Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours

Schellens, Jan H.M.; Ma, Jingfei; Planting, A. S. T.; Burg, M.E.L. van der; Meerten, Esther van; Boer-Dennert, M. de; Schmitz, P. I. M.; Stoter, G.; Verweij, Jaap

doi:10.1038/bjc.1996.296

Cited by 120 publications

(88 citation statements)

References 46 publications

(12 reference statements)

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“…However, as most of the above studies did not include pharmacokinetic measurements, the possibility cannot be excluded that the variation in adduct levels in PBLs was simply a reflection of pharmacokinetic variability. Indeed, in support of this latter suggestion, the study described by Ma et al (1994) and Schellens et al (1996) did show a relationship between both adduct levels and cisplatin AUC, and AUC and response, as well as adduct levels and response.…”

Section: Discussionmentioning

confidence: 61%

“…More recently, in patients with a variety of tumour types, Blommaert et al (1993) found that immunohistological staining of buccal cells for carboplatininduced adducts was significantly higher in partial responders than in non-responders. Measurement of PBL Pt-DNA adduct levels by AAS also demonstrated higher levels in responding vs nonresponding patients (Parker et al, 1991) and it has been reported that response to single agent cisplatin, or cisplatin plus etoposide, was related to PBL adduct levels measured by AAS in a mixed group of 43 patients (Ma et al, 1994;Schellens et al, 1996). These separate studies support the concept that there may be a 'parallel' between malignant tumour tissues and normal cells, including PBLs, in their capacity to form, repair, or otherwise retain Pt-DNA adducts.…”

Section: Discussionmentioning

confidence: 95%

“…A major limitation of these studies is that the influence of pharmacokinetic variation was not investigated. This parameter has been examined in a recent study by Schellens et al (1996) that revealed a correlation between area under the plasma free-drug concentration vs time curve (AUC) and area under the leucocyte Pt-DNA adduct level vs time curve for the first course of cisplatin treatment in a group of adult patients with solid tumours. No studies have been reported conceming the molecular pharmacodynamics of cisplatin or carboplatin in paediatric patients.…”

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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: Discussionmentioning

confidence: 61%

Section: Discussionmentioning

confidence: 95%

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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“…Cytotoxicity from cisplatin and other platinum-containing drugs, such as oxaliplatin, results from the formation of platinum DNA adducts (Schellens et al, 1996;van de Vaart et al, 2000). One determinant of the level of platinum DNA adducts in the tissue of patients treated with platinum-containing drugs is the rate of DNA repair.…”

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confidence: 99%

ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen

et al. 2008

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Molecular markers involved in DNA repair can help to predict survival in gastric cancer patients treated with 5-FU plus platinum chemotherapy. Excision repair cross-complementing 1 (ERCC1) and thymidylate synthase (TS) mRNA expression levels were assessed in advanced gastric cancer tumour samples using real-time quantitative PCR in 76 patients treated with a modified FOLFOX (biweekly oxaliplatin plus 5-FU and folinic acid) regimen. Median survival time in patients with low ERCC1 levels was significantly longer than in those with high levels (15.8 vs 6.2 months; Po0.0001). Patients with high TS levels had longer survival than those with low levels (12.2 vs 10.1 months; P ¼ 0.01). Forty-eight patients with low ERCC1 and high TS levels had a median survival of 16.1 months (Po0.0001). The hazard ratio for patients with high ERCC1 expression was 9.4 (Po0.0001). In patients with high mRNA levels of ERCC1, alternative chemotherapy regimens should be considered.

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“…In a pharmocokinetic -dynamic study in 29 patients who received weekly cisplatin plus daily low-dose VP16, a significant correlation was found between the area under the unbound plasma concentration -time curve (AUC) of cisplatin (measured as platinum by atomic spectroscopy (AAS)) and the likelihood of tumour response (Schellens et al, 1996). In addition, a highly significant difference was found between DNA-adduct levels of platinum, as measured in peripheral white blood cells (WBC) by AAS in responders (n ¼ 10) and non-responders (n ¼ 19).…”

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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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Relationship between the exposure to cisplatin, DNA-adduct formation in leucocytes and tumour response in patients with solid tumours

Cited by 120 publications

References 46 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

ERCC1 mRNA levels and survival of advanced gastric cancer patients treated with a modified FOLFOX regimen

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

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