The inefficiency of incisions of ecteinascidin 743–DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent

Zewail-Foote, Maha; Li, Ven Shun; Kohn, Harold; Bearss, David J.; Guzman, Mary; Hurley, Laurence H.

doi:10.1016/s1074-5521(01)00071-0

Cited by 73 publications

(51 citation statements)

References 43 publications

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“…The formation of a putative Rad13/DNA-trabectedin cytotoxic ternary complex is consistent with earlier proposals that a protein/ DNA-trabectedin intermediate in the NER processing of trabectedin-DNA adducts could be trapped and give rise to the formation of cytotoxic complexes (17,38). DNA repair inhibition, rather than excision of the lesion, due to direct immobilization of NER factors by another type of adduct, has also been reported (39).…”

Section: Discussionsupporting

confidence: 90%

Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

et al. 2006

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Trabectedin (Yondelis) is a potent antitumor drug that has the unique characteristic of killing cells by poisoning the DNA nucleotide excision repair (NER) machinery. The basis for the NER-dependent toxicity has not yet been elucidated but it has been proposed as the major determinant for the drug's cytotoxicity. To study the in vivo mode of action of trabectedin and to explore the role of NER in its cytotoxicity, we used the fission yeast Schizosaccharomyces pombe as a model system. Treatment of S. pombe wild-type cells with trabectedin led to cell cycle delay and activation of the DNA damage checkpoint, indicating that the drug causes DNA damage in vivo. DNA damage induced by the drug is mostly caused by the NER protein, Rad13 (the fission yeast orthologue to human XPG), and is mainly repaired by homologous recombination. By constructing different rad13 mutants, we show that the DNA damage induced by trabectedin depends on a 46-amino acid region of Rad13 that is homologous to a DNA-binding region of human nuclease FEN-1. More specifically, an arginine residue in Rad13 (Arg961), conserved in FEN1 (Arg314), was found to be crucial for the drug's cytotoxicity. These results lead us to propose a model for the action of trabectedin in eukaryotic cells in which the formation of a Rad13/DNAtrabectedin ternary complex, stabilized by Arg961, results in cell death. (Cancer Res 2006; 66(16): 8155-62)

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Section: Discussionsupporting

confidence: 90%

Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

et al. 2006

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“…1C), whereas the disfavored sequence studied, CGA (34, 35), was not stabilized at all (data not shown). These results are consistent with previous findings using plasmid DNA molecules (35,36) and argues strongly in favor of the view that the hampering of DNA strand separation brought about by the covalent adduct may result in a strong blockade of transcription and replication forks in living cells. This behavior is reminiscent of that elicited by other antineoplastic drugs that give rise to true ICLs such as MMC (37).…”

Section: A Single Trabectedin Adduct Greatly Stabilizes Dsdnasupporting

confidence: 92%

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

Casado

Rı́o

Marco³

et al. 2008

Molecular Cancer Therapeutics

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Trabectedin (Yondelis; ET-743) is a potent anticancer drug that binds to DNA by forming a covalent bond with a guanine in one strand and one or more hydrogen bonds with the opposite strand. Using a fluorescence-based melting assay, we show that one single trabectedin-DNA adduct increases the thermal stability of the double helix by >20°C. As deduced from the analysis of phosphorylated H2AX and Rad51 foci, we observed that clinically relevant doses of trabectedin induce the formation of DNA double-strand breaks in human cells and activate homologous recombination repair in a manner similar to that evoked by the DNA interstrand cross-linking agent mitomycin C (MMC). Because one important characteristic of this drug is its marked cytotoxicity on cells lacking a functional Fanconi anemia (FA) pathway, we compared the response of different subtypes of FA cells to MMC and trabectedin. Our data clearly show that human cells with mutations in FANCA, FANCC, FANCF, FANCG, or FANCD1 genes are highly sensitive to both MMC and trabectedin. However, in marked contrast to MMC, trabectedin does not induce any significant accumulation of FA cells in G 2 -M. The critical relevance of FA proteins in the response of human cells to trabectedin reported herein, together with observations showing the role of the FA pathway in cancer suppression, strongly suggest that screening for mutations in FA genes may facilitate the identification of tumors displaying enhanced sensitivity to this novel anticancer drug.

