药物基因组学在新药临床试验及个体化用药中的应用

药物安全性和有效性评价是药物临床试验和个体化用药的核心,也是药物基因组学研究的主要内容。药物基因组学研究贯穿于药物 研发、上市评价和临床应用整个过程, 根据药物代谢酶、转运体、受体相关基因多态性对用药者进行分层分析,评价与药物体内的处置过程、 安全性、有效性个体差异的相关性。综述药物基因组学在新药临床试验、个体化用药中的应用研究新进展。     

肺癌铂类化疗所致周围神经毒性与SNP相关性研究

目前肺癌发病率与死亡率均居恶性肿瘤首位,铂类药物已广泛应用于肺癌等多种癌症的治疗。然而,铂类药物化疗取得较佳疗效的同时,往往由于严重的毒副反应而限制了其使用剂量,从而难以达到最佳疗效。其中,铂类药物化疗所引起的周围神经毒性(peripheral neurotoxicity,PN)十分常见。与此同时,临床中周围神经毒性的发生存在较大的个体性差异,其药物代谢相关基因的单核苷酸多态性(single nucleotide polymorphism,SNP)的遗传变异可能是引起PN发生个体差异的重要原因之一。本文就DNA修复酶、药物代谢酶、转运体等相关基因的SNP与铂类化疗引起的PN之间的相关性作一综述。     

美国癌症研究所(NCI)科研规划简介(续)

3 临床治疗 3.1 临床肿瘤学拨款临床肿瘤学规划提供的拨款,支持研究治疗人类癌症中抗癌剂的应用及其效果的评估。它包括四个特殊领域:化疗药物的毒性和效果,单独激素治疗或同其它治疗方式相结合的临床研究;用动物模型和细胞系统发展治疗研究;对可能干扰抗癌药物活性,与癌有关的失调进行研究;进行癌症临床试验新方法的研究。该规划拨款还对癌症治疗时引起癌症患者承担的潜伏生命威胁处境给予支持。出血控制时的血小板转输,白血球输送,     

药物基因组学

目前,临床上最常见的一个现象就是不同的病人对同一种药物有不同的反应,这一直是困扰临床治疗的一个重大问题。近几年来,人们发现这些差异大多源于基因差异,基于此,有人提出“药物基因组学”的概念,它主要研究病人对药物的反应是如何受其基因影响的,以解决为什么不同的病人对同一种药物有不同反应的临床难题。基因多态性是药物基因组学的分子基础。影响药物作用的遗传差异的发现将导致新的诊断程序和治疗产品的开发,从而可以有选择地给病人用药,做到既有效又安全。1.药物基因组学的诞生早在50年代,人们就已经发现不同的遗传背景会导致药物反…     

雷公藤内酯醇和Ce6光激活脂质体协同给药治疗肝癌

正肝细胞癌(hepatocellularcarcinoma,HCC)是世界范围内第二常见的主要癌症,因为它对化疗和药物治疗的反应都很差。雷公藤内酯醇(TP)是一种二萜类三环氧化物,对包括肝癌在内的多种癌症具有有效的抗癌作用,是一种很有前途的治疗药物。然而,由于其严重的全身毒性、低溶解度和快速的体内清除率,其临床应用受到限制。来自南方医科大学的喻志强团队近日克服了上述困难,结合光敏剂Ce6和TP的光激活脂质体(TP/Ce6 LP)被设计用于肝癌治疗中的药物控制释放和协同光动力治疗。     

