CYP3A5和GSTP1基因多态性与多西他赛联合塞替派治疗转移性乳腺癌近期疗效的相关性研究

周心娜 董宁宁 余靖 王小利 任军 邵宏

中国药学杂志 ›› 2012, Vol. 47 ›› Issue (2) : 127-131.

PDF(951 KB)
中国药学杂志
PDF(951 KB)
中国药学杂志 ›› 2012, Vol. 47 ›› Issue (2) : 127-131.
论著

CYP3A5和GSTP1基因多态性与多西他赛联合塞替派治疗转移性乳腺癌近期疗效的相关性研究

  • 周心娜1，2，董宁宁2，余靖2，王小利2，任军2*，邵宏1*
作者信息 +

Study on the Polymorphisms of CYP3A5 and GSTP1 Genes in the Prediction of Short-Term Efficacy of Docetaxel Plus Thiotepa For Patients With Metastatic Breast Cancer

Author information +
文章历史 +

摘要

目的 获得中国人群药物代谢酶CYP3A5基因和GSTP1基因两个位点的多态性及其与转移性乳腺癌近期疗效的相关性。方法 所有患者均采用多西他赛联合塞替派化疗方案，对患者每2周期疾病控制率（disease control rate， DCR）进行评估。采用基质辅助激光解吸电离飞行时间质谱（atrix assisted laser desorption ionization/ time of flight， MALDI-TOF）确定两个位点的基因型，比较不同基因型与该化疗方案近期疗效的关系。结果 93例转移性乳腺癌患者中具有CYP3A5 A6986G纯合突变型（GG）的DCR（77.8%），显著高于AA+AG基因型的（57.4%） ( P<0.05)；具有GSTP1 A313G突变型（AG+GG）的DCR（81.6%）显著高于野生型（AA）（57.4%）(P<0.05)；对两个基因多态性位点的联合分析显示，同时具有GSTP1 AG+GG和CYP3A5 GG基因型的DCR最高，为84.2% (P<0.05)。结论 CYP3A5和GSTP1的基因多态性与化疗疗效有关， GSTP1 A313G突变型（AG+GG）和/或CYP3A5 A6986G纯合突变型（GG）的患者使用多西他赛联合塞替派方案近期化疗疗效最好，可为临床用药提供参考。

Abstract

OBJECTIVE To investigate whether the polymorphisms of cytochrome P450 3A5 (CYP3A5) gene and glutathione S-transferase P1 (GSTP1) gene are associated with the short-term efficacy of docetaxel plus thiotepa for Chinese patients with metastatic breast cancer. METHODS All patients received docetaxel plus thiotepa chemotherapy. CYP3A5 and GSTP1 were genotyped by matrix assisted laser desorption ionization/ time of flight (MALDI-TOF). Disease control rate (DCR) was evaluated every two chemotherapy cycles， and was compared between different genotypes. RESULTS Among 93 enrolled patients， people with CYP3A5 A6986G GG genotype showed a statistically higher DCR than those with AG+GG genotype (77.8% versus 57.4%， P<0.05)， and the DCR of the patients with GSTP1 A313G AG+GG was statistically higher than that of patients with AA (81.6% versus 57.4%， P<0.05). Combination analysis showed that patients with GSTP1 A313G AG+GG and CYP3A5 A6986G GG had the highest DCR (84.2%， P<0.05). CONCLUSION CYP3A5 and GSTP1 polymorphisms are associated with the short-term efficacy of docetaxel plus thiotepa. Higher DCRs were seen in patients carrying GSTP1 A313G AG+GG and/or CYP3A5 A6986G GG genotype， which might be a reference for clinical chemotherapy.

关键词

乳腺癌 / 药物代谢酶 / CYP3A5 / GSTP1 / 多西他赛 / 塞替派

Key words

breast cancer / drug metabolizing enzyme / polymorphism / CYP3A5 / GSTP1 / docetaxel / thiotepa

引用本文

EndNote

Ris (Procite)

Bibtex

导出引用
周心娜 董宁宁 余靖 王小利 任军 邵宏. CYP3A5和GSTP1基因多态性与多西他赛联合塞替派治疗转移性乳腺癌近期疗效的相关性研究[J]. 中国药学杂志, 2012, 47(2): 127-131
Study on the Polymorphisms of CYP3A5 and GSTP1 Genes in the Prediction of Short-Term Efficacy of Docetaxel Plus Thiotepa For Patients With Metastatic Breast Cancer[J]. Chinese Pharmaceutical Journal, 2012, 47(2): 127-131

