Formation of DNA Adducts by the Anticancer Drug Carboplatin: Different Nucleotide Sequence Preferences in Vitro and in Cells

Blommaert, F.A.; Dijk-Knijnenburg, H.C.M. van; Dijt, Fransje J.; Engelse, L. Den; Baan, R.A.; Berends, Frits J.; Fichtinger-Schepman, Anne Marie J.

doi:10.1021/bi00026a031

Cited by 149 publications

(104 citation statements)

References 20 publications

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“…4. However, with carboplatin, the major adducts are 1,3-d(GXG) (36%) and 1,2-d(GG) (30%) (44). Despite these variations in the spectrum of cytotoxic DNA adducts formed with these different cisplatin analogs, both demonstrate synergistic activity with TPT.…”

Section: Discussionmentioning

confidence: 99%

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

Waardenburg

Jong

Eijndhoven

et al. 2004

Journal of Biological Chemistry

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Camptothecins constitute a novel class of chemotherapeutics that selectively target DNA topoisomerase I (Top1) by reversibly stabilizing a covalent enzyme-DNA intermediate. This cytotoxic mechanism contrasts with that of platinum drugs, such as cisplatin, which induce inter-and intrastrand DNA adducts. In vitro combination studies using platinum drugs combined with Top1 poisons, such as topotecan, showed a schedule-dependent synergistic activity, with promising results in the clinic. However, whereas the molecular mechanism of these single agents may be relatively well understood, the mode of action of these chemotherapeutic agents in combination necessitates a more complete understanding. Indeed, we recently reported that a functional homologous recombination pathway is required for cispla- TPT and CPT-11 have been approved for first and second line treatment of advanced colorectal cancer and second line treatment for ovarian cancer (7-9). As with most chemotherapeutics, these CPT analogs are administered in combination with other agents (10 -13). Although the molecular mechanisms of single agents may be well understood, the combination of two or more agents often induces surprising interactions, which necessitates a more complete understanding of the cytotoxic lesions induced by such combinations for optimal efficacy. For example, in vitro combination experiments using platinum agents, such as cisplatin (cDDP), carboplatin, or oxaliplatin, with a Top1 poison, TPT or CPT-11, demonstrated a sequencedependent synergy in various human tumor cell lines (14 -16). The most cytotoxic sequence was a platinum drug followed by a Top1 poison. Moreover, chemotherapeutic regimens that combine TPT/CPT-11 with platinum drug are showing some promise in the clinic (see Refs. 17-19 and references therein). However, the lack of insight into the mechanism of synergy hampers the optimal design of clinical studies based on the combination of platinum drugs and Top1 poisons.We recently reported genetic evidence that homologous recombination (HR) is responsible for the synergistic cytotoxicity of certain drug/Top1 poison combinations (20). Indeed, a functional HR pathway was required for the synergistic activity of platinum or X-irradiation in combination with TPT yet acted to suppress the synergistic combination of 1-␤-D-arabinofuranosyl cytidine

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Section: Discussionmentioning

confidence: 99%

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

Waardenburg

Jong

Eijndhoven

et al. 2004

Journal of Biological Chemistry

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“…These damages contribute 90% of the total damage introduced by cisplatin [5][6][7][8] . The intra-strand crosslinks induced by platinum-based therapeutic agents are mainly processed by nucleotide excision repair (NER), which is carried out by a minimal set of proteins including XPA, XPC-RAD23B, XPG, RPA, ERCC1-XPF, TFIIH, PCNA, DNA polymerase δ or ε, and DNA ligase I, in human cells [9,10] .…”

Section: Repair Of Intra-strand Crosslinksmentioning

confidence: 99%

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

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The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.

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“…The 1,3-d(GpXpG) cis-diammineplatinum(II) cross-links are the most abundant lesions produced by carboplatin whereas 1,2-d(GpG) cis-diammineplatinum (II) adducts that are preferred by cisplatin. 4 DNA damage induced by platinum-based drugs has been mainly investigated with the use of purified DNA. In a cellular environment, however, DNA is compacted in highly condensed chromatin structures, the fundamental building blocks of which are the nucleosomes.…”

Section: Introductionmentioning

confidence: 99%

Cisplatin Damage Overrides the Predefined Rotational Setting of Positioned Nucleosomes

Ober

Lippard

2007

J. Am. Chem. Soc.

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Cisplatin and carboplatin are used successfully to treat various types of cancer. The drugs target the nucleosomes of cancer cells and form intrastrand DNA cross-links that are located in the major groove. We constructed two site-specifically modified nucleosomes containing defined intrastrand cis-{Pt(NH 3 ) 2 } 2+ 1,3-d(GpTpG) cross-links. Histones from HeLa-S3 cancer cells were transferred onto synthetic DNA duplexes having nucleosome positioning sequences. The structures of these complexes were investigated by hydroxyl radical footprinting. Employing nucleosome positioning sequences allowed us to quantify the structural deviation induced by the cisplatin adduct. Our experiments demonstrate that a platinum cross-link locally overrides the rotational setting predefined in the nucleosome positioning sequence such that the lesion faces toward the histone core. Identical results were obtained for two DNA duplexes in which the sites of platination differed by approximately half a helical turn. Additionally, we determined that cisplatin unwinds nucleosomal DNA globally by approximately 24°. The intrastrand cis-{Pt(NH 3 ) 2 } 2+ 1,3-d(GpTpG) cross-links are located in an area of the nucleosome that contains locally overwound DNA in undamaged reference nucleosomes. Because most nucleosome positions in vivo are defined by the intrinsic DNA sequence, the ability of cisplatin to influence the structure of these positioned nucleosomes may be of physiological relevance.

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Formation of DNA Adducts by the Anticancer Drug Carboplatin: Different Nucleotide Sequence Preferences in Vitro and in Cells

Cited by 149 publications

References 20 publications

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

Platinated DNA Adducts Enhance Poisoning of DNA Topoisomerase I by Camptothecin

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Cisplatin Damage Overrides the Predefined Rotational Setting of Positioned Nucleosomes

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