Current sample handling methods for measurement of platinum-DNA adducts in leucocytes in man lead to discrepant results in DNA adduct levels and DNA repair

Ma, Jingfei; Verweij, Jaap; As, Planting; M, de Boer-Dennert; He, van Ingen; Me, van der Burg; Stoter, G.; Jh, Schellens

doi:10.1038/bjc.1995.102

Cited by 27 publications

(21 citation statements)

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“…This effect was attributed to the reaction of cisplatin present in the whole blood with DNA in cells that had become permeabilized. The extraction method used in the present work differs in detail to that tested by Ma et al (1995), and certain aspects of the data presented are not consistent with the possibility that the adduct levels were influenced to a large extent by carry-over of active drug in the blood sample. For example, the levels of adducts were lower at 6 h after the start of cisplatin infusion than at 24 h, despite the fact that the concentration of free drug was essentially equal at these two time points.…”

Section: Resultscontrasting

confidence: 59%

“…The immunoassay used here, readily detected adducts at the levels found in PBLs of paediatric patients receiving conventional doses of cisplatin. Pt-DNA adduct levels ranged up to 5.9 nmol g-I DNA, values much higher than those determined by Reed (1990) (up to 0.4 nmol g-1 DNA), but similar to those determined by Fichtinger-Schepman (1990) (up to 10 nmol g-I DNA) and Ma (1995) (mean values 13 and 7 nmol g-' DNA). In the case of carboplatin, adduct levels were generally low and were only just detectable by the ELISA.…”

Section: Discussionsupporting

confidence: 62%

“…Effects of the DNA extraction method During the course of this work, Ma et al (1995) reported that extraction of DNA from frozen whole-blood samples resulted in higher adduct levels than were observed when white blood cells were British Journal of Cancer (1997) Figure 6 Model for the proposed reaction of cisplatin and carboplatin with DNA isolated from the fresh blood sample before freezing. This effect was attributed to the reaction of cisplatin present in the whole blood with DNA in cells that had become permeabilized.…”

Section: Resultsmentioning

confidence: 99%

“…However, to verify that the present results were not influenced by carry-over of active drug, cisplatin and carboplatin were added to samples of freshly obtained blood. The samples were then divided immediately and either frozen and extracted by our standard method, or processed according to the buffy coat method of Ma et al (1995). DNA extracted from frozen whole blood containing 1 JUM cisplatin (representing the mean concentration of free drug present in blood samples removed for adduct measurements) was not significantly more immunoreactive than DNA from blood not treated with platinum complexes.…”

Section: Resultsmentioning

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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Section: Resultscontrasting

confidence: 59%

Section: Discussionsupporting

confidence: 62%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

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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“…The volume of each sample was 4 ml except at time points 0, 4 and 21 h where a volume of 16 ml was collected. Samples at these three time points were also used for the collection of WBC and measurement of platinum DNA-adduct levels, according to a previously validated quantitative assay (Ma et al, 1995).…”

Section: Treatment Schedulementioning

confidence: 99%

Adaptive intrapatient dose escalation of cisplatin in combination with low-dose vp16 in patients with nonsmall cell lung cancer

et al. 2003

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The objective of this phase II and pharmacologic study was to explore the feasibility, toxicity and activity of adaptive intrapatient dose escalation of cisplatin in a dose-intensive weekly schedule using predefined levels of exposure, with the ultimate aim to improve the antitumour activity of the therapy in patients with nonsmall cell lung cancer (NSCLC). Platinum DNA-adduct levels in peripheral white blood cells during treatment were used as the primary parameter for adaptive dosing. If DNA-adduct levels were not available, the area under the concentration -time curve (AUC) of unbound platinum in plasma was used for dose adaptation. Target levels for DNA-adducts and AUC have been defined in a previously performed pharmacologic study. The feasibility of adaptive dosing was tested in 76 patients with stage IIIB and IV NSCLC, who were planned to receive 6 weekly courses of cisplatin at a starting dose of 70 mg m À2 , together with daily low oral dose of 50 mg VP16. In total, 37 patients (49%) who were given more than one course received a dose increase varying from 10 to 55%. The majority of patients reached the defined target levels by a dose increase during course two. Relevant grade 2 neurotoxicity was observed in eight (10%) patients and reversible ototoxicity grade 2 in 14 (18%) patients. The strategy of adaptive intrapatient dose adjustment of cisplatin is practically feasible in a research setting even when results for dose adaptation have to be reported within a short time-period of 1 week. The toxicity appeared to be manageable in this cohort of patients. In some patients, exposure after the standard dose was substantially lower than the defined target level and significant dose escalations of more than 50% had to be applied. The response rate (RR) was relatively high: overall 40% (29 out of 72 patients) partial remission (PR), in patients with stage IIIB the RR was 60% (15 out of 25 patients) and with stage IV 30% (14 out of 47 patients). Randomised studies are needed to determine whether the adaptive dosing strategy results in better efficacy than standard dosing.