参考文献


[1] JEMAL A， BRAY F， CENTER M M， et al. Global cancer statistics[J]. CA Cancer J Clin， 2011， 61(2)：69-90.
[2] GAO B， KLUMPEN H J， GURNEY H. Dose calculation of anticancer drugs[J]. Expert Opin Drug Metab Toxicol， 2008， 4(10)：1307-1319.
[3] EVANS W E， RELLING M V. Pharmacogenomics： translating functional genomics into rational therapeutics[J]. Science， 1999， 286(5439)：487-491.
[4] SCRIPTURE C D， SPARREBOOM A， FIGG W D. Modulation of cytochrome P450 activity： implications for cancer therapy[J]. Lancet Oncol， 2005， 6(10)：780-789.
[5] DEENEN M J， CATS A， BEIJNEN J H， et al. Part 1： background， methodology， and clinical adoption of pharmacogenetics[J]. Oncologist， 2011， 16(6)：811-819.
[6] YU J， DI L， SONG G，et al. Randomized clinical case-control trial for the comparison of docetaxel plus thiotepa versus docetaxel plus capecitabine in patients with metastatic breast cancer[J]. J Peking Univ (Health Sci Ed)（北京大学学报：医学版）， 2011， 43(1)：151-156.
[7] LU Z H， JIA J， DI L J， et al. DNA Methyltransferase inhibitor CDA-2 synergizes high-dose thiotepa and paclitaxel in killing breast cancer stem cells[J]. Front Biosci (Elite Ed)， 2011，12(3)：240-249.
[8] CHOI J Y， NOWELL S A， BLANCO J G， et al. The role of genetic variability in drug metabolism pathways in breast cancer prognosis[J]. Pharmacogenomics， 2006， 7(4)：613-624.
[9] JACOBSON P A， GREEN K， BIRNBAUM A， et al. Cytochrome P450 isozymes 3A4 and 2B6 are involved in the in vitro human metabolism of thiotepa to TEPA[J]. Cancer Chemother Pharmacol， 2002， 49(6)：461-467.
[10] DIRVEN H A， DICTUS E L， BROEDERS N L， et al. The role of human glutathione S-transferase isoenzymes in the formation of glutathione conjugates of the alkylating cytostatic drug thiotepa[J]. Cancer Res， 1995， 55(8)：1701-1706.
[11] XIE H G，WOOD A J， KIM R B， et al. Genetic variability in CYP3A5 and its possible consequences[J]. Pharmacogenomics， 2004，5(3)：243-272.
[12] YANG G， SHU X O， RUAN Z X，et al. Genetic polymorphisms in glutathione-S-transferase genes (GSTM1， GSTT1， GSTP1) and survival after chemotherapy for invasive breast carcinoma[J]. Cancer，2005， 103(1)：52-58.
[13] EKHART C， DOODEMAN V D， RODENHUIS S， et al. Polymorphisms of drug-metabolizing enzymes (GST， CYP2B6 and CYP3A) affect the pharmacokinetics of thiotepa and tepa[J]. Br J Clin Pharmacol， 2009， 67(1)：50-60.
[14] BAKER S D， VERWEIJ J， CUSATIS G A， et al. Pharmacogenetic pathway analysis of docetaxel elimination[J]. Clin Pharmacol Ther， 2009， 85(2)：155-163.
[15] CNUBBEN N H， ROMMENS A J， OUDSHOORN M J， et al. Glutathione-dependent biotransformation of the alkylating drug thiotepa and transport of its metabolite monoglutathionylthiotepa in human MCF-7 breast cancer cells[J]. Cancer Res， 1998， 58(20)：4616-4623.
[16] TEW K D， MONKS A， BARONE L， et al. Glutathione-associated enzymes in the human cell lines of the National Cancer Institute Drug Screening Program[J]. Mol Pharmacol， 1996， 50(1)：149-159.
[17] JOHANSSON A S， STENBERG G， WIDERSTEN M， et al. Structure-activity relationships and thermal stability of human glutathione transferase P1-1 governed by the H-site residue 105[J]. J Mol Biol， 1998， 278(3)：687-698.
[18] DEENEN M J， CATS A， BEIJNEN J H， et al. Part 3： Pharmacogenetic variability in phase II anticancer drug metabolism[J]. Oncologist， 2011， 16(7)：992-1005.
[19] SAU A， PELLIZZARI TREGNO F， VALENTINO F， et al. Glutathione transferases and development of new principles to overcome drug resistance[J]. Arch Biochem Biophys， 2010， 500(2)：116-122.
[20] PUSZTAI L， SYMMANS F W， HORTOBAGYI G N. Development of pharmacogenomic markers to select preoperative chemotherapy for breast cancer[J]. Breast Cancer， 2005，12(2)：73-85.
[21] LARAPN J R， REDMAN M W， KELLY K， et al. Disease control rate at 8 weeks predicts clinical benefit in advanced non-small-cell lung cancer： results from Southwest Oncology Group randomized trials[J]. J Clin Oncol， 2008，26(3)：463-467.
PDF(951 KB)

Accesses

Citation

Detail
段落导航
相关文章

/

〈 〉