结直肠癌化疗药物基因多态性研究进展

药物化疗是结直肠癌抗肿瘤治疗的重要手段,氟尿嘧啶类、铂类、伊立替康是结直肠癌化疗的常规用药。但在临床中,肿瘤患者个体之间存在化疗效果和不良反应的差异,这种差异与参与药物代谢、转运和失活的多种蛋白密切相关,其相应的基因多态性是导致个体之间化疗反应差异的重要物质基础,因此明确这些基因多态性位点对于实现肿瘤的个体化治疗、提高化疗效果具有重要意义。结合国内外药物基因组学最新的研究进展,系统综述了结直肠癌主要的化疗药物相关基因多态性与结直肠癌化疗敏感性研究的关系,以期为结直肠癌个体化化疗提供依据。     

基于药物基因组学指导转移性结直肠癌化疗药物个体化用药的研究现状

转移性结直肠癌患者的化疗反应存在较大的个体差异,这种差异可能由遗传和药物的相互作用等因素引起。基于药物基因组学指导转移性结直肠癌患者化疗方案的个体化用药有助于确保化疗疗效,降低药物不良反应。本文通过系统梳理转移性结直肠癌患者化疗药物基因组学相关内容及临床用药指南,并简要介绍了中药联合化疗药物在其治疗中的临床应用情况,以期为转移性结直肠癌患者的个体化治疗提供用药参考建议。     

结直肠癌细胞对单药及组合化疗药物体外敏感性的测定

结直肠癌是较常见的恶性肿瘤，死亡率高，手术切除是主要治疗手段，但易发生局部复发或转移，因此术后化疗是综合治疗结直肠癌的必要手段。由于肿瘤的异质性，存在着明显的个体差异，目前还没有发现哪一种单药或联合用药能对所有结直肠癌病人有效。因此采用体外肿瘤细胞药敏试验来筛选敏感化疗药物，是提高化疗效果的一种较好的方法。四氮唑盐（MTT）法是一种简便而快速的测定肿瘤细胞体外药物敏感性的实验方法，已有文献报道用此法检测大肠癌细胞的体外药物敏感性，但考察的单药和联合用药方案各不相同。本研究用MTT法对25例病人的结直肠癌细胞进行单药和联合用药的体外敏感性测定，并对实验结果进行分析整理，以期为结直肠癌的临床个体化化疗方案的选择提供帮助。     

二甲双胍联合化疗药物抗肿瘤的研究进展

二甲双胍作为治疗2型糖尿病的一线降糖药,不仅具有降糖作用,还可以对多种肿瘤起到防治作用,包括乳腺癌、肺癌、肝癌、子宫内膜癌、结直肠癌、胰腺癌、前列腺癌等。近年来,越来越多的研究倾向于将二甲双胍与临床中常用的化疗药物联合,从而使化疗药物增效减毒并提高患者生存率以及改善预后。本文主要对二甲双胍联合化疗药物抗肿瘤的作用机制及其在临床研究中的应用展开综述。     

结直肠癌FOLFOX方案化疗时不良反应的观察与护理

结直肠癌是我国一些地区的常见恶性肿瘤,发病率和死亡率逐渐上升。治疗首选根治性切除,为了减灭可能残留的肿瘤细胞,Ⅱ、Ⅲ期患者应行术后辅助化疗。随着新一代化疗药物的问世,结直肠癌的临床化疗疗效和可耐受性,取得了长足的进步。奥沙利铂是继顺铂和卡铂后的第三代铂类抗肿瘤药,与5-FU／CF联合化疗（FOLFOX方案）是结直肠癌常用化疗的方案之一,针对此方案常见的不良反应的观察和护理,进行总结,报告如下。     

卡培他滨个体化治疗结直肠癌研究进展

结直肠癌是最常见的癌症之一,每年可造成数十万人死亡,死亡率和发病率都呈逐年上升趋势。卡培他滨用于治疗结直肠癌已有十年的时间,其更好的疗效和用药依从性使其成为一种治疗结直肠癌的主要药物,但其同样有着不可忽视的毒副作用。研究发现卡培他滨疗效和毒副作用同其代谢基因的多态性有极大的关联,基因多态可在一定程度上解释其疗效和毒副作用的差异性。随着精准医疗的发展,制定精准高效的治疗策略,在基于分子生物学研究进展的基础上开展抗肿瘤药物的"个体化"治疗方案制订,是抗肿瘤药物治疗迫切需要研究的内容。卡培他滨药代动力学和药效学、药物相互作用、代谢相关基因多态性和临床应用的综述可以为卡培他滨个体化药物治疗方案的制订提供参考。     