小细胞肺癌患者铂类化疗 所致周围神经毒性与SNP相关性

小细胞肺癌(SCLC)患者的治疗正在发生改变,但含铂双药联合化疗仍然是大多数SCLC患者的治疗基础。SCLC患者在接受化学治疗同时,还需忍受药物毒性引起的周围神经毒性(peripheral neurotoxicity,PN)等相关毒副作用。周围神经毒性主要表现为刺痛、麻木、虚弱或灼痛,且呈剂量依赖性。药物基因组学现已发展为一种有效的研究方法,目前可以利用基因组学获得关于药物反应的个体间差异的相关遗传信息,从而避免周围神经毒性的发生,以达到精准治疗的目的。单核苷酸多态性(single nucleotide polymorphism,SNP)定义为在基因组水平上由于单个核苷酸的变异而导致的DNA序列多态性。人类可遗传变异中最多的就是SNP,甚至在已知的所有多态性中90%以上都是单核苷酸变异。本文就小细胞肺癌患者铂类药物引起的周围神经毒性与相关GSTP1和GSTM1基因、ERCC1基因、ABCC2和ABCC4基因、SCNAs基因、CYP2C8基因、AGXT基因的SNP之间的关系作一简要综述。     

抗体能否有助于癌症治疗？

抗体治疗的发展带给我们治疗癌症的新希望和,新方法。基于抗体的冶疗药物在商业上相当成功,这主要是因为它们对癌症和炎症相关疾病的临床治疗效果良好。单就治疗肿瘤的抗体药物在2012年的计划销售额预计将达到250亿美元以上。     

抗肿瘤抗体-药物偶联物的临床研究进展

个体化靶向治疗已成为肿瘤临床治疗的新趋势.抗肿瘤靶向药物与传统的细胞毒性化疗药物相比具有特异性高、选择性强和非细胞毒性等优点,近年来发展迅速.抗体-药物偶联物(ADCs)属于抗肿瘤靶向药物,由抗体、“弹头”药物(细胞毒性药物)通过链分子连接而成.ADCs将抗体的靶向性与细胞毒性药物的抗肿瘤作用相结合,可以降低细胞毒性抗肿瘤药物的不良反应,提高肿瘤治疗的选择性,还能更好地应对靶向单抗的耐药性问题.目前,FDA已批准2种ADC药物上市,即Mylotarg和Adcetris,有多种ADCs处于Ⅰ～Ⅲ期临床试验阶段,取得了显著的临床效果.本文概述了以美登素,卡奇霉素、Auristantin等三种细胞毒性药物为“弹头”药物的ADCs药物的临床研究状况及临床试验结果,为ADCs的研究和应用提供参考.     

ADC药物的抗体组成及其作用靶点研究进展*

抗体药物偶联物(antibody-drug conjugates,ADC)是一类由单克隆抗体和小分子细胞毒性药物通过连接子偶联而成的新型生物治疗药物。与传统的细胞毒药物相比,ADC具有靶向性强、毒副作用小等优势,在临床上展现较好的治疗潜力。其中,抗体部分通过与肿瘤细胞表面的靶向抗原结合,精准地将小分子细胞毒性药物递送至肿瘤部位,从而实现肿瘤特异性杀伤效果,是影响ADC疗效的核心要素之一。对近年来ADC药物中抗体的组成及其作用靶点的研究进展进行了综述。     

肿瘤化疗药物外渗局部毒性的临床分析及护理

化学药物治疗是当前治疗恶性肿瘤的重要手段之一。随着癌症发病率的不断增高,化学药物在临床的应用也越来越广泛。而采用静脉注射细胞毒性化疗药物发生渗漏性损伤约4·65%[1]。一旦发生化疗药物外渗,轻者造成局部疼痛,重者可引起干性坏死,导致皮肤溃疡及疤痕形成,增加患者的痛苦。由此可见,掌握化疗药物外渗的局部毒性反应,正确观察和处理化疗药物外渗,是肿瘤化疗护士面临的重要课题。现将我科收治的5例强刺激性药物引起局部毒性情况分析如下。1临床资料1·1一般资料本组5例患者,男2例,女3例(均为2次癌症术后),其中应用阿霉素2例,长春瑞滨3…     

Genetic regressive trajectories in colorectal cancer: A new hallmark of oligo-metastatic disease?

