药物基因组学在细胞毒类抗肿瘤药物个体化治疗中的应用
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摘要
细胞毒类抗肿瘤药物具有治疗指数狭窄,毒性反应严重,疗效个体差异巨大的特点,而药物基因组学研究可提供用于预测化疗药物疗效和毒性反应的生物标志物。药物基因组学生物标志物在预测癌症治疗的安全性,毒性和疗效方面显示出其重要作用。通过鉴定特定的药物基因组学标志物多态性,为患者治疗与护理提供临床决策。文章主要阐述目前用于指导治疗决策及可能在未来具有临床应用价值的种系PGx标志物,包括硫嘌呤甲基转移酶与硫嘌呤、NUDT15与硫嘌呤、UGT1A1与伊利替康、DPYD与氟尿嘧啶、CYP2D6与他莫昔芬及TPMT与顺铂。
Cytotoxic anti-tumor drugs are characterized by narrow therapeutic indexes,severe toxicity and great difference in the effects of individualized therapies,while studies of pharmacogenomics(PGx)can provide biomarkers for predicting the efficacy and toxicity of chemotherapy drugs. PGx biomarkers play an important role in predicting the safety,toxicity and effects of drugs in the treatment of tumors. By identifying specific polymorphisms of PGx biomarkers,physicians could select and customize medication regimens based on the patient's genetic profile. This review focuses on the germline PGx biomarkers that are currently used for guiding therapeutic decisions and have potential clinical application values,including thiopurine S-methyltransferase and thiopurine,NUDT15 and thiopurine,UGT1 A1 and irinotecan,DPYD and fluorouracil,CYP2 D6 and tamoxifen,and TPMP and cisplatin.
Cytotoxic anti-tumor drugs are characterized by narrow therapeutic indexes,severe toxicity and great difference in the effects of individualized therapies,while studies of pharmacogenomics(PGx)can provide biomarkers for predicting the efficacy and toxicity of chemotherapy drugs. PGx biomarkers play an important role in predicting the safety,toxicity and effects of drugs in the treatment of tumors. By identifying specific polymorphisms of PGx biomarkers,physicians could select and customize medication regimens based on the patient's genetic profile. This review focuses on the germline PGx biomarkers that are currently used for guiding therapeutic decisions and have potential clinical application values,including thiopurine S-methyltransferase and thiopurine,NUDT15 and thiopurine,UGT1 A1 and irinotecan,DPYD and fluorouracil,CYP2 D6 and tamoxifen,and TPMP and cisplatin.
引文
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[24]Boige V,Vincent M,Alexandre P,et al.DPYD Genotyping to Predict Adverse Events Following Treatment WithFlourouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer:A Secondary Analysis of the PETACC-8 Randomized Clinical Trial[J].JAMA Oncol,2016,2(5):655.
[25]Schroth W,Goetz MP,Hamann U,et al.Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen[J].JAMA,2009,302(13):1429-1436.
[26]Zsiros J,Brugieres L,Brock P,et al.Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma(SIO-PEL-4):a prospective,single-arm,feasibility study[J].Lancet Oncol,2013,14(9):834-842.
[27]Karasawa T,Steyger PS.An integrated view of cisplatin-induced nephrotoxicity and ototoxicity[J].Toxicol Lett,2015,237(3):219-227.
[28]Ross CJ,Katzov-Eckert H,DubéMP,et al.Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy[J].Nat Genet,2009,41(12):1345-1349.
[2]Weng L,Zhang L,Peng Y,et al.Pharmacogenetics and pharmacogenomics:a bridge to individualized cancer therapy[J].Pharmacogenomics,2013,14(3):315-324.
[3]Appell ML,Berg J,Duley J,et al.Nomenclature for alleles of the thiopurine methyltransferase gene[J].Pharmacogenet Genomics,2013,23(4):242-248.
[4]Yates C,Krynetski E,Loennechen T,et al.Molecular diagnosis of thiopurine S-methyltransferase deficiency:genetic basis for azathioprine and mercaptopurine intolerance[J].Ann Intern Med,1997,126(8):608-614.
[5]Relling M,Gardner E,Sandborn W,et al.Clinical pharmacogenetics implementation consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing:2013 update[J].Clin Pharmacol Ther,2013,93(4):324-325.
[6]Relling M,Gardner E,Sandborn W,et al.Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing[J].Clin Pharmacol Ther,2011,89(3):387-391.
[7]Moriyama T,Nishii R,Perez-Andreu V,et al.NUDT15 polymorphisms alter thiopurine metabolism and hematopoietic toxicity[J].Nat Genet,2016,48(4):367-373.
[8]Tanaka Y,Kato M,Hasegawa D,et al.Susceptibility to 6-MP toxicity conferred by a NUDT15 variant in Japanese children with acute lymphoblastic leukaemia[J].Br J Haematol,2015,171(1):109-115.
