Immunochemical quantitation of adducts induced in DNA by cis-diamminedichloroplatinum(II) and analysis of adduct-related DNA-unwinding

Fichtinger-Schepman, Anne Marie J.; Baan, R.A.; Luiten-Schuite, A.; Dijk, Margriet van; Lohman, P.H.M.

doi:10.1016/s0009-2797(85)80135-6

Cited by 69 publications

(29 citation statements)

References 12 publications

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“…Pt complexes exert their anti-tumour effect by reacting with DNA (Roberts and Thomson, 1979;Sherman and Lippard, 1987;Fichtinger-Schepman et al, 1995 (Poirier et al, 1982;Fichtinger-Schepman et al, 1985;Terheggen et al, 1988; Tilby et al, 1991). Preliminary clinical results with immunoassays for Pt-DNA adducts support the suggestion that adduct formation may relate to anti-tumour activity.…”

mentioning

confidence: 99%

“…The presumed cytotoxic lesions are Pt-DNA intra-and interstrand cross-links. To perform measurements of Pt-DNA adduct levels in the clinical setting, a number of groups have developed highly sensitive immunoassays (Poirier et al, 1982;Fichtinger-Schepman et al, 1985;Terheggen et al, 1988;Tilby et al, 1991). Preliminary clinical results with immunoassays for Pt-DNA adducts support the suggestion that adduct formation may relate to anti-tumour activity.…”

mentioning

confidence: 99%

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Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

Peng

Tilby²,

English³

et al. 1997

Br J Cancer

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Summary Platinum (Pt)-DNA adducts were measured in peripheral blood leucocytes (PBLs) from 24 children with solid tumours after standard cisplatin and/or carboplatin treatment. The relationship between Pt-DNA adduct levels and pharmacokinetics of cisplatin and carboplatin was investigated. Adduct measurements were performed by competitive enzyme-linked immunosorbent assay (ELISA) and plasma unbound Pt concentrations were measured by atomic absorption spectrophotometry (AAS). There was considerable interindividual variation in Pt-DNA adduct level that was weakly correlated (r 2 = 0.32) with the area under the unbound drug concentration vs time curve (AUC) at 6 h after the start of cisplatin infusion, indicating that the variation in Pt-DNA adduct levels was primarily determined by factors other than AUC. No clear relationship between AUC and adduct levels was seen at 24 and 48 h after cisplatin or at 6, 24 or 48 h after carboplatin. Carboplatin produced lower levels of immunoreactive adducts than did cisplatin (1.3±0.6 nmol Pt g-1 DNA vs 3.2 ± 1.7 nmol Pt g-' DNA), despite a 20-fold higher unbound drug AUC for carboplatin (8.0 ± 3.5 mg ml-' min vs 0.4 ± 0.2 mg ml-' min). This study demonstrates that, after cisplatin and carboplatin treatment the drug-target interaction is determined by both pharmacokinetic and, predominantly, cellular factors. Intrinsic differences between the two complexes, primarily reactivity, probably explain the lower adduct levels observed after carboplatin treatment.Keywords: cisplatin; carboplatin; Pt-DNA adduct; pharmacokinetics; child cancer Cisplatin and carboplatin are widely used in the treatment of solid tumours in childhood (Pinkerton et al, 1986;Pearson et al, 1992;Doz and Pinkerton, 1994). The activity and toxicity of cisplatin and carboplatin depend upon both pharmacokinetic and pharmacodynamic factors. A number of clinical pharmacokineticpharmacodynamic relationships have been described for cisplatin (Campbell et al, 1983;Reece et al, 1987;Thomas et al, 1994) and carboplatin (Egorin et al, 1984;Newell et al, 1987Newell et al, , 1993Harland et al, 1991;Horwich et al, 1991;Sorensen et al, 1991;Jodrell et al, 1992), and interpatient variability in tumour response to and/or tolerance of platinum (Pt)-complex therapy may relate to plasma levels more closely than to dose. Therefore optimum treatment with Pt drugs may necessitate adjustment for interindividual pharmacokinetic differences. Renal function-based dosing formulae have been developed for carboplatin administration to children (Marina et al, 1993;Newell et al, 1993;Chatelut et al, 1996) because carboplatin is cleared primarily by glomerular filtration.Although pharmacokinetics is one determinant of the clinical efficacy of Pt complexes, intracellular factors are certain to play an additional role. Pt complexes exert their anti-tumour effect by reacting with DNA (Roberts and Thomson, 1979;Sherman and Lippard, 1987;Fichtinger-Schepman et al, 1995 (Poirier et al, 1982;Fichtinger-Schepman et al, 1985;Terheggen et al, 1988; Tilby...