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Prediction of treatment outcome by cisplatin‐DNA adduct formation in patients with stage III/IV head and neck squamous cell carcinoma, treated by concurrent cisplatin‐radiation (RADPLAT)

Hoebers¹,

Pluim²,

Verheij³

et al. 2006

Intl Journal of Cancer

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The purpose of our study was to test the predictive value of cisplatin-DNA adduct levels in head and neck squamous cell carcinoma (HNSCC) patients treated with cisplatin-radiation. Patients with advanced-stage HNSCC were treated within a randomized trial, investigating the optimal route of cisplatin administration, concurrently with radiation. Cisplatin was administered intra-arterially (IA, 150 mg/m 2 , with systemic rescue by sodium thiosulfate) or intravenously (IV, 100 mg/m 2 ). In a subgroup, adducts were quantified in normal tissue and tumor.32 P-postlabeling was used to quantify intrastrand guanosine-guanosine adducts (GG-adducts) and adenosine-guanosine adducts (AG-adducts). Adduct levels were correlated with treatment outcome. Thirty-five patients were included (21 IV and 14 IA). At median follow-up of 27 months, locoregional (LR) control was 75% at 1 and 70% at 2 years. Adduct levels in tumor were 4-5-fold higher than in white blood cells (WBC) for both IA and IV treatment (p 5 0.01). Adduct formation in WBC and buccal cells was higher in IV treated patients compared with IA infusion (p 5 0.049 and 0.005 for GG-adducts in WBC and buccal cells, respectively). Adducts in tumors after IA infusion were not statistically different from those after IV. A strong correlation was observed between GG-and AG-adduct formation (r 5 0.86, p < 0.001). Patients with higher GG adduct levels (>median) in primary tumor had significantly better disease free survival (DFS) than patients with lower ( median) adduct levels (p 5 0.02). For overall survival (OS), a nonsignificant trend was observed, again in favor of patients with higher adduct levels (p 5 0.06). In conclusion, cisplatin-DNA adduct formation in primary tumor appears to be predictive for DFS in HNSCC. No differences were observed in intratumoral adduct levels between IA and IV treatments, despite selective infusion of high-dose cisplatin with the IA procedure. However, systemic adduct levels (WBC and buccal cells) from IV patients were higher than in IA patients, consistent with less systemic exposure after IA administration. ' 2006 Wiley-Liss, Inc.Key words: head and neck cancer; chemoradiation; cisplatin; DNA adducts Outcomes for patients with advanced stage head and neck squamous cell carcinoma (HNSCC) have been unsatisfactory for treatment by radiation alone. Several strategies have been pursued to improve results of radiotherapy, including neoadjuvant chemotherapeutic regimens, adjuvant systemic treatment and the concurrent administration of chemotherapy during the radiation treatment course. In several studies on locally advanced HNSCC, it was shown that cisplatin-based chemotherapy, given concurrently with radiation therapy, improved both locoregional (LR) control and overall survival (OS). [1][2][3][4] This combined treatment is now considered the standard of care not only in advanced stage HNSCC but also in a variety of other solid tumors. [5][6][7][8][9] However, further improvement is warranted since LR recurrence rates of up to 30-40% are observed.I...

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Current sample handling methods for measurement of platinum-DNA adducts in leucocytes in man lead to discrepant results in DNA adduct levels and DNA repair

Cited by 27 publications

References 10 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

Adaptive intrapatient dose escalation of cisplatin in combination with low-dose vp16 in patients with nonsmall cell lung cancer

Prediction of treatment outcome by cisplatin‐DNA adduct formation in patients with stage III/IV head and neck squamous cell carcinoma, treated by concurrent cisplatin‐radiation (RADPLAT)

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