Colorectal cancer (CRC) originates as consequence of multiple genetic alterations. Some of the involved genes have been extensively studied (APC, TP53, KRAS, SMAD4, PIK3CA, MMR genes) in highly heterogeneous and poly-metastatic cohorts. However, about 10% of metastatic CRC patients presents with an indolent oligo-metastatic disease differently from other patients with poly-metastatic and aggressive clinical course. Which are the genetic dynamics underlying the differences between oligo- and poly-metastatic CRC? The understanding of the genetic trajectories (primary→metastatic) of CRC, in patients selected to represent homogenous clinical models, is crucial to make genotype/phenotype correlations and to identify the molecular events pushing the disease towards an increasing malignant phenotype. This information is crucial to plan innovative therapeutic strategies aimed to reverse or inhibit these phenomena. In the present study, we review the genetic evolution of CRC with the intent to give a developmental perspective on the border line between oligo- and poly-metastatic diseases.     

A unified theory for the development of cancer

It is postulated that cancer is the result of genetic and epigenetic changes that occur mainly in stem (precursor) cells of various cell types. I propose that there are three classes of genes which are involved in the development of cancer. These are: Class I, II and III oncogenes. The classification is based on the way the oncogene acts at the cellular level to further the development of cancer. Genetic changes, that is point mutations, deletions, inversions, amplifications and chromosome translocations, gains or losses in the genes themselves or epigenetic changes in the genes (e.g. DNA hypomethylation) or in the gene products (RNA or protein) are responsible for the development of cancer. Changes of oncogene activity have a genetic or epigenetic origin or both and result in quantitative or qualitative differences in the oncogene products. These are involved in changing normal cells into the cells demonstrating a cancer phenotype (usually a form of dedifferentiated cell) in a multistep process. There are several pathways to cancer and the intermediate steps are not necessarily defined in an orderly fashion. Activation of a particular Class I or II oncogene and inactivation of a Class III oncogene could occur at any step during the development of cancer. Most benign or malignant tumors consist of a heterogeneous mixture of dedifferentiated cells arising from a single cell.     

Metabolic targeted therapy of cancer: current tracer technologies and future drug design strategies in the old metabolic network

Targeted drugs tailored against genes and signaling proteins have formed the new era termed Targeted Therapies. Although the field is relatively young, since only about 5 years ago clinical trials started showing promise, there have are already been significant setbacks due to drug resistance caused by point mutations, alterations in gene expression or complete loss of target proteins with disease progression. Although new drugs are continuously designed and tried, it seems inevitable that genetic and signal protein targets pose too broad flexibility and variability, often changing target characteristics and thus escape treatments turning “magic bullets” into rather “wondering bullets”. This is especially true in cancer, where old and new targeted therapies continue to fail and the most recent ones do not offer much improvement on clinical outcome parameters. Metabolic targeted therapies are aimed at control points of the metabolic network by targeting particular enzymes of major macromolecule synthesis pathways in cancer. This review summarizes the potential benefits of targeted therapies in the metabolic network as applied with genetic and proteomic approaches. The metabolic target approach is most efficient if and when pathway flux information is available for drug target development using the stable isotope based dynamic metabolic profile (SIDMAP) of tumor cells, in vitro or in vivo.This revised version was published online in June 2005. The previous version did not contain colour images.     

The role of companion diagnostics in the development and use of mutation-targeted cancer therapies

Among all the known differences between cancer and normal cells, it is only the genetic differences that unequivocally distinguish the former from the latter. It is therefore not surprising that recent therapeutic advances are based on agents that specifically target the products of the genes that are mutated in cancer cells. The ability to identify the patients most likely to benefit from such therapies is a natural outgrowth of these discoveries. Development of companion diagnostic tests for this identification is proceeding but should receive much more attention than it currently does. These tests can simplify the drug discovery process, make clinical trials more efficient and informative, and be used to individualize the therapy of cancer patients.     

Genome sequencing and comparison of two nonhuman primate animal models, the cynomolgus and Chinese rhesus macaques

The nonhuman primates most commonly used in medical research are from the genus Macaca. To better understand the genetic differences between these animal models, we present high-quality draft genome sequences from two macaque species, the cynomolgus/crab-eating macaque and the Chinese rhesus macaque. Comparison with the previously sequenced Indian rhesus macaque reveals that all three macaques maintain abundant genetic heterogeneity, including millions of single-nucleotide substitutions and many insertions, deletions and gross chromosomal rearrangements. By assessing genetic regions with reduced variability, we identify genes in each macaque species that may have experienced positive selection. Genetic divergence patterns suggest that the cynomolgus macaque genome has been shaped by introgression after hybridization with the Chinese rhesus macaque. Macaque genes display a high degree of sequence similarity with human disease gene orthologs and drug targets. However, we identify several putatively dysfunctional genetic differences between the three macaque species, which may explain functional differences between them previously observed in clinical studies.     

Prevalent mutations in prostate cancer

Quantitative and structural genetic alterations cause the development and progression of prostate cancer. A number of genes have been implicated in prostate cancer by genetic alterations and functional consequences of the genetic alterations. These include the ELAC2 (HPC2), MSR1, and RNASEL (HPC1) genes that have germline mutations in familial prostate cancer; AR, ATBF1, EPHB2 (ERK), KLF6, mitochondria DNA, p53, PTEN, and RAS that have somatic mutations in sporadic prostate cancer; AR, BRCA1, BRCA2, CHEK2 (RAD53), CYP17, CYP1B1, CYP3A4, GSTM1, GSTP1, GSTT1, PON1, SRD5A2, and VDR that have germline genetic variants associated with either hereditary and/or sporadic prostate cancer; and ANXA7 (ANX7), KLF5, NKX3-1 (NKX3.1), CDKN1B (p27), and MYC that have genomic copy number changes affecting gene function. More genes relevant to prostate cancer remain to be identified in each of these gene groups. For the genes that have been identified, most need additional genetic, functional, and/or biochemical examination. Identification and characterization of these genes will be a key step for improving the detection and treatment of prostate cancer.     

Breast cancer family history and allele-specific DNA methylation in the legacy girls study

Family history, a well-established risk factor for breast cancer, can have both genetic and environmental contributions. Shared environment in families as well as epigenetic changes that also may be influenced by shared genetics and environment may also explain familial clustering of cancers. Epigenetic regulation, such as DNA methylation, can change the activity of a DNA segment without a change in the sequence; environmental exposures experienced across the life course can induce such changes. However, genetic-epigenetic interactions, detected as methylation quantitative trait loci (mQTLs; a.k.a. meQTLs) and haplotype-dependent allele-specific methylation (hap-ASM), can also contribute to inter-individual differences in DNA methylation patterns. To identify differentially methylated regions (DMRs) associated with breast cancer susceptibility, we examined differences in white blood cell DNA methylation in 29 candidate genes in 426 girls (ages 6–13 years) from the LEGACY Girls Study, 239 with and 187 without a breast cancer family history (BCFH). We measured methylation by targeted massively parallel bisulfite sequencing (bis-seq) and observed BCFH DMRs in two genes: ESR1 (Δ4.9%, P = 0.003) and SEC16B (Δ3.6%, P = 0.026), each of which has been previously implicated in breast cancer susceptibility and pubertal development. These DMRs showed high inter-individual variability in methylation, suggesting the presence of mQTLs/hap-ASM. Using single nucleotide polymorphisms data in the bis-seq amplicon, we found strong hap-ASM in SEC16B (with allele specific-differences ranging from 42% to 74%). These findings suggest that differential methylation in genes relevant to breast cancer susceptibility may be present early in life, and that inherited genetic factors underlie some of these epigenetic differences.