基羰基、碳數6~16之芳基或碳數7~22之芳烷基;R3表示羥基、碳數1~24之烷氧基、碳數1~12之醯氧基、碳數2~13之烷氧基羰氧基、碳數6~16之芳氧基、碳數7~22之芳烷氧基或胺基〕;(g)於投與4~12小時後採取尿試料之步驟;(h)測定尿試料中卟啉類量之步驟。
- 如請求項6之方法,其進而具備以下之(i)步驟:(i)測定尿試料中之肌酸(creatine)量,將(h)步驟中測定之卟啉類量除以前述肌酸量而算出卟啉類修正值(nmol/gCre)之步驟。
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