Pharmacogenetic Analyses of Cisplatin-induced Nephrotoxicity Indicate a Renoprotective Effect of
            <i>ERCC1</i>
            Polymorphisms

Tzvetkov, Mladen V.; Behrens, Gerrit; O’Brien, Valerie P.; Hohloch, Karin; Brockmöller, Jürgen; Benöhr, Peter

doi:10.2217/pgs.11.93

Cited by 38 publications

(36 citation statements)

References 52 publications

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“…It is a kind of abitrary because the creatinine clearance after CDDP injection is also tightly related to the baseline value of creatinine clearance, which was not adjusted in this study. According to other studies (Tzvetkov et al 2011; Sprowl et al 2012), we chose the change ratio of eGFR as the indicator of renal function. To determinate the boundary of nephrotoxicity, we abitrarily employed the change of eGFR to baseline lower than −30 %, which seldom happened in patients with CBP-based chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

Aging increases the susceptibility of cisplatin-induced nephrotoxicity

Wen

Zeng

Shu

et al. 2015

AGE

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Cisplatin (CDDP) nephrotoxicity is one of the most common side effects in cancer treatment, causing the disruption of chemotherapy. In this study, we analyzed the influence of nongenetic factors on CDDP-induced nephrotoxiciy using the data from 182 CDDP-treated and 52 carboplatin (CBP)-treated patients. The mean change of eGFR (100 % to baseline) in CDDP-treated patients was −9.2 %, which was significantly lower than that in the population with CBP therapy. By using the chi-squared test and multivariate logistic regression analysis, age (≥50 years) is found associated with CDDP-induced nephrotoxicity, with odds ratio (OR) of 9.167 and 11.771, respectively. Three- and 18-month-old mice were employed to study the age-dependent susceptibility of CDDP-induced nephrotoxicity. Biochemical parameters, histopathogical examination, and mRNA biomarkers indicated that old mice were subjected to more severe kidney injury. In addition, old mice accumulated more CDDP in kidney than young mice, and the protein level of CDDP efflux transporter, MATE1, in aged mice kidney was 35 % of that in young mice. Moreover, inflammatory receptor TLR4 was higher in the kidney of old mice, indicating the alteration of inflammatory signaling in old mice. After CDDP administration, the induced alterations of TNF-α, ICAM-1, and TLR4 were more extensive in old mice. To summarize, aging increased the susceptibility of CDDP-induced renal function decline or nephrotoxicity.Electronic supplementary materialThe online version of this article (doi:10.1007/s11357-015-9844-3) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Aging increases the susceptibility of cisplatin-induced nephrotoxicity

Wen

Zeng

Shu

et al. 2015

AGE

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“…In another study, it was found that the same nonsynonymous single-nucleotide polymorphism in the OCT2 gene was associated with reduced cisplatin-induced nephrotoxicity in patients [173]. On the contrary, screening the DNA of 79 cancer patients receiving cisplatin-containing chemotherapy showed that polymorphisms in hOCT2 genes were not associated with cisplatin-induced nephrotoxicity [178]. Studying a total of 53 patients with advanced carcinomas, it was demonstrated that cancer patients carrying the OCT2 (A270S) genotype were less susceptible to cisplatin-induced nephrotoxicity, but not to hematological toxicity [179].…”

Section: Cellular Transport Of Cisplatinmentioning

confidence: 99%

Membrane Transporters as Mediators of Cisplatin Effects and Side Effects

2012

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Transporters are important mediators of specific cellular uptake and thus, not only for effects, but also for side effects, metabolism, and excretion of many drugs such as cisplatin. Cisplatin is a potent cytostatic drug, whose use is limited by its severe acute and chronic nephro-, oto-, and peripheral neurotoxicity. For this reason, other platinum derivatives, such as carboplatin and oxaliplatin, with less toxicity but still with antitumoral action have been developed. Several transporters, which are expressed on the cell membranes, have been associated with cisplatin transport across the plasma membrane and across the cell: the copper transporter 1 (Ctr1), the copper transporter 2 (Ctr2), the P-type copper-transporting ATPases ATP7A and ATP7B, the organic cation transporter 2 (OCT2), and the multidrug extrusion transporter 1 (MATE1). Some of these transporters are also able to accept other platinum derivatives as substrate. Since membrane transporters display a specific tissue distribution, they can be important molecules that mediate the entry of platinum derivatives in target and also nontarget cells possibly mediating specific effects and side effects of the chemotherapeutic drug. This paper summarizes the literature on toxicities of cisplatin compared to that of carboplatin and oxaliplatin and the interaction of these platinum derivatives with membrane transporters.

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“…However the results have been inconclusive, which might explain why we only got two hits in our literature-based approach. DNA-repair genes have previously been shown to play a role in the pharmacogenetics of platinum-based effects (28,29,32). One of our hits in the literature-based approach was a genetic variant in ERCC5, a DNA-repair gene, but this variant the genotyping failed in the validation cohort and it has a low minor allele frequency.…”

Section: Discussionmentioning

confidence: 99%

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

Gréen

Hasmats

Kupershmidt

et al. 2016

Clinical Cancer Research

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Purpose: Chemotherapies are associated with significant interindividual variability in therapeutic effect and adverse drug reactions. In lung cancer, the use of gemcitabine and carboplatin induces grade 3 or 4 myelosuppression in about a quarter of the patients, while an equal fraction of patients is basically unaffected in terms of myelosuppressive side effects. We therefore set out to identify genetic markers for gemcitabine/carboplatin-induced myelosuppression.Experimental Design: We exome sequenced 32 patients that suffered extremely high neutropenia and thrombocytopenia (grade 3 or 4 after first chemotherapy cycle) or were virtually unaffected (grade 0 or 1). The genetic differences/polymorphism between the groups were compared using six different bioinformatics strategies: (i) whole-exome nonsynonymous single-nucleotide variants association analysis, (ii) deviation from Hardy-Weinberg equilibrium, (iii) analysis of genes selected by a priori biologic knowledge, (iv) analysis of genes selected from gene expression meta-analysis of toxicity datasets, (v) Ingenuity Pathway Analysis, and (vi) FunCoup network enrichment analysis.Results: A total of 53 genetic variants that differed among these groups were validated in an additional 291 patients and were correlated to the patients' myelosuppression. In the validation, we identified rs1453542 in OR4D6 (P ¼ 0.0008; OR, 5.2; 95% CI, 1.8-18) as a marker for gemcitabine/carboplatin-induced neutropenia and rs5925720 in DDX53 (P ¼ 0.0015; OR, 0.36; 95% CI, 0.17-0.71) as a marker for thrombocytopenia. Patients homozygous for the minor allele of rs1453542 had a higher risk of neutropenia, and for rs5925720 the minor allele was associated with a lower risk for thrombocytopenia.Conclusions: We have identified two new genetic markers with the potential to predict myelosuppression induced by gemcitabine/carboplatin chemotherapy. Clin Cancer Res; 22(2); 366-73.Ó2015 AACR.

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Pharmacogenetic Analyses of Cisplatin-induced Nephrotoxicity Indicate a Renoprotective Effect of ERCC1 Polymorphisms

Abstract: Genetic polymorphisms in ERCC1 may be valuable predictors of cisplatin-induced nephrotoxicity.

Cited by 38 publications

References 52 publications

Aging increases the susceptibility of cisplatin-induced nephrotoxicity

Aging increases the susceptibility of cisplatin-induced nephrotoxicity

Membrane Transporters as Mediators of Cisplatin Effects and Side Effects

Using Whole-Exome Sequencing to Identify Genetic Markers for Carboplatin and Gemcitabine-Induced Toxicities

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