中华血液学杂志
中華血液學雜誌
중화혈액학잡지
Chinese Journal of Hematology
2012年
3期
177-182
,共6页
钟健生%孟凡义%徐丹%周红升%戴敏
鐘健生%孟凡義%徐丹%週紅升%戴敏
종건생%맹범의%서단%주홍승%대민
伊马替尼%白血病,髓样,慢性%血药浓度
伊馬替尼%白血病,髓樣,慢性%血藥濃度
이마체니%백혈병,수양,만성%혈약농도
Imatinib%Leukemia,myeloid,chronic%Plasma concentration
目的 研究慢性髓系白血病(CML)患者用伊马替尼(IM)治疗期间的血浆谷浓度、骨髓细胞内浓度、骨髓细胞hOCT1和ABCB1基因的mRNA表达水平与疗效的关系及其影响因素.方法 CML慢性期患者80例,男56例,女24例,中位年龄39.5 (6～76)岁.IM中位剂量为400( 200～800) mg/d,中位疗程24(3～90)个月.有28例患者在检测血药浓度的同时检测其骨髓细胞内IM浓度,36例用实时定量RT-PCR法检测骨髓细胞hOCT1及ABCB1基因mRNA的表达,IM浓度检测采用高效液相色谱-质谱串联法,检测范围为2～10 000 μg/L,采用免疫比浊法同时检测血清α1-酸性糖蛋白(AGP)水平.按疗效分为主要分子遗传学缓解(MMR)组、完全细胞遗传学缓解(CCyR)组、部分细胞遗传学缓解(PCyR)组及耐药组.结果 80例患者IM血浆谷浓度为(1274.1±559.1)(109.0～3400.0)μg/L.其中59例(73.8％)患者IM剂量为400 mg/d,其血浆谷浓度为(1252.0±569.5)(109.0～3400.0)μg/L,包括37例(62.7％)浓度≥1000 μg/L,9例(15.3％)浓度≥800～1000 μg/L.MMR组IM血药谷浓度为(1533.9±634.1)μg/L,高于PCyR组[(812.8±480.3)μg/L]及耐药组[( 875.2±243.1)μg/L](P值均＜0.05)；CCyR组[(1288.4±498.2)μg/L]高于PCyR组(P=0.027)；MMR组与CCyR组比较,差异无统计学意义(P=0.136).CCyR组患者骨髓细胞内中位IM浓度[12.6(2.4～90.4)μg/L]高于耐药组[6.6(2.6～111.0)μg/L]和PCyR组[2.7(2.4～4.7)μg/L](P =0.013).CCyR组患者骨髓细胞hOCT1基因mRNA的中位相对表达水平[25.9(0.7～123.9)×10-5]高于耐药组[7.8(2.5～33.5)×10-5]和PCyR组[4.2(1.4～11.9)×10-5](P=0.036).耐药组患者骨髓细胞ABCB1基因mRNA相对中位表达水平[136.7(15.0-604.9)×10-5]高于CCyR组[129.1(12.9 ～783.3) ×10-5]和PCyR组[34.4(2.2～108.2)×10-5](P=0.013).IM血浆谷浓度与剂量及AGP呈正相关(r值分别为0.446和0.346,P值分别为0.000和0.002)；与身高、体重、体表面积无显著相关性(P值均＞0.05).不同疗程之间IM谷浓度差异无统计学意义(P值均＞0.05).结论 检测CML患者IM血浆谷浓度和骨髓细胞内谷浓度水平有助于判断疗效和指导治疗.同时检测血清AGP和骨髓细胞hOCT1和ABCB1基因mRNA表达水平有助于理解疗效与IM浓度之间的机制.
