Role of metallothionein in cisplatin sensitivity of germ-cell tumours

Meijer, Coby; Timmer, Albertus; Vries, Elisabeth G.E. de; Groten, J.P.; Knol, Ageeth J.; Zwart, Nynke; Dam, Wendy; Sleijfer, Dirk; Mulder, Nanno

doi:10.1002/(sici)1097-0215(20000315)85:6<777::aid-ijc6>3.0.co;2-d

Cited by 40 publications

(15 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…In this study, we used an adduct-specific monoclonal antibody in combination with digital image analysis to visualise and quantify levels of distinct DNA platination products within the nuclei of individual cells. The degree of DNA adduct formation by cisplatin is cell-type specific and may likely depend on a number of pharmacokinetic parameters such as drug export by membrane transporters [42] or cytoplasmic detoxification [43].…”

Section: Discussionmentioning

confidence: 99%

Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature

Barr

Gray

Hoffmann³

et al. 2013

PLoS ONE

238

180

View full text Add to dashboard Cite

IntroductionInherent and acquired cisplatin resistance reduces the effectiveness of this agent in the management of non-small cell lung cancer (NSCLC). Understanding the molecular mechanisms underlying this process may result in the development of novel agents to enhance the sensitivity of cisplatin.MethodsAn isogenic model of cisplatin resistance was generated in a panel of NSCLC cell lines (A549, SKMES-1, MOR, H460). Over a period of twelve months, cisplatin resistant (CisR) cell lines were derived from original, age-matched parent cells (PT) and subsequently characterized. Proliferation (MTT) and clonogenic survival assays (crystal violet) were carried out between PT and CisR cells. Cellular response to cisplatin-induced apoptosis and cell cycle distribution were examined by FACS analysis. A panel of cancer stem cell and pluripotent markers was examined in addition to the EMT proteins, c-Met and β-catenin. Cisplatin-DNA adduct formation, DNA damage (γH2AX) and cellular platinum uptake (ICP-MS) was also assessed.ResultsCharacterisation studies demonstrated a decreased proliferative capacity of lung tumour cells in response to cisplatin, increased resistance to cisplatin-induced cell death, accumulation of resistant cells in the G0/G1 phase of the cell cycle and enhanced clonogenic survival ability. Moreover, resistant cells displayed a putative stem-like signature with increased expression of CD133+/CD44+cells and increased ALDH activity relative to their corresponding parental cells. The stem cell markers, Nanog, Oct-4 and SOX-2, were significantly upregulated as were the EMT markers, c-Met and β-catenin. While resistant sublines demonstrated decreased uptake of cisplatin in response to treatment, reduced cisplatin-GpG DNA adduct formation and significantly decreased γH2AX foci were observed compared to parental cell lines.ConclusionOur results identified cisplatin resistant subpopulations of NSCLC cells with a putative stem-like signature, providing a further understanding of the cellular events associated with the cisplatin resistance phenotype in lung cancer.

show abstract

Section: Discussionmentioning

confidence: 99%

Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature

Barr

Gray

Hoffmann³

et al. 2013

PLoS ONE

238

180

View full text Add to dashboard Cite

show abstract

“…In the case of head and neck squamous cell carcinoma, expression of MT in samples isolated following treatment with cisplatin was significantly higher than that in untreated tumors [20]. In the cases of germ cell tumors and testicular germ cell tumors, no relationship could be demonstrated between expression of MT and response to cisplatin therapy [16,18]. Wrigley et al [32] studied a group of 80 cases of ovarian cancer of a variable grade, stage and histology (59 cases involved primary laparotomies and 21 samples originated from second-look procedures, but not from the same patients).…”