雷替曲塞治疗结直肠癌的研究进展

目的：综述结直肠癌化疗药物的临床疗效及药物经济学评价结果。方法：基于结直肠癌的流行病学特征和治疗发展趋势,选取临床应用较多的以雷替曲塞或5- 氟尿嘧啶为主的化疗方案,并检索国内外相关文献,对其治疗结直肠癌的临床疗效和经济性进行综合分析。结果：各治疗方案表现出不同的临床疗效,而较少的药物经济学研究显示了雷替曲塞为主的化疗方案经济性。结论：雷替曲塞的临床疗效和经济性在总体上有优势,但还需更深入的研究。     

临床药师在1例CAPEOX方案联合贝伐珠单抗致严重不良反应治疗中的作用

目的 ：探讨临床药师在CAPEOX方案联合贝伐珠单抗导致的严重不良反应治疗中的作用。方法 ：临床药师为1例应用CAPEOX方案联合贝伐珠单抗治疗的晚期直肠癌患者提供药学服务，并对其严重腹泻、手足综合征进行相关性分析，对患者进行DPYD、MTHFR、ABCB1、GSTP1基因多态性检测。结果 ：临床药师积极参与患者救治过程，准确解读基因检测结果，协助医师制定个体化给药方案。结论 ：临床药师应对恶性肿瘤患者加强药学监护，针对特殊患者开展相应的药物相关基因多态性检测，协助医师优化药物治疗方案，保障患者用药安全、有效。     

增强紫杉醇对结直肠癌化疗疗效的研究进展

结直肠癌作为我国发病率逐年增高的一种恶性肿瘤,由于其隐匿的临床表现及有限的筛查手段,许多患者确诊时已发生较深的肿瘤浸润或出现了远处转移,此时则需要做术后化疗或新辅助化疗。而现有的结直肠癌化疗方案由于其不良反应多且易产生耐药性,故许多学者均在积极探索新的其他可用于结直肠癌的化疗药物。紫杉醇是治疗乳腺癌、卵巢癌、胰腺癌等恶性肿瘤的一线化疗药物,但结直肠癌细胞却易对其产生耐药性,治疗效果不理想,但可以通过开发新的给药系统、与其他药物联合用药等方式增强对结直肠癌的疗效。针对紫杉醇治疗结直肠癌的有效治疗策略进行综述,以期为结直肠癌更有效的化疗方案提供新的思路。     

节拍化疗的药动学研究进展

节拍化疗是一种高频次、低剂量且毒副反应较轻的化疗方式。节拍化疗近年来在乳腺癌辅助治疗以及联合抗血管生成药物治疗转移性结直肠癌方面取得了良好的效果。深入了解节拍化疗的药动学特点对临床方案制定和治疗至关重要。然而,目前对节拍化疗的药动学研究较少,其给药方案的制定如确定给药剂量、给药时间间隔等均依赖于经验用药。因此,本文对一些化疗药物节拍化疗的临床前和临床药动学研究现状、优势以及目前面临的挑战等进行了总结,并对药动学研究在优化节拍化疗方案制定过程中的应用情况进行了综述。     

