In summary, our results show that chloroacetaldehyde influences the oxidative phosphorylation in mitochondria, however, this is observed only in high concentrations and is not of clinical relevance because the tumor cells regenerate ATP by anaerobic glycolysis. Nevertheless, chloroacetaldehyde causes DNA-strand-breaks and strong inhibition of DNA-synthesis.

The goal of CESAR-EWIV is the development of new antitumoral agents and/or therapies and/or therapeutic strategies based on expertise in the fields of tumor biology, molecular biology, chemistry, pharmacology, clinical pharmacology and clinical oncology. The inter-disciplinary working group (CESAR-APOH) consists of clinical oncologists, pediatric oncologists, clinical pharmacologists and clinical pharmacists who meet once a year to discuss their latest scientific results. Within this meeting, the 10th interdisciplinary workshop of the Cooperative Study Group Cellular Resistance (www.cellular-resistance.de) has also been integrated. The personal host was Professor Dr. Frank Gieseler, to whom, on behalf of all participants, I would like to extend heartfelt appreciation for the outstanding organization. Two issues, the importance of basic research and the challenges of applied clinical research have been emphasized. Due to the carefully chosen topics and the fact that all speakers were allowed enough time for an in-depth discussion, a well-founded debate was possible. We are pleased to present this special issue as an example for interdisciplinary cooperation on a high scientific level.

ABSTRACT:Dexamethasone induces the hepatic cytochrome P450 3A and, therefore, is predicted to change the pharmacokinetics, activities, and side effects of drugs metabolized by cytochrome P450 3A. The aim of this study was to determine whether the pharmacokinetics of the cytochrome P450 3A-dependent oxazaphosphorine cytostatic drug ifosfamide is influenced by short-term antiemetic use of dexamethasone in patients. The peak concentration and area under the curve (AUC) were determined for the parent compound and the metabolites 4-hydroxyifosfamide and chloracetaldehyde in eight patients who received two cycles of ICE chemotherapy (ifosfamide 5 g/m 2 day 1, carboplatin 300 mg/m 2 day 1, etoposide 100 mg/m 2 days 1-3). One cycle included concomitant administration of dexamethasone (40 mg over 30 min, 16 h and 1 h before chemotherapy), whereas the other did not. The half-lives of ifosfamide, 4-hydroxyifosfamide, and chloracetaldehyde were shorter with concomitant administration of dexamethasone, but the differences were not statistically significant. In addition, there were no significant differences in the ifosfamide and active 4-hydroxyifosfamide peak concentrations and AUCs when dexamethasone was included. After dexamethasone administration, the chloracetaldehyde peak concentration was slightly increased by 1.5-fold and the AUC by 1.3-fold; however, these increases were not statistically significant. In conclusion, dexamethasone comedication in ICE chemotherapy did not change the ifosfamide pharmacokinetics. Thus, dexamethasone can be used safely as an antiemetic drug in ifosfamide chemotherapy.Dexamethasone (DEX) is frequently used as an antiemetic with highly emetogenic chemotherapy regimens, enhancing the antiemetic potential of 5-hydroxytryptamine 3 antagonists (Perez, 1998). DEX is known to induce hepatic cytochrome P450 3A via the SXR nuclear receptor (Xie et al., 2000) and thus could alter the pharmacokinetics, activities, and side effects of other cytochrome P450-dependent drugs, including oxazaphosphorine cytostatic ifosfamide (IFO) and cyclophosphamide. Both these prodrugs require hepatic activation to form 4-hydroxymetabolites (Furlanut and Franceschi, 2003). For IFO, a second metabolic pathway catalyzed by cytochromes P450 3A4 and 2B6 (Granvil et al., 1999;Huang et al., 2000) leads to the release of chloracetaldehyde (CAA). CAA is responsible for some side effects of IFO (Nicolao and Giometto, 2003;Aleksa et al., 2004) and has been reported to exert cytotoxic effects on tumor cells in vitro and in vivo, by inhibition of DNA synthesis and induction of DNA strand breaks (Brüggemann et al., 1997(Brüggemann et al., , 2006Börner et al., 2000;Brueggemann et al., 2002). Changes in the metabolism of IFO could result in unpredictable antitumor activities and side effects. Using cyclophosphamide in male rats, Yu et al. (1999) found DEX to increase the CAA values almost 10-fold compared with the controls without DEX administration. The peak levels and AUC of 4-hydroxycyclophosphamide were reduced by DEX administra...

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