[9]Yang S-K,Hong M,Baek J,et al.A common missense variant in NUDT15 confers susceptibility to thiopurine-induced leukopenia[J].Nat Genet,2014,46(9):1017-1020.
[10]Kham S,Soh C,Liu T,et al.Thiopurine S-methyltransferase activity in three major Asian populations:a population-based study in Singapore[J].Eur J Clin Pharmacol,2008,64(4):373-379.
[11]Saltz LB,Cox JV,Blanke C,et al.Irinotecan plus Fluorouracil and Leucovorin for Metastatic Colorectal Cancer[J].N Engl J Med,2000,343(13):905-914.
[12]Mathijssen R,van Alphen R,Verweij J,et al.Clinical pharmacokinetics and metabolism of irinotecan(CPT-11)[J].Clin Cancer Res,2001,7(8):2182-2194.
[13]Wang Y,Shen L,Xu N,et al.UGT1A1 predicts outcome in colorectal cancer treated with irinotecan and fluorouracil[J].World J Gastroenterol,2012,18(45):6635-6644.
[14]Etienne-Grimaldi MC,Boyer JC,Thomas F,et al.UGT1A1 genotype and irinotecan therapy:general review and implementation in routine practice[J].Fundam Clin Pharmacol,2015,29(3):219-237.
[15]Cecchin E,Innocenti F,D’Andrea M,et al.Predictive role of the UGT1A1,UGT1A7,and UGT1A9 genetic variants and their haplotypes on the outcome of metastatic colorectal cancer patients treated with fluorouracil,leucovorin,and irinotecan[J].J Clin Oncol,2009,27(15):2457-2465.
[16]Hazama S,Mishima H,Tsunedomi R,et al.UGT1A1*6,1A7*3,and 1A9*22 genotypes predict severe neutropenia in FOLFIRI-treated metastatic colorectal cancer in two prospective studies in Japan[J].Cancer Sci,2013,104(12):1662-1669.
[17]Tsunedomi R,Hazama S,Fujita Y,et al.A novel system for predicting the toxicity of irinotecan based on statistical pattern recognition with UGT1A genotypes[J].Int J Oncol,2014,45(4):1381-1390.
[18]Chen S,Laverdiere I,Tourancheau A,et al.A novel UGT1 marker associated with better tolerance against irinotecan-induced severe neutropenia in metastatic colorectal cancer patients[J].Pharmacogenomics J,2015,15(6):513.
[19]Rosmarin D,Palles C,Pagnamenta A,et al.A candidate gene study of capecitabine-related toxicity in colorectal cancer identifies new toxicity variants at DPYD and a putative role for ENOSF1 rather than TYMS[J].Gut,2015,64(1):111.
[20]van Kuilenburg A.Dihydropyrimidine dehydrogenase and the efficacy and toxicity of 5-fluorouracil[J].Eur J Cancer,2004,40(7):939-950.
[21]Boisdron-Celle M,Capitain O,Faroux R,et al.Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening:Assessment of a multiparametric approach[J].Semin Oncol,2017,44(1):13-23.
[22]Kuilenburg ABP,Vreken P,Beex LVAM,et al.Heterozygosity for a point mutation in an invariant splice donor site of dihydropyrimidine dehydrogenase and severe 5-fluorouracil related toxicity[J].Eur J Cancer,1997,33(13):2258-2264.
[23]Lee JJ,Beumer JH,Chu E.Therapeutic drug monitoring of 5-fluorouracil[J].Cancer Chemother Pharmacol,2016,78(3):447-464.
[24]Boige V,Vincent M,Alexandre P,et al.DPYD Genotyping to Predict Adverse Events Following Treatment WithFlourouracil-Based Adjuvant Chemotherapy in Patients With Stage III Colon Cancer:A Secondary Analysis of the PETACC-8 Randomized Clinical Trial[J].JAMA Oncol,2016,2(5):655.
[25]Schroth W,Goetz MP,Hamann U,et al.Association Between CYP2D6 Polymorphisms and Outcomes Among Women With Early Stage Breast Cancer Treated With Tamoxifen[J].JAMA,2009,302(13):1429-1436.
[26]Zsiros J,Brugieres L,Brock P,et al.Dose-dense cisplatin-based chemotherapy and surgery for children with high-risk hepatoblastoma(SIO-PEL-4):a prospective,single-arm,feasibility study[J].Lancet Oncol,2013,14(9):834-842.
[27]Karasawa T,Steyger PS.An integrated view of cisplatin-induced nephrotoxicity and ototoxicity[J].Toxicol Lett,2015,237(3):219-227.
[28]Ross CJ,Katzov-Eckert H,DubéMP,et al.Genetic variants in TPMT and COMT are associated with hearing loss in children receiving cisplatin chemotherapy[J].Nat Genet,2009,41(12):1345-1349.