G>C SNP of thymidylate synthase with respect to colorectal cancer

Several studies indicate that low thymidylate synthase (TS) protein levels in tumor and normal tissues of colorectal cancer patients are associated with better clinical response to fluorouracil-based chemotherapy and higher risk of toxicity. However, no correlation or even reverse correlation has also been reported. These conflicting results may be partly due to the methodological limitations of the immunohistochemical techniques generally used to quantify thymidylate synthase expression. In this sense, a genetic approach aiming at determining the influence of the TS gene polymorphisms on clinical outcome seems more appealing. So far three polymorphisms have been identified and studied in the TYMS gene: the variable number of 28-bp tandem repeats (2R or 3R) in the 5 UTR; the G>C substitution at the 12th nucleotide in the second repeat of the 3R allele (3RG>3RC) and the 6-bp deletion in the 3 UTR (+6bp/-6bp 3 UTR). In vitro studies indicate that each of these polymorphisms can influence thymidylate synthase expression. In particular, the G>C SNP, which alters the E-box sequence binding an upstream stimulatory factor (USF-1), seems more important than the variable number of tandem repeats in determining TS gene expression in that the 3RC allele has a reduced translational activity compared with the 3RG allele, while showing the same activity as the 2R allele. In contrast with the in vitro findings, the clinical studies in colorectal patients failed to find a consistent relationship between the G>C polymorphism and clinical outcome measures (response, survival or toxicity). This discrepancy may be due to methodological heterogeneities amongst the studies, including genotyping in normal or tumor tissues, loss of heterozygosity in tumor cells not evaluated, variable doses and schedules of fluorouracil-based therapy, and variable tumor stage. The complexity of TYMS gene regulation, and the possibility that other polymorphisms may contribute to fluorouracil response, call for further studies before TYMS genotyping can be used in clinical practice to select colorectal cancer patients who are most likely to benefit from chemotherapy.     

Linkage disequilibrium between the 677C>T and 1298A>C polymorphisms in human methylenetetrahydrofolate reductase gene and their contributions to risk of colorectal cancer

A common polymorphism in a folate-metabolizing gene, methylenetetrahydrofolate reductase (MTHFR) 677C>T has been associated with reduced risk of colorectal cancer. In this study, we investigated whether a second common polymorphism of the gene, MTHFR 1298A>C, is an independent risk factor for colorectal cancer and if it is associated with plasma folate and total homocysteine (tHcy) levels. We also examined whether the 677C>T and 1298A>C polymorphisms are in linkage disequilibrium and whether combined heterozygosity confers additional (or reduced) risk of colorectal cancer. We conducted a nested case-control study of 211 incident colorectal cancer cases and 343 controls in the prospective Physicians' Health Study. The MTHFR 677C>T and 1298A>C polymorphisms were in linkage disequilibrium in this population. Compared to MTHFR 1298AA genotype, multivariate-adjusted relative risk of colorectal cancer was 0.73 (95% CI 0.37-1.43) for the MTHFR 1298CC genotype. The slight reduction in risk was not a result of its linkage disequilibrium with the 677C>T polymorphism. This polymorphism was not significantly correlated with the plasma folate and tHcy levels. The combined heterozygosity did not modify the cancer risk; nor did it change the plasma folate and tHcy significantly. We conclude that the MTHFR 1298A>C polymorphism is a less substantial independent risk factor for colorectal cancer compared to the 677C>T polymorphism.     

Pharmacogenetics of colorectal cancer

Colorectal cancer is one of the most common types of cancer in both men and women. Multiple chemotherapy combinations exist; however, there is currently no strategy for individualised therapy selection prior to treatment. Genetic polymorphisms in genes involved in the metabolism, transport or targets for the commonly used chemotherapy drugs (5-fluorouracil, irinotecan and oxaliplatin) have been described. Many require validation in large prospective trials before they can be used as markers for outcome and/or toxicity. This review describes the data available on polymorphisms in key genes that are associated with chemotherapy toxicity and response in colorectal cancer.     

ERCC1 BRCA1 TYMS 的 mRNA 表达水平和 UGT1A1多态性检测在结直肠癌患者个体化化疗中的临床意义

目的 探讨结直肠癌肿瘤组织的切除修复交叉互补基因1（ERCC1）、乳腺癌易感基因1（BRCA1）和胸苷酸合成酶基因（TYMS）的信使RNA（mRNA）表达水平及尿苷葡萄糖醛酸转移酶基因（UGT1A1）多态性检测在结直肠癌患者个体化化疗中的临床意义。方法 选取2010年10月至2011年10月收治的进展期结直肠癌患者230例,分为个体化化疗组（41例）和常规化疗组（189例）,分别进行个体化化疗和常规化疗。个体化化疗组通过检测患者 ERCC1、BRCA1和TYMS基因中的mRNA表达水平以及UGT1A1基因多态性,指导患者选用敏感且毒性反应小的化疗药物,比较两组患者化疗后的无进展生存期（PFS）、无病生存率（DFS）和毒性反应发生率。结果 个体化化疗组患者中位 PFS 为（26.00±1.60）个月,常规化疗组患者中位PFS为（25.00±0.27）个月,两组比较,差异有统计学意义（P〈0.01）。两组患者化疗后1、2年DFS比较,差异均无统计学意义（P〉0.05）。个体化化疗组患者血液毒性、腹泻、肝功能损害和血尿素氮升高发生率较常规化疗组低,差异均有统计学意义（P〈0.05）;而神经毒性、心脏毒性和血肌酐升高发生率与常规化疗组比较,差异均无统计学意义（P〉0.05）。结论 以上基因检测使进展期结直肠癌患者在临床个体化化疗中获益,PFS延长,部分毒性反应发生率降低。     

