Mechanism of toxicity of platinum(II) compounds in repair-deficient strains of Escherichia coli

Alazard, Robert; Germanier, Maryse; Johnson, Neil P.

doi:10.1016/0027-5107(82)90148-8

Cited by 61 publications

(26 citation statements)

References 13 publications

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“…The significance of repair of DNA lesions for cellular tolerance to cis-DDP is demonstrated by studies of repair deficient baceria (13,14,15,16), yeast cells (17), Chinese hamster cells (18) and human xeroderma pigInentosum cells (19,20,21). It has been shown in vitro that the E. coli UvrABC nuclease incises the 8th phosphodiester bond 5' and the 4th phosphodiester bond 3' to GG intrastrand cross-links, thus excising an oligomer containing the adduct (16).…”

Section: Introductionmentioning

confidence: 99%

Repair synthesis by human cell extracts in DNA damaged bycis- andtrans-diamminedichloroplatinum(II)

Hansson¹,

Wood

1989

Nucl Acids Res

109

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DNA damage was induced in closed circular plasmid DNA by treatment with cis-or transdiamminedichloroplatinum(l). These plasmids were used as substrates in reactions to give quantitative measurements of DNA repair synthesis mediated by cell free extracts from human lymphoid cell lines. Adducts induced by both drugs stimulated repair synthesis in a dose dependent manner by an ATP-requiring process. Measurements by an isopycnic gradient sedimentation method gave an upper limit for the average patch sizes in this in vitro system of around 140 nucleotides. It was estimated that up to 3% of the drug adducts induce the synthesis of a repair patch. The repair synthesis is due to repair of a small fraction of frequent drug adducts, rather than extensive repair of a rare subclass of lesions. Nonspecific DNA synthesis in undamaged plasmids, caused by exonucleolytic degradation and resynthesis, was reduced by repeated purification of intact circular forms. An extract made from cells belonging to xeroderma pigmentosum complementation group A was deficient in repair synthesis in response to the presence of cis-or trans-diamminedichloroplatinum(ll) adducts in DNA.

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Section: Introductionmentioning

confidence: 99%

Repair synthesis by human cell extracts in DNA damaged bycis- andtrans-diamminedichloroplatinum(II)

Hansson¹,

Wood

1989

Nucl Acids Res

109

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“…Trans-DDP forms similar adducts to those of cis-DDP with the exception that it cannot form 1,2-intrastand cross links (Pinto and Lippard, 1985) which represents greater than 90% of all adducts formed by cis-DDP. As a consequence of the damage in DNA caused by both platinum compounds, DNA replication is blocked and additionally cis-DDP induces a block in gene transcription (Pinto and Lippard, 1985;Alazard et al, 1982). Consequently, apoptosis induction by cis-DDP should not be related exclusively to the inhibition in DNA synthesis but additional mechanisms might trigger induction of this process.…”

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confidence: 99%

Cisplatin induces a persistent activation of JNK that is related to cell death

1998

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Genotoxic stress triggers signalling pathways that either mediate cell killing or protection of a ected cells. While induction of p53 is observed for most of the genotoxins, activation of MAPK/SAPK cascades is not a general response. The role of MAPK/SAPK activation on cell fate, seems to be dependent, in some systems, on the balanced response among both cascades. We have here examined the e ect of cis and trans-DDP on the activation of ERK and JNK activities. While no signi®cant induction of ERK was observed with the compounds, both of them are able to strongly activate JNK. Trans-DDP response is rapid and transient while the cis-DDP one is slow and persistent. In contrast with the observed nuclear translocation of JNK in response to U.V. light, none of the platinum compounds induces translocation, on the contrary, activation of JNK occurs in both the nuclear and cytoplasmic compartments. Inhibition of tyrosine phosphatases by orthovanadate pretreatment prolongs the time of JNK induction in response to both platinum compounds. The positive modulation of JNK activation correlates with an increase in toxicity that, for cis-DDP corresponds to a tenfold decrease in the IC 50 . A strong increase in MKP-1 levels was observed only in response to trans-DDP suggesting the involvement of this activity in the downregulation of JNK activity in response to this compound. Altogether the results suggest that the prolonged activation of JNK in response to cis-DDP contributes to cell death induction.

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“…[For a more extensive discussion of the structure activity-relationship of platinum(II) complexes, the reader is referred to reviews in the literature [-26-30].] The great differences in the antitumor activities of the stereoisomers of diamminedichloroplatinum(II) (cisplatin is a very potent drug, transplatin is ineffective) are attributed to a faster repair of the transplatin-DNA lesions [31][32][33][34]. The repair-resistant intrastrand crosslinks are formed by cisplatin but not by its trans isomer, for stereochemical reasons.…”

Section: Discussionmentioning

confidence: 99%

Dichlorobis(cycloalkylamin)platin(II)-Komplexe. Struktur ? Wirkungsbeziehungen an der menschlichen MDA-MB-231 Brustkrebszellinie

Kritzenberger

Bernhardt²,

Gust³

et al. 1993

Monatsh Chem

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Summary. The syntheses of dichlorobis(cycloalkylamine)platinum(II) complexes with cis and transcycloalkytamine ligands 2 to cis-PtC12(CaHlsNH2)2 (3-8) and trans-PtC12-(CTH13NH2)2 (9) and trans-PtC12(CsH~sNH2)2 (10)] are described. The distinction between cis and trans isomers was achieved by ~H-NMR spectroscopy. The antitumor activity was determined on the cell proliferation of the human MDA-MB-231 breast cancer ceil line during long-term drug exposure. The complexes with small cycloalkylamine ligands (3-6) were inferior, those with large cycloalkylamine ligands were comparable (7) or superior (8) to cisplatin. Surprisingly, the cis/trans isomers 7/9 and 8/10 were equally active. All cycloalkylamine ligands were inactive. IR-spectroscopic studies showed that the size of the cycloalkylamine ring does not lead to significant differences in the Pt-C1 binding strength. Therefore it is assumed that the markedly stronger antitumor activity of the higher homologues, 7-10, is not the result of a faster reaction with bionucleophils such as DNA. A possible explanation of the high activity of 7-10 is the strong lipophilicity of the complexes. This assumption was confirmed by toxicity tests against confluent cultures. Keywords. cis-and trans-Dichlorobis(cycloalkylamine)platinum(II)complexes

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Mechanism of toxicity of platinum(II) compounds in repair-deficient strains of Escherichia coli

Cited by 61 publications

References 13 publications

Repair synthesis by human cell extracts in DNA damaged bycis- andtrans-diamminedichloroplatinum(II)

Repair synthesis by human cell extracts in DNA damaged bycis- andtrans-diamminedichloroplatinum(II)

Cisplatin induces a persistent activation of JNK that is related to cell death

Dichlorobis(cycloalkylamin)platin(II)-Komplexe. Struktur ? Wirkungsbeziehungen an der menschlichen MDA-MB-231 Brustkrebszellinie

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