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confidence: 99%

mentioning

confidence: 99%

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

Peng

Tilby²,

English³

et al. 1997

Br J Cancer

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“…Whether platinum-protein actions should be taken into account or whether an altered frequency distribution of the platinum-DNA adducts should be considered under hyperthermic conditions cannot be determined from our data. However, an altered frequency distribution seems not to be very likely, because Fichtinger-Schepman et al (1985) found no change in adduct pattern when they incubated salmon sperm DNA with cisplatin at different temperatures. Determination of the precise contribution of platinum-DNA adduct formation in the thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin and absolute comparison of platinum-DNA adducts between the drugs is therefore not possible.…”

Section: Discussionmentioning

confidence: 93%

Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells

Rietbroek

Vaart

Haveman

et al. 1997

J Cancer Res Clin Oncol

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Disclaimer/Complaints regulationsIf you believe that digital publication of certain material infringes any of your rights or (privacy) interests, please let the Library know, stating your reasons. In case of a legitimate complaint, the Library will make the material inaccessible and/or remove it from the website. Please Ask the Library: http://uba.uva.nl/en/contact, or a letter to: Library of the University of Amsterdam, Secretariat, Singel 425, 1012 WP Amsterdam, The Netherlands. You will be contacted as soon as possible. Abstract The cytotoxicity of cisplatin and cisplatin-DNA adduct formation in vitro and in vivo is clearly enhanced by hyperthermia. We investigated whether cytotoxicity and platinum-DNA adduct formation of two promising new third-generation platinum derivatives, lobaplatin [1,2-diamminomethylcyclobutane platinum(II) lactate] and oxaliplatin [oxalato-l,2-diaminocyclohexane platinum(II)], are also enhanced by hyperthermia. Cisplatin was used for comparison. SW 1573 cells were incubated with cisplatin, lobaplatin or oxaliplatin at different concentrations for 1 h at 37 ~ 41 ~ and 43~ The reproductive capacity of cells was determined by cloning experiments. Immunocytochemical detection of platinum-DNA adducts was performed with the rabbit antiserum NKI-A59. At 37~ cisplatin was the most cytotoxic, followed by oxaliplatin and lobaplatin. Hyperthermia clearly enhanced the cytotoxicity of cisplatin, lobaplatin and oxaliplatin. There was no further increase in cytotoxicity at 43~ compared to 41~ for cisplatin and oxaliplatin. A further increase in cytotoxicity at 43~ was observed for lobaplatin. At 43~ thermal enhancement was higher for lobaplatin than for oxaliplatin, with the reverse pattern at 41~ For both drugs, thermal enhancement of cytotoxicity was lower than observed for cisplatin. Immunocytochemical detection of platinum-DNA adducts was feasible for all the drugs. Adduct formation was enhanced at 43~ for cisplatin, lobaplatin and oxaliplatin with a relative increase of 410%, 170% and 180%. These results seem to confirm that an increase in platinum-DNA adduct formation is involved in the in vitro thermal enhancement of cytotoxicity. The observed thermal enhancement of cytotoxicity of lobaplatin and oxaliplatin in vitro warrants further in vivo investigations.