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“…According to the proposed mechanism of action, trabectedin interacts with the transcription-coupled NER system forming cytotoxic complexes that cannot be resolved during the NER processing of DNA adducts (5). Then unrepaired adducts lead to formation of double-strand breaks and subsequent cell-cycle blocking (6) accounting for the fact that the homologous recombination repair (HRR) pathway has also been reported as important for modulating trabectedin response as the NER system (7,8). In line with these data, a number of works predicted that the clinical sensitivity to trabectedin could be defined by assessing the expression of a series of NER genes independently or along with selected repair factors from the HRR pathway (7,9).…”

Section: Introductionmentioning

confidence: 99%

Analysis of DNA Repair–Related Genes in Breast Cancer Reveals CUL4A Ubiquitin Ligase as a Novel Biomarker of Trabectedin Response

García

Saucedo-Cuevas

Muñoz-Repeto

et al. 2013

Molecular Cancer Therapeutics

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Trabectedin is more active in nucleotide excision repair (NER)-efficient and homologous recombination repair (HRR)-deficient cells. As up to 25% of sporadic breast tumors present somatic inactivation of the HRR pathway (BRCAness phenotype), we sought to characterize trabectedin effect in BRCA1-proficient and BRCA1-null breast cancer cell lines. We evaluated whether HRR and NER gene expression correlates with trabectedin sensitivity and explored the response predictive value of the CUL4A ubiquitin ligase, which ubiquitinates NER pathway members. We characterized trabectedin cytotoxicity, cell-cycle effects, and BRCA1, BRCA2, XRCC3, XPG, ERCC1, and CUL4A expression in 10 breast cancer cell lines. Gene expression and trabectedin sensitivity association were determined in cell lines. Survival assays after trabectedin treatment were conducted in CUL4A-silenced BRCA1-proficient and -deficient cells. Because of limited phase II clinical trials evaluating trabectedin efficacy in patients with breast cancer, we assessed CUL4A immunohistochemical staining in a retrospective series of 118 sarcomas from trabectedin-treated patients to validate in vivo our in vitro observations. In cell lines, greater trabectedin sensitivity was associated with higher CUL4A expression and lower BRCA1/ERCC5, BRCA1/CUL4A, and XRCC3/CUL4A expression ratios. In agreement, BRCA1-deficient CUL4A-knockdown cells presented higher cell survival after trabectedin exposure than did scramble control cells. Lack of effect in BRCA1-proficient cells suggests that HRR impairment is key in CUL4A-mediated trabectedin sensitivity. High CUL4A expression in nontranslocation-related patients with sarcoma predicted improved progression-free survival [PFS; HR, 0.37; 95% confidence interval (CI), 0.20-0.68, P ¼ 0.001] and overall survival (OS; HR, 0.44; 95% CI, 0.21-0.93, P ¼ 0.026). Our observations support the notion of greater trabectedin activity in tumors exhibiting BRCAness and reveal CUL4A as a potential biomarker for definition of trabectedin target patients. Mol Cancer Ther; 12(4); 530-41. Ó2013 AACR.

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The inefficiency of incisions of ecteinascidin 743–DNA adducts by the UvrABC nuclease and the unique structural feature of the DNA adducts can be used to explain the repair-dependent toxicities of this antitumor agent

Cited by 73 publications

References 43 publications

Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

Cross-Talk between Nucleotide Excision and Homologous Recombination DNA Repair Pathways in the Mechanism of Action of Antitumor Trabectedin

Relevance of the Fanconi anemia pathway in the response of human cells to trabectedin

Analysis of DNA Repair–Related Genes in Breast Cancer Reveals CUL4A Ubiquitin Ligase as a Novel Biomarker of Trabectedin Response

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