Section: Discussionmentioning

confidence: 99%

Augmented expression of metallothionein and glutathione S-transferase pi as unfavourable prognostic factors in cisplatin-treated ovarian cancer patients

et al. 2005

View full text Add to dashboard Cite

Resistance to cis- or carboplatin represents the principal cause of therapeutic failures in ovarian carcinoma. The phenomenon of resistance to platinum-based drugs is partly related to expression of metallothionein (MT) and of glutathione S-transferase pi (GST-pi), but opinion on the subject is discordant. Documentation of a negative predictive effect of MT and GST-pi expression for the therapy employing platinum-based drugs would permit to select resistant cases in which other therapeutic approaches could be employed. The present study aimed at examining the relation between intensities of MT and GST-pi expressions in ovarian carcinomas and dynamics of the clinical course in the neoplastic disease in a group of cisplatin-treated patients. The analyses were performed on samples of ovarian carcinoma originating from 43 first-look laparotomies (FLLs) and, in 30 cases, from second-look laparotomies (SLL) from the same patients. Immunohistochemical reactions were performed on paraffin sections of studied tumors, using monoclonal antibodies to MT and GST-pi. The calculations showed that in cases with augmented expression of MT, mortality was higher. On the other hand, augmented expression of GST-pi predisposed to more frequent relapses, deaths and progression of the tumor. Kaplan-Meier analysis showed that a significantly shorter survival time was linked to cases of higher expression of MT at FLL and of higher expression of GST-pi at FLL, whereas a shorter progression-free time was manifested by cases with higher expression of GST-pi at FLL. The performed investigations indicate that augmented expressions of MT at FLL and GST-pi at FLL in ovarian cancer represent an unfavourable predictive factor in cisplatin-treated patients.

show abstract

“…Several genes are involved in the carboplatin drug pathway (platinating agents pathway PharmGKB: Supplementary Figure 1; see online at www.futuremedicine.com/doi/suppl/10.2217/pgs.14.107). Intracellular levels of carboplatin are regulated by drug transporters SLC31A1 (CTR1), ABCC2 (MRP2), ATP7A and ATP7B [7], as well as drug-metabolizing enzymes including MPO, SOD1, GSTM1, NQO1, GSTP1 and MT, which are implicated in the development of cellular resistance to these drugs [8–11]. Genes of pharmacodynamic significance include HMGB1 , which is involved in recognition and cellular response to platinum–DNA adducts and DNA repair genes including mismatch repair genes MSH6 and MLH1 , and nucleotide excision repair genes XRCC1 , ERCC1 , ERCC2 and XPA [12,13].…”

Section: Introductionmentioning

confidence: 99%

Genetic Variation in Platinating Agent and Taxane Pathway Genes as Predictors of Outcome and Toxicity in Advanced Non-Small-Cell Lung Cancer

et al. 2014

View full text Add to dashboard Cite

Aim Lung carcinoma is the most common malignancy and the leading cause of cancer deaths worldwide. Although clinical factors including age, performance status and stage influence the likelihood of benefit from and tolerability of chemotherapy, the genetic profile of individual patients may be an independent predictor of response and toxicity. The present study aimed to identify pharmacogenetic markers associated with clinical response and toxicity in patients with advanced non-small cell lung cancer (NSCLC) treated primarily with carboplatin and paclitaxel. Materials & methods Genomic DNA samples from 90 adult male patients diagnosed with stage IIIB/IV NSCLC were genotyped for SNPs in candidate genes of relevance to platinating agents and paclitaxel and analyzed for association with survival and toxicities in univariate and multivariate models. Results After adjusting for performance status and stage, SNPs in the drug transporters ABCB1 and ABCC1, as well as within NQO1 were associated with progression-free survival. With respect to hematological and nonhematological toxicities, SNPs in drug transporters (ABCB1 and ABCG2) were associated with thrombocytopenia, nausea and neutropenia, whereas SNPs in the DNA repair pathway genes ERCC4 and XPC were significantly associated with neutropenia and sensory neuropathy, respectively. Conclusion Our study evaluated and identified SNPs in key candidate genes in platinating agent and taxane pathways associated with outcome and toxicity in advanced NSCLC. If validated in large prospective studies, these findings might provide opportunities to personalize therapeutic strategies.

show abstract

Role of metallothionein in cisplatin sensitivity of germ-cell tumours

Cited by 40 publications

References 18 publications

Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature

Generation and Characterisation of Cisplatin-Resistant Non-Small Cell Lung Cancer Cell Lines Displaying a Stem-Like Signature

Augmented expression of metallothionein and glutathione S-transferase pi as unfavourable prognostic factors in cisplatin-treated ovarian cancer patients

Genetic Variation in Platinating Agent and Taxane Pathway Genes as Predictors of Outcome and Toxicity in Advanced Non-Small-Cell Lung Cancer

Contact Info

Product

Resources

About