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“…The reaction of MOAB F7-26 with drug-treated cells was explained by the distortion of conformation and by the appearance of single-stranded regions in alkylated DNA. Decreased stability of alkylated DNA was demonstrated in biochemical and cytochemical studies (1,6,13,17) but no technique for sensitive and reproducible measurements of local DNA denaturation in the cells treated with alkylating agents was developed. Selective binding of MOAB F7-26 to antigens exposed on single-stranded regions in alkylated DNA may be a valuable tool for the evaluation of distortions in the DNA double-helix.…”

Section: Discussionmentioning

confidence: 99%

Detection of cells resistant to alkylating agents by flow cytometric analysis of DNA damage

Frankfurt¹,

Seckinger²,

Sugarbaker³

1990

Cytometry

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DNA damage was measured by flow cytometric analysis of cells sensitive and resistant to alkylating agents. Human ovarian carcinoma cell line A2780 and a subline which is 7 times more resistant to L-phenylalanine mustard (L-PAM) were treated with the drug, fixed, and stained with monoclonal antibody (MOAB) F7-26 which detects single-stranded regions in alkylated DNA. Mean fluorescent intensity was measured on a flow cytometer. Cells were heated before staining to amplify single-strandedness in alkylated DNA. Significantly larger amount of MOAB was bound to DNA in sensitive than in resistant cells. We conclude that staining with MOAB F7-26 can be used as an indicator of cell sensitivity or resistance to alkylating agents. Detection of minor subsets of resistant cells in heterogeneous populations by FCM analysis may be useful for monitoring emerging drug resistance.Key terms: Monoclonal antibodies, flow cytometry, human ovarian carcinoma cell line A2780 Emergence of tumor cell populations which have resistance to anticancer drugs is a major problem in the successful application of cancer chemotherapy. Detection of resistant cells in heterogeneous populations may, therefore, have a critical role for selection and monitoring of tumor treatment.DNA damage is considered to be a target for antitumor and cytotoxic actions of alkylating agents. Biochemical methods were applied extensively for the analysis of DNA damage induced by these drugs (2,5,11,12,15,19). However, no methods for the measurement of DNA damage a t a cellular level applicable to heterogeneous cell populations were developed.In previous reports, the detection of DNA damage in individual cells using anti-DNA monoclonal antibody (MOAB) was described (7,s). The binding of MOAB F7-26 to DNA, in fixed EDTA-treated cells, correlated well with the decrease in cell viability induced by alkylating agents. However, the fluorescence intensity was not sufficient for complete separation between populations of control and drug-treated cells in fluorescence histograms or for the detection of cells with clinically relevant levels of drug resistance.In the current work, a modified highly sensitive procedure for FCM analysis of DNA damage was applied. The new procedure is based on the amplification of single-strandedness in alkylated DNA by heating in the presence of Mgzi. The effects of drug treatment on the binding of MOAB F7-26 to DNA in the cells sensitive and resistant to alkylating agents were compared in order to evaluate the ability of staining procedure to predict drug resistance. Since fluorescence difference in sensitive and resistant cells was sufficient to distinguish between two cell types, the method was then applied to heterogeneous populations of tumor cells. Mixed populations of sensitive and resistant cells were used as a model of tumors containing minor subsets of resistant cells.

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Immunochemical quantitation of adducts induced in DNA by cis-diamminedichloroplatinum(II) and analysis of adduct-related DNA-unwinding

Cited by 69 publications

References 12 publications

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

Platinum-DNA adduct formation in leucocytes of children in relation to pharmacokinetics after cisplatin and carboplatin therapy

Hyperthermia enhances the cytotoxicity and platinum-DNA adduct formation of lobaplatin and oxaliplatin in cultured SW 1573 cells

Detection of cells resistant to alkylating agents by flow cytometric analysis of DNA damage

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