目的 研究慢性髓繫白血病(CML)患者用伊馬替尼(IM)治療期間的血漿穀濃度、骨髓細胞內濃度、骨髓細胞hOCT1和ABCB1基因的mRNA錶達水平與療效的關繫及其影響因素.方法 CML慢性期患者80例,男56例,女24例,中位年齡39.5 (6～76)歲.IM中位劑量為400( 200～800) mg/d,中位療程24(3～90)箇月.有28例患者在檢測血藥濃度的同時檢測其骨髓細胞內IM濃度,36例用實時定量RT-PCR法檢測骨髓細胞hOCT1及ABCB1基因mRNA的錶達,IM濃度檢測採用高效液相色譜-質譜串聯法,檢測範圍為2～10 000 μg/L,採用免疫比濁法同時檢測血清α1-痠性糖蛋白(AGP)水平.按療效分為主要分子遺傳學緩解(MMR)組、完全細胞遺傳學緩解(CCyR)組、部分細胞遺傳學緩解(PCyR)組及耐藥組.結果 80例患者IM血漿穀濃度為(1274.1±559.1)(109.0～3400.0)μg/L.其中59例(73.8％)患者IM劑量為400 mg/d,其血漿穀濃度為(1252.0±569.5)(109.0～3400.0)μg/L,包括37例(62.7％)濃度≥1000 μg/L,9例(15.3％)濃度≥800～1000 μg/L.MMR組IM血藥穀濃度為(1533.9±634.1)μg/L,高于PCyR組[(812.8±480.3)μg/L]及耐藥組[( 875.2±243.1)μg/L](P值均＜0.05)；CCyR組[(1288.4±498.2)μg/L]高于PCyR組(P=0.027)；MMR組與CCyR組比較,差異無統計學意義(P=0.136).CCyR組患者骨髓細胞內中位IM濃度[12.6(2.4～90.4)μg/L]高于耐藥組[6.6(2.6～111.0)μg/L]和PCyR組[2.7(2.4～4.7)μg/L](P =0.013).CCyR組患者骨髓細胞hOCT1基因mRNA的中位相對錶達水平[25.9(0.7～123.9)×10-5]高于耐藥組[7.8(2.5～33.5)×10-5]和PCyR組[4.2(1.4～11.9)×10-5](P=0.036).耐藥組患者骨髓細胞ABCB1基因mRNA相對中位錶達水平[136.7(15.0-604.9)×10-5]高于CCyR組[129.1(12.9 ～783.3) ×10-5]和PCyR組[34.4(2.2～108.2)×10-5](P=0.013).IM血漿穀濃度與劑量及AGP呈正相關(r值分彆為0.446和0.346,P值分彆為0.000和0.002)；與身高、體重、體錶麵積無顯著相關性(P值均＞0.05).不同療程之間IM穀濃度差異無統計學意義(P值均＞0.05).結論 檢測CML患者IM血漿穀濃度和骨髓細胞內穀濃度水平有助于判斷療效和指導治療.同時檢測血清AGP和骨髓細胞hOCT1和ABCB1基因mRNA錶達水平有助于理解療效與IM濃度之間的機製.
목적 연구만성수계백혈병(CML)환자용이마체니(IM)치료기간적혈장곡농도、골수세포내농도、골수세포hOCT1화ABCB1기인적mRNA표체수평여료효적관계급기영향인소.방법 CML만성기환자80례,남56례,녀24례,중위년령39.5 (6～76)세.IM중위제량위400( 200～800) mg/d,중위료정24(3～90)개월.유28례환자재검측혈약농도적동시검측기골수세포내IM농도,36례용실시정량RT-PCR법검측골수세포hOCT1급ABCB1기인mRNA적표체,IM농도검측채용고효액상색보-질보천련법,검측범위위2～10 000 μg/L,채용면역비탁법동시검측혈청α1-산성당단백(AGP)수평.안료효분위주요분자유전학완해(MMR)조、완전세포유전학완해(CCyR)조、부분세포유전학완해(PCyR)조급내약조.결과 80례환자IM혈장곡농도위(1274.1±559.1)(109.0～3400.0)μg/L.기중59례(73.8％)환자IM제량위400 mg/d,기혈장곡농도위(1252.0±569.5)(109.0～3400.0)μg/L,포괄37례(62.7％)농도≥1000 μg/L,9례(15.3％)농도≥800～1000 μg/L.MMR조IM혈약곡농도위(1533.9±634.1)μg/L,고우PCyR조[(812.8±480.3)μg/L]급내약조[( 875.2±243.1)μg/L](P치균＜0.05)；CCyR조[(1288.4±498.2)μg/L]고우PCyR조(P=0.027)；MMR조여CCyR조비교,차이무통계학의의(P=0.136).CCyR조환자골수세포내중위IM농도[12.6(2.4～90.4)μg/L]고우내약조[6.6(2.6～111.0)μg/L]화PCyR조[2.7(2.4～4.7)μg/L](P =0.013).CCyR조환자골수세포hOCT1기인mRNA적중위상대표체수평[25.9(0.7～123.9)×10-5]고우내약조[7.8(2.5～33.5)×10-5]화PCyR조[4.2(1.4～11.9)×10-5](P=0.036).내약조환자골수세포ABCB1기인mRNA상대중위표체수평[136.7(15.0-604.9)×10-5]고우CCyR조[129.1(12.9 ～783.3) ×10-5]화PCyR조[34.4(2.2～108.2)×10-5](P=0.013).IM혈장곡농도여제량급AGP정정상관(r치분별위0.446화0.346,P치분별위0.000화0.002)；여신고、체중、체표면적무현저상관성(P치균＞0.05).불동료정지간IM곡농도차이무통계학의의(P치균＞0.05).결론 검측CML환자IM혈장곡농도화골수세포내곡농도수평유조우판단료효화지도치료.동시검측혈청AGP화골수세포hOCT1화ABCB1기인mRNA표체수평유조우리해료효여IM농도지간적궤제.
