Antibodies elicited against cis-diamminedichloroplatinum(II)-modified DNA are specific for cis-diamminedichloroplatinum(II)-DNA adducts formed in vivo and in vitro.

Poirier, Miriam C.; Lippard, Stephen J.; Zwelling, Leonard A.; Ushay, H. Michael; Kerrigan, Donna; Thill, Curtis C.; Santella, Regina M.; Grünberger, Dezider; Yuspa, Stuart H.

doi:10.1073/pnas.79.21.6443

Cited by 88 publications

(45 citation statements)

References 14 publications

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“…The study included the following: cisplatin, CDDP, for injection into animals, 0.5 mg/ml (Bristol-Myers Squibb); Anti-CDDP-DNA rabbit antiserum, NKI-A59 (gift from Dr. Leo den Engelse, Netherlands Cancer Institute, Amsterdam) (16,19); goat-antirabbit immunoglobulin, GAR (Dakopatts, Copenhagen, Denmark); rabbit peroxidase antiperoxidase complex (PAP, American Qualex, La Mirada, CA); calf thymus DNA, CT-DNA (Boehringer-Mannheim, Mannheim, Germany); Diaminobenzidine, DAB (Saveen Biotech, Malmo, Sweden); methyl-green, color index 42590 (Merck, Darmstadt, Germany); and Pertex (Histolab, Gothenburg, Sweden). PBS buffer was always prepared with 0.04% Triton-X.…”

Section: Immunoreagentsmentioning

confidence: 99%

Evaluation of a method for quantitative immunohistochemical analysis of cisplatin‐DNA adducts in tissues from nude mice

et al. 1994

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The reproducibility of an immunohistochemical method for visualization and quantitation of the cytotoxic drug cisplatin (CDDP) in its active position, bound to nuclear DNA, was investigated in tissues from CDDP-treated nude mice. Kidney, liver, and tumor sections were stained with a PAP technique using an antiserum elicited against CDDP-DNA adducts. The resulting brown nuclear precipitate was quantitated using a CAS 200 image analyzer. The variance components of the errors in the staining procedure and in the image analysis were estimated. The method was found to be feasible for comparisons between slides of the same type of tissue, stained in the same batch, and measured by one observer on one occasion. The method should be a valuable tool for studies of CDDP pharmacodynamics, sensitivity prediction, and the effects of interactions between CDDP and other drugs and chemomodulators.

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Section: Immunoreagentsmentioning

confidence: 99%

Evaluation of a method for quantitative immunohistochemical analysis of cisplatin‐DNA adducts in tissues from nude mice

et al. 1994

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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.…”

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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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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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“…The development of antisera against platinated DNA has opened the way for the detection of low-level Pt-DNA adducts in human material (Poirier et al, 1982;Lippard et al, 1983;Fichtinger-Schepman et al, 1985;Plooy et al, 1985;Sundquist et al, 1987;Terheggen et al, 1987Terheggen et al, , 1991Tilby et al, 1991;Chao et al, 1994). Until now, no serial measurements of Pt-DNA adducts have been performed in tumour cells of CDDP-treated patients.…”

Section: Discussionmentioning

confidence: 99%

Immunocytochemical analysis of cisplatin-induced platinum-DNA adducts with double-fluorescence video microscopy

Meijer

Vries²,

Dam³

et al. 1997

Br J Cancer

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SummaryTo detect low-level DNA platination, a sensitive immunocyto-and histochemical technique was developed using a polyclonal antibody. The antibody GPt, derived after immunization of rabbits with highly platinated DNA and purified with affinity chromatography, detected the main platinum (Pt)-containing intrastrand and interstrand adducts. Double-fluorescence microscopy image analysis was used to quantify Pt-DNA adducts with Hoechst 33258 fluorescence to locate the nuclei and with fluorescein isothiocyanate fluorescence to measure the immunosignal. A two-to five-fold dose-dependent difference in the level of cisplatin (CDDP)-induced Pt-DNA adducts between a CDDPsensitive and -resistant human tumour cell line was detected. Large differences in Pt-DNA adduct levels after in vitro CDDP incubation between human buccal cells, lymphocytes and biopsies of different tumour types were observed. Pt-DNA adduct levels were fivefold higher in human testicular tumours than in colon tumours, representing CDDP-sensitive and -resistant tumours, respectively, in the clinic. These data suggest the possibility of predictive testing by measuring Pt-DNA adduct levels. Pt-DNA adducts in patients after treatment with CDDP were shown in normal buccal cells and in imprints of fresh tumour biopsies as well as in paraffin-embedded tumour cells. The analysis of Pt-DNA adducts at a single-cell level in small samples of normal and tumour cells during and/or after treatment is feasible with GPt and will hopefully enable more selective treatment of patients.Keywords: cisplatin; platinum-DNA adducts; immunocytochemistry; histochemistry; polyclonal antibody; image analysis CDDP and its analogues are among the most important chemotherapeutic drugs in clinical practice with a broad spectrum of activity. Almost all patients treated for testicular cancer with CDDP-containing combinations respond, and approximately 80% are cured. In contrast, no cures can be obtained in the case of colon cancer and most other solid tumours, even when initially sensitive to this drug, for example in the case of small-cell lung cancer (Loehrer and Einhorn, 1984). In all of these settings, a number of patients will not respond to therapy, although side-effects will be similar to those of responders. It would be desirable to be able to predict response to therapy as, for non-responders, either dose intensification or other forms of treatment would be preferable to standard CDDP treatment.In the past, rather unsuccessful attempts have been made to predict responses to therapy. Studies were performed with detection methods for cell kill (Hamburger and Salmon, 1977) or proliferation inhibition (Mosman, 1983; Weisenthal et al, 1983) in solid tumour samples exposed to drugs in vitro. Attempts to predict the effects of treatment of childhood lymphoblastic leukaemia by exposure of (non-proliferating) peripheral blood blast cells in vitro to drugs before systemic treatment have been more successful (Pieters et al, 1991). For (Poirier et al, 1985(Poirier et al, , 1992Reed et...

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Antibodies elicited against cis-diamminedichloroplatinum(II)-modified DNA are specific for cis-diamminedichloroplatinum(II)-DNA adducts formed in vivo and in vitro.

Cited by 88 publications

References 14 publications

Evaluation of a method for quantitative immunohistochemical analysis of cisplatin‐DNA adducts in tissues from nude mice

Evaluation of a method for quantitative immunohistochemical analysis of cisplatin‐DNA adducts in tissues from nude mice

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

Immunocytochemical analysis of cisplatin-induced platinum-DNA adducts with double-fluorescence video microscopy

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