Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation

Fichtinger-Schepman, Anne Marie J.; Veer, J. L. Van Der; Hartog, J. H. J. Den; Lohman, P.H.M.; Reedijk, J.

doi:10.1021/bi00324a025

Cited by 1,001 publications

(666 citation statements)

References 13 publications

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“…To address this issue, we first studied dose-and time-dependent effects of CDDP on NCCIT cells. Experiments indicated that following application of an optimal concentration of 50 mM CDDP, the apoptotic rate of tumour cells increased from approximately 10% at the beginning to about 95% at 24 h. Significant differences in the degree of apoptosis between CDDP-treated and untreated cells were, however, not observed before 6 h. In the light of previous data indicating that CDDP exerts its cytotoxicity via the formation of mono-, inter-, and intrastrand CDDP-DNA adducts, which can ultimately result in cell cycle arrest at G1, S or G2-M and in the induction of apoptosis (Fichtinger-Schepman et al, 1985;Sorenson and Eastman, 1988;Eastman, 1990), we hypothesised that within 6 h after application CDDP upregulated proapoptotic and/or downregulated antiapoptotic genes, thus mediating apoptosis in NCCIT cells. For a scanning view of differentially regulated genes, we investigated the expression profile of 205 apoptosis-related genes by applying a commercially available cDNA macroarray.…”

Section: Discussionmentioning

confidence: 46%

“…Cisplatin is a potent inducer of apoptosis in different cell types and is one of the most effective and widely used chemotherapeutic agents in the treatment of human cancers. Although CDDP-induced apoptosis is known to be the result of its ability to damage DNA (Wyllie et al, 1980;Fichtinger-Schepman et al, 1985;Sorenson and Eastman, 1988;Eastman, 1990), the mechanisms by which CDDP initiates apoptosis in TGCT are not completely understood.…”

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confidence: 99%

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Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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Testicular germ cell tumours (TGCT) represent the most common malignancies in young males. Whereas in 1970s, the survival rate in patients with metastatic testicular tumours was only 5%, these days, 80% of the patients treated by modern chemotherapy will survive their disease. The drug that revolutionised the cure rate for patients with metastatic testicular tumours was cisdiamminedichloroplatinum (cisplatin, CDDP). In vitro experiments on neoplastic germ cell lines showed that their exquisite sensitivity to CDDP could be attributed to p53-dependent and -independent pathways. Applying cDNA macroarray, semiquantitative RT -PCR and Western blot analyses, blocking experiments, caspase activity assays, and morphological methods, we sought here to define the p53-independent pathway(s) involved in the CDDP-induced apoptosis. For this purpose, we used the human TGCT cell line NCCIT, the mutated p53 of which is known to remain inactive during the course of CDDP-induced apoptosis. Our experiments showed that within hours of CDDP application, two prototype members of the 'mitogen-activated protein kinase' (MAPK) family, designated 'MAPK ERK kinase' (MEK) and 'extracellular signal-regulated kinase' (ERK), were dually phosphorylated and caspase-3 became active. Functional assays using MEK inhibitors demonstrated that the phosphorylation of MEK and ERK was required for the activation of caspase-3 as the executing caspase. Interestingly, experiments with the human malignant germ cell line NTERA, which is known to possess wild-type p53, revealed the same results. Thus, our data suggest that CDDP mediates its p53-independent apoptosis-inducing effect on the malignant human testicular germ cells -at least partially -through activation of the MEK -ERK signalling pathway.

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Section: Discussionmentioning

confidence: 46%

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confidence: 99%

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

et al. 2004

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“…The structures of both complexes were determined by X-ray crystallography. For K 2 [PtCl 2 (ace) 2 ] the platinum atom is coordinated to two Cl À and two N-acesulfamate atoms forming a trans-square planar geometry. Each K + ion interacts with two oxygen atoms of the S(@O) 2 group of each acesulfamate.…”

Section: Introductionmentioning

confidence: 99%

Pt(II) and Ag(I) complexes with acesulfame: Crystal structure and a study of their antitumoral, antimicrobial and antiviral activities

Cavicchioli

Massabni

Heinrich

et al. 2010

Journal of Inorganic Biochemistry

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“…[1] Among several platinum-containing candidates, cisplatin, carboplatin, and oxaliplatin have been approved for clinical use. [2] Investigation into the activity of cisplatin at the biomolecular level indicates that genomic DNA is the primary target, where cisplatin forms an adduct with adjascent purine bases, [3] particularly with guanine. [4][5][6] This coordination results in distortion of the DNA helix towards the major groove followed by unwinding of the DNA.…”

Section: Introductionmentioning

confidence: 99%

Phenanthroline Derivatives with Improved Selectivity as DNA‐Targeting Anticancer or Antimicrobial Drugs

et al. 2008

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Phenanthroline derivatives are of interest due to their potential activity against cancer, and viral, bacterial, and fungal infections. In a search for highly specific antitumor and antibacterial compounds, we report the activities of 1,10‐phenanthroline‐5,6‐dione (phendione or L1), dipyrido[3,2‐a:2′,3′‐c]phenazine (dppz or L2), and their corresponding platinum complexes ([PtL1Cl2] and [PtL2Cl2]), and provide the solid‐state 3D structure for [PtL1Cl2]. It is generally known that a toxic metal ion coordinated to an active organic moiety leads to a synergistic effect; however, we report herein that the platinum complexes [PtL1Cl2] and [PtL2Cl2] have weaker activities relative to those of the free ligands, especially against bacteria. Testing these agents against a variety of human cancer cell lines revealed that L1 and [PtL1Cl2] were at least as active as cisplatin against several of the cell lines (including a cisplatin‐resistant cell line). The absence of antibacterial activity of [PtL1Cl2] removes the detrimental effect of phenanthrolines toward intestinal flora, suggesting a highly promising new strategy for the development of anticancer drugs with reduced side effects.

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Adducts of the antitumor drug cis-diamminedichloroplatinum(II) with DNA: formation, identification, and quantitation

Cited by 1,001 publications

References 13 publications

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Cisplatin-induced apoptosis in human malignant testicular germ cell lines depends on MEK/ERK activation

Pt(II) and Ag(I) complexes with acesulfame: Crystal structure and a study of their antitumoral, antimicrobial and antiviral activities

Phenanthroline Derivatives with Improved Selectivity as DNA‐Targeting Anticancer or Antimicrobial Drugs

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