Objective To determine plasma imatinib concentration,intracellular imatinib concentration,and hOCT1 and ABCB1 mRNA expression in bone marrow cells of CML patients to further evaluate the potential usefulness of these measures as markers of imatinib efficacy and their clinical relationships.Methods Eighty CML patients in chronic phase receiving imatinib were enrolled in this study,including 56 males and 24 females with a median age of 39.5(6-76) years.Imatinib was administered at a median dose of 400 (200-800) mg/d orally per day with a median course of 24 (3-90) months.The intracellular imatinib concentrations in bone marrow cells of 28 patients were simultaneously determined.Real-time quantitative PCR with a taqman probe was used to assess hOCT1 and ABCB1 mRNA expression on bone marrow cells of 36 patients.Imatinib trough concentration was determined by high-performance liquid chromatography-tandem mass spectrometry with a detectability of 2-10 000 μg/L.Serum α1-acid glycoprotein (AGP) was measured by immune turbidimetry on a BNProspec protein analyzer (Dade Behring,USA).All patients were divided into MMR,CCyR,PCyR or drug-resistant groups according to response.Results Plasma imatinib trough concentration of 80 patients was (1274.1±559.1) (109.0-3400.0) μg/L.The plasma imatinib trough concentration of 59 (73.8 ％) patients with a dose of 400 mg/d was (1252.0±569.5) (109-3400) g/L,including 37(62.7％) patients with concentrations of more than 1000 μg/L and 9 (15.2％) patients more than 800 μg/L.Plasma imatinib trough concentration in the MMR group [(1531.9±634.1) μg/L]was significant higher than in the PCyR [(812.8±480.3) μg/L]or drug-resistant group [(875.2±243.1) μg/L](P＜0.05).Plasma imatinib trough concentration in the CCyR group [(88.4±498.2) μg/L]was significant higher than in the PCyR group (P=0.027).There was no significant difference between CCyR and MMR groups with regard to plasma imatinib trough concentration (P=0.136).The intracellular imatinib concentration in bone marrow cells in the CCyR group [12.6(2.4-90.4) μg/L]was significantly higher than drug-resistant [6.6(2.6-111.0) μg/L]or PCyR [2.7(2.4-4.7)μg/L]groups (P=0.013).The hOCT1 mRNA expression on bone marrow cells in the CCyR group [25.9(0.7 -123.9)×10-5]was significantly higher than in drug-resistant [7.8(2.5-33.5)×10-5]or PCyR [4.2(1.4-11.9)×10-5]groups (P =0.036).The ABCB1 mRNA expression on bone marrow cells in drug-resistant group [136.7( 15.0-1604.9)×10-5]was significantly higher than in CCyR [129.1 (12.9-783.3)×10-5]or PCyR [34.4(2.2-108.2)×10-5]groups (P=0.013).Plasma imatinib trough concentration was positively correlated.with AGP (r=0.446,P =0.000) or dose (r=0.346,P=0.002).There were no significant correlations between plasma imatinib trough concentration and height,weight or body surface area (P＞0.05).There were no significant differences among different courses with regard to plasma imatinib trough concentration (P＞0.05).Conclusion Clinical responses in CML patients were correlated with plasma and intracellular imatinib trough concentrations.Imatinib concentration was regulated by AGP and the activities of hOCT1 and ABCB1.
