In vivo effects of cis- and trans-diamminedichloroplatinum(II) on SV40 chromosomes: differential repair, DNA-protein crosslinking, and inhibition of replication

Ciccarelli, Richard B.; Solomon, Mark J.; Varshavsky, Alexander; Lippard, Stephen J.

doi:10.1021/bi00347a005

Cited by 207 publications

(123 citation statements)

References 19 publications

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“…In other investigations increased DNA repair synthesis induced by cis-DDP has been demonstrated in resistant tumor cells (25,26,27). It has been proposed that the lower cytotoxicity of trans-DDP is due to a more rapid repair of trans-than cis-DDP-DNA adducts (28), but other investigators have been unable to find any difference in the rate of removal of cis-DDP and trans-DDP adducts from the DNA of mammalian cells (29).…”

Section: Introductionmentioning

confidence: 97%

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: 97%

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

Hansson¹,

Wood

1989

Nucl Acids Res

109

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“…It would seem possible, then, that DAC-induced hypomethylation might reveal additional cDDP binding sites, particularly in GC-rich regions such as occur frequently in eukaryotic promotors and other regulatory sites. In favour of such suggestion is the observation that increased protein binding to DNA was found at hemymethylated sites after DAC treatment (Michalowsky & Jones, 1987); since cDDP crosslinks both proteins and DNA (Ciccarelli et al, 1985) such sites could provide for an excellent substrate for cDDP binding. However, against this explanation is the fact that we were able to demonstrate synergy between DAC and cDDP in a system where further hypomethylation could not occur, i.e.…”

Section: Discussionmentioning

confidence: 99%

2'-deoxy-5-azacytidine increases binding of cisplatin to DNA by a mechanism independent of DNA hypomethylation

Ellerhorst

Frost²,

Abbruzzese³

et al. 1993

Br J Cancer

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SummaryThe chemotherapeutic agents 2'-deoxy-5-azacytidine (DAC) and cisplatin (cDDP) have been shown in vitro to be synergystic in their cytotoxicity toward human tumour cells. We have investigated possible molecular mechanisms underlying this synergy using the plasmid pSVE3 in vitro and after transfection into CMT3 cells. Increased binding of cDDP to DAC-substituted DNA generated in vivo was confirmed by flameless atomic absorption spectrophotometry (FAAS). The Many factors are considered when selecting the drugs to be included in a regimen of combination chemotherapy. Frequently, agents are chosen based on toxicity profiles and demonstrated efficacy in clinical trials. Occasionally, in vitro cytotoxicity assays will suggest a synergistic interaction (i.e. the effect of the two drugs together is greater than the predicted additive effect), and this information can be used in designing treatment protocols. Previous studies from our laboratory, using human tumour cell lines, showed that synergistic cytotoxicity can be demonstrated between 2'-deoxy-5-azacytidine (DAC) and cis-dichlorodiaminoplatinum (cDDP) (Frost et al., 1990). The mechanism for synergy between cDDP and DAC remains to be elucidated. Theoretically, synergy between two drugs can occur at several cellular levels. One drug may increase cellular uptake of a second drug, or inhibit its removal from the cell. Metabolism of the second drug could be altered in a way that the drug persists in an active form for a longer time. For compounds that act at the level of DNA, incorporation or binding may be enhanced. The synergistic interaction between cDDP and DAC may likely take place at the DNA level, as this is where both drugs are known to exert their effects. cDDP binds directly to DNA, producing both intrastrand and interstrand crosslinks (Bird, 1978;Caradona et al., 1982;Pinto & Lippard, 1985). The intrastrand crosslinking is most frequent at N7 of adjacent guanosines. DAC is an analog of deoxycytidine, substituting a nitrogen for carbon 5 of the pyrimidine ring. DAC is incorporated into DNA (Vesely & Cihak, 1977) and functions as a DNA methyltransferase inhibitor (Creusot et al., 1982). The resulting DNA hypomethylation has been shown to be associated with changes in gene expression and cell differentiation (Jones & Taylor, 1980;Razin & Riggs, 1980 Materials and methods Plasmid preparationThe plasmid pSVE3 (Hartman et al., 1982), was isolated from E. coli DH5 cells (Hanahan, 1983) using the alkaline extraction method followed by CsCl density centrifugation and extensive dialysis as previously described (Sambrook et al., 1989).Cells and culture conditions CMT3 cells (Gerard & Gluzman, 1985) were maintained in Dulbecco's Modified Eagle Medium (DMEM) (Gibco, Grand Island, NY) supplemented with L-glutamine (292 yg ml-'), penicillin (500 U ml-1), streptomycin sulphate (100 fig ml-'), 10% fetal bovine serum (Hazleton, Lenexa, KS) at 37°C in a 10% CO2 humidified incubator.Determination of DAC incorporation into DNA CMT3 cells were plated in two 35 mm diameter...

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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%

“…Intrastrand crosslinks, especially between adjacent guanosine molecules, are not efficiently recognized and repaired. Therefore they accumulate in the DNA leading to the antitumor effect of cisplatin [33].…”

Section: Discussionmentioning

confidence: 99%

Dichlorobis(cycloalkylamine)platinum(II) complexes structure activity relationship on the human MDA-MB-231 breast cancer cell line

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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In vivo effects of cis- and trans-diamminedichloroplatinum(II) on SV40 chromosomes: differential repair, DNA-protein crosslinking, and inhibition of replication

Cited by 207 publications

References 19 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)

2'-deoxy-5-azacytidine increases binding of cisplatin to DNA by a mechanism independent of DNA hypomethylation

Dichlorobis(cycloalkylamine)platinum(II) complexes structure activity relationship on the human MDA-MB-231 breast cancer cell line

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