Molecular mechanisms of resistance and toxicity associated with platinating agents

Rabik, Cara A; Dolan, M. Eileen

doi:10.1016/j.ctrv.2006.09.006

Cited by 1,388 publications

(1,192 citation statements)

References 153 publications

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“…Cisplatin is one of the most effective chemotherapeutic agents used for osteosarcoma treatment. As the NER pathway is responsible for the removal of DNA adducts induced by platinum compounds, 6 we analyzed the association between treatment response and polymorphisms in the NER genes ERCC2, XPC, ERCC1, ERCC4, ERCC5 and XPA in osteosarcoma patients treated with cisplatin. In our study, carrying at least one G allele in ERCC2 Lys751Gln conferred an estimated fivefold risk of poor tumor response in osteosarcoma patients treated with cisplatin.…”

Section: Discussionmentioning

confidence: 99%

“…2 Cisplatin causes DNA lesions by forming intra-strand and inter-strand cross-links that result in DNA distortion and inhibition of DNA replication. 6 The nucleotide excision repair (NER) pathway is one of the major DNA repair systems involved in the removal of platinum adducts. 7 The NER pathway is formed by a complex network of many proteins involved in lesion recognition, excision, DNA resynthesis and ligation.…”

Section: Introductionmentioning

confidence: 99%

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Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

et al. 2009

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Platinum agents cause DNA cross-linking. Nucleotide excision repair genes play a key role in DNA damage repair. This study aims to investigate whether polymorphisms in these genes are associated with tumor response and survival in cisplatin-treated osteosarcoma patients. Eight single nucleotide polymorphisms in ERCC2, XPC, XPA, ERCC1, ERCC4 and ERCC5 genes were analyzed in 91 patients diagnosed with osteosarcoma and treated with cisplatin. A significant association with tumor response, after correction for multiple testing, was found for the Lys751Gln polymorphism in the ERCC2 gene. We found that only 45% of patients with at least one polymorphic G allele responded compared with 80% of patients homozygous for the common T allele (odds ratio ¼ 4.9, 95% confidence interval ¼ 1.64-14.54, adjusted P-value ¼ 0.047). In addition, carrying at least one ERCC2 Lys751GlnG allele was significantly associated with shorter event-free survival (median ¼ 184 months, compared with 240 months for T T homozygotes; hazard ratio ¼ 5.76, 95% confidence interval ¼ 1.30-25.55; P-value ¼ 0.021). Although ototoxicity was only recorded in 32 patients, we found weak evidence of an association with the CC genotype of XPC Lys939Gln (P-value ¼ 0.042). This is the first pharmacogenetic study focused on osteosarcoma treatment providing evidence that polymorphic variants in DNA repair genes could be useful predictors of response to cisplatin chemotherapy in osteosarcoma patients.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

et al. 2009

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“…3 However, acquired resistance to the drug 4 and undesirable side effects including oto-, neuro-, and nephrotoxicities are severe limitations to its clinical use. In the wake of the success of cisplatin, thousands of cisplatin analogues were synthesized and evaluated with the aim of lessening or removing its toxic side effects, overcoming resistance, and providing oral bioavailability.…”

Section: ■ Introductionmentioning

confidence: 99%

Polymorphism in Cisplatin Anticancer Drug

et al. 2013

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This study reports a combined experimental and theoretical study of the solid-state polymorphism of the anticancer agent cisplatin. A complete assignment was performed for the inelastic neutron scattering (INS) and Raman spectra collected simultaneously for cisplatin, at different temperatures, with a view to obtain reliable and definitive evidence of the relative thermal stability of its α and β polymorphic species. A marked temperature-dependent hysteresis was observed, as previously reported in the literature. Theoretical calculations were carried out at the density functional theory level, using a plane-wave basis set approach and pseudopotentials. A detailed comparison with the experimental Raman and INS data showed that the α polymorph is present at the lowest temperatures, whereas the β form occurs near room temperature. Furthermore, regions of coexistence of both forms are identified, which depend on the working mode (heating or cooling). These findings imply that Raman spectroscopy allows clear identification of the α and β polymorphs at a given temperature and can unambiguously discriminate between them. Elucidation of the polymorphic equilibrium of this widely used anticancer drug is paramount for its pharmaceutical preparation and storage conditions.

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“…Platinum-based anticancer drugs, cisplatin, carboplatin and oxaliplatin, have been used world-wide to treat various cancers including testicular, ovarian and colorectal tumours in clinical settings [16,58]. The anticancer action of these platinum drugs results from their capacity to form DNAplatinum covalent adducts, which ultimately lead to apoptosis of cancer cells [76].…”

Section: Introductionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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Molecular mechanisms of resistance and toxicity associated with platinating agents

Cited by 1,388 publications

References 153 publications

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

Common variations in ERCC2 are associated with response to cisplatin chemotherapy and clinical outcome in osteosarcoma patients

Polymorphism in Cisplatin Anticancer Drug

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

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