Pharmacogenetics of colorectal cancer

Colorectal cancer is one of the most common types of cancer in both men and women. Multiple chemotherapy combinations exist; however, there is currently no strategy for individualised therapy selection prior to treatment. Genetic polymorphisms in genes involved in the metabolism, transport or targets for the commonly used chemotherapy drugs (5-fluorouracil, irinotecan and oxaliplatin) have been described. Many require validation in large prospective trials before they can be used as markers for outcome and/or toxicity. This review describes the data available on polymorphisms in key genes that are associated with chemotherapy toxicity and response in colorectal cancer.     

Methylenetetrahydrofolate reductase (MTHFR) variants and fluorouracil-based treatments in colorectal cancer

5-fluorouracil (5FU)-based treatments remain the main chemotherapy for colorectal cancer. Optimal cytotoxicity of fluoropyrimidines requires elevated CH(2)FH(4) tumoral concentrations, controlled by the methylenetetrahydrofolate reductase (MTHFR) enzyme, which irreversibly converts CH(2)FH(4) into 5-methyltetrahydrofolate. The MTHFR gene is subject to several polymorphisms, of which the 677C>T and 1298A>C SNPs are the two most commonly linked with altered enzyme activity. Since a drop in MTHFR enzymatic activity may theoretically favor an increase in intracellular CH(2)FH(4) concentrations, it can be hypothesized that tumors exhibiting the rare MTHFR variants may be more sensitive to 5FU cytotoxicity. Accordingly, experimental data have shown that rare MTHFR variants in position 677 and 1298 are more sensitive to 5FU. However, results of clinical data do not concord regarding the influence of MTHFR genotype on tumoral CH(2)FH(4) concentration, 5FU responsiveness, patient survival and 5FU-related toxicity. These discrepancies may result from the interpatient variability arising from the individual folate status, as well as from the limited role of fluoropyrimidines in the current chemotherapy regimen administered in colorectal cancer.     

The impact of pharmacogenomics on gastrointestinal cancer therapy

Recently, we have seen major advances in the chemotherapy of gastrointestinal tumors, in particular colorectal cancer, leading to a substantial increase in overall survival of the patients. However, clinical efficacy and also toxicity of a given chemotherapy are still largely unpredictable for the individual patient. Amongst other variables, genetic polymorphisms determine the interindividual heterogeneity in both toxicity and therapeutic efficacy. In this review we present current evidence on host genetic polymorphisms that affect the toxicity or efficacy of three drugs commonly used for the treatment of gastrointestinal malignancies, 5-fluorouracil, irinotecan and oxaliplatin.     

SIRT1 基因多态性与肺癌化疗敏感性的关系

目的探讨S1RTl基因多态性与肺癌对以铂类为基础的化疗敏感性的关系。方法选取338名肺癌患者（其中184名对化疗耐药和154名对化疗敏感）为研究对象,所有患者均接受以铂类（顺铂、卡铂）为基础的化疗。分析其SIRTl的所有单核苷酸多态性,最后筛选出4个tagSNPs进行基因分型。OR和CI用来评估SIRTl基因多态性与肺癌患者化疗效果的相关性。结果在〉60岁的肺癌患者中,rs3758391的基因多态性与铂类化疗疗效显著相关（OR=0．38,P=0．049）。rs3740051、rsl2778366的遗传多态性与铂类化疗疗效之间无显著相关性。结论SIRTlrs3758391基因多态性可以显著影响肺癌患者铂类化疗的敏感性,SIRTl可能作为肺癌铂类化疗疗效评估的标志物。