Pharmacogenetics for individualized cancer chemotherapy

Efferth, Thomas; Volm, M

doi:10.1016/j.pharmthera.2005.02.005

Cited by 137 publications

(85 citation statements)

References 220 publications

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“…Intrinsic and/or acquired resistance as well as toxicities associated with cisplatin are major limitations of this drug [1,4,6,10,11]. For example, about 85% of ovarian cancer patients relapse following initial response [1].…”

Section: Introductionmentioning

confidence: 99%

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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Objectives-Cisplatin is a widely used chemotherapeutic agent; however, nephrotoxicity and neuropathy are obstacles for drug efficacy. Little is known about the genes or genetic variants contributing to the risk of developing these toxicities or chemotherapeutic response. Thus, we have applied a cell-based model to identify and characterize previously unknown genes that may be involved in cellular susceptibility to cisplatin.Methods-Lymphoblastoid cell lines from 27 large Centre d'Etude du Polymorphisme Humain pedigrees were used to elucidate the genetic contribution to cisplatin-induced cytotoxicity. Phenotype was defined as cell growth inhibition following exposure of cell lines to increasing concentrations of cisplatin for 48 h.Results-Significant heritability, ranging from 0.32 to 0.43 (P < 10 −7 ), was found for the cytotoxic effects of each concentration (1, 2.5, 5, 10, and 20 μmol/l) and IC50, the concentration required for 50% cell growth inhibition. Linkage analysis revealed 11 genomic regions on six chromosomes with logarithm of odds (LOD) scores above 1.5 for cytotoxic phenotypes. The highest LOD score was found on chromosome 4q21.3−q35.2 (LOD = 2.65, P = 2.4 × 10 −4 ) for 5 μmol/l cisplatin. Quantitative transmission disequilibrium tests were performed using 191 973 nonredundant single nucleotide polymorphisms (SNPs) located in the 1 LOD confidence interval of these 11 regions. Twenty SNPs, with 10 SNPs located in five genes, were significantly associated with cisplatin-induced cytotoxicity (P ≤ 1 × 10 −4 ). Four of these 20 SNPs were found to explain over 10% of the variation in cisplatininduced apoptosis.Conclusions-Our results suggest that genetic factors involved in cytotoxicity also contribute to cisplatin-induced apoptosis. These cell lines provide a paradigm to identify previously unknown pharmacogenetic variants associated with drug cytotoxicity.

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Section: Introductionmentioning

confidence: 99%

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Shukla

Duan²,

Badner³

et al. 2008

Pharmacogenetics and Genomics

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“…It is also necessary to bring pharmacogenetics itself to the lay public and explain how they influence drug response. 6,71,72 Therefore, incorporation of the pharmacogenetic data into clinical practice (risk assessment and treatment decision) is a challenge for the future.…”

Section: Discussionmentioning

confidence: 99%

Pharmacogenetics and the concept of individualized medicine

2005

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“…To realize personalized medicine, it is critically important to observe individual differences in drug response and the role of genetic polymorphisms that are relevant to the pathways of drug metabolism and the biology of drug responses in the pharmacogenomics of common diseases. 4 With this background, the Food and Drug Administration (FDA) recognizes the importance of pharmacogenomics and has issued a guidance that encourages pharmacogenomics during drug development. 5 Many pharmacogenomics studies have been launched worldwide, such as a combination of a pharmaco-kinetic (PK) study and analyses of single nucleotide polymorphisms (SNPs) in a candidate gene or in a genome-wide approach.…”

Section: Introductionmentioning

confidence: 99%

A new statistical screening approach for finding pharmacokinetics-related genes in genome-wide studies

et al. 2008

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Biomedical researchers usually test the null hypothesis that there is no difference of the population mean of pharmacokinetics (PK) parameters between genotypes by the Kruskal-Wallis test. Although a monotone increasing pattern with a number of alleles is expected for PK-related genes, the Kruskal-Wallis test does not consider a monotonic response pattern. For detecting such patterns in clinical and toxicological trials, a maximum contrast method has been proposed. We show how that method can be used with pharmacogenomics data to a develop test of association. Further, using simulation studies, we compare the power of the modified maximum contrast method to those of the maximum contrast method and the KruskalWallis test. On the basis of the results of those studies, we suggest rules of thumb for which statistics to use in a given situation. An application of all three methods to an actual genome-wide pharmacogenomics study illustrates the practical relevance of our discussion.

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Pharmacogenetics for individualized cancer chemotherapy

Cited by 137 publications

References 220 publications

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Susceptibility loci involved in cisplatin-induced cytotoxicity and apoptosis

Pharmacogenetics and the concept of individualized medicine

A new statistical screening approach for finding pharmacokinetics-related genes in genome-wide studies

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