M.G.W. den Boer

Growth inhibition, cytokinesis failure and apoptosis of multidrug-resistant leukemia cells after treatment with P-glycoprotein inhibitory agents

The multidrug transporter P-glycoprotein (Pgp), which is frequently overexpressed in multidrug resistant leukemia, has many proposed physiological functions including involvement in transmembraneous transport of certain growth-regulating cytokines. Therefore, we studied cell growth of three pairs of drug resistant and sensitive leukemia cell lines (KG1a, K562 and HL60) exposed to three different inhibitors of Pgp. The resistant KG1a and K562 sublines, which expressed high levels of Pgp, responded to low doses of the cyclosporin SDZ PSC 833, the cyclopeptolide SDZ 280–446, and the cyclopropyldibenzosuberane LY335979 with a dose-dependent growth inhibition. In the resistant variants of KG1a and K562 cells the mean half-maximal growth inhibitory doses (GI50) of SDZ PSC 833 were 312 (SE 41) and 414 (SE 50) nM, those of SDZ 280–446 were 685 (SE 51) and 578 (SE 54) nM, and those of LY335979 were 66 (SE 1) and 48 (SE 8) nM, respectively. Exposure to 1 μM SDZ PSC 833 resulted in tetraploidization, cytokinesis failure and apoptosis of the KG1a and K562 MDR variants. Conversely, parental cells with no or low levels of Pgp and the non-Pgp resistant variant of HL60 cells were not receptive to these cytotoxic effects. We conclude that inhibition of Pgp may exercise selective cytotoxicity in Pgp-rich leukemia cells indicating a possible therapeutic target in multiresistant leukemia.

Diverse effects of P-glycoprotein inhibitory agents on human leukemia cells expressing the multidrug resistance protein (MRP).

UNLABELLED Multidrug resistance (MDR) to cancer chemotherapy is frequently associated with decreased drug accumulation in cancer cells due to drug expulsion by multidrug transporters such as P-glycoprotein (Pgp) and multidrug resistance protein (MRP). The novel resistance modifying agents PSC 833, 280-446, and LY 335979 are primarily targeted at inhibition of Pgp, and their MRP inhibitory potential is largely unknown. OBJECTIVE In the present study we addressed the effect of these agents on MRP-derived drug resistance. MATERIALS Drug-resistant human leukemia cells with Pgp+/MRP- (KG1a/200, K562/150) and Pgp-/MRP+ (HL60/130) phenotypes were maintained in suspension cultures for experimental studies of drug accumulation and drug sensitization by Pgp inhibitors. METHODS Intracellular accumulation of the fluorescent anthracycline daunorubicin was measured by flow cytometry and fluorescence detection. Daunorubicin dose-response curves were generated by non-linear regression of electronically measured cell counts of 72- - 96-h cultures. The half-maximal growth inhibitory dose (GI50) was used as measure of growth inhibition. RESULTS All MDR phenotypes studied exercised significant resistance to daunorubicin. PSC 833, 280-446 and LY335979 were equal in sensitizing Pgp+/MRP- cells to daunorubicin-induced growth inhibition (p < 0.0001). The Pgp-/MRP+ cells responded to PSC 833 and 280-446 by increased accumulation of daunorubicin (p = 0.0022 and p = 0.0005, respectively) and sensitization to the drug (p = 0.0009 and p = 0.0007, respectively). Conversely, LY335979 did not affect accumulation of daunorubicin in Pgp-/MRP+ cells nor sensitize these cells to daunorubicin. CONCLUSION Pgp inhibitory agents have differential effects on MRP-derived drug resistance which could be exploited in treatment of multidrug resistance in cancer patients.

The Fight Against Organised Crime in Europe: A Comparative Perspective

This article provides an overview of the measures and actions taken by the Member States of the European Union in their fight against organised crime and transborder crime. The Action Plan to Combat Organized Crime adopted by the Ministers for Justice and Home Affairs during the Dutch EU Presidency, submitted some 30 recommendations with respect to greater harmonisation regarding the fight against organised crime in the EU Member States. The author gives a concise summary of the most relevant changes and the structural characteristics per Member State, paying attention to developments in the specific countries and the organisations involved. One of the conclusions reached is that few or no reforms within national investigative and prosecution authorities may be directly traced back to the regulatory impulses of the EU. Although the EU Action Plan has not yet realised a convergence of the systems, the European process of integration has increased the mutual transparency and knowledge of one anothers systems.This article provides an overview of the measures and actions taken by the Member States of the European Union in their fight against organised crime and transborder crime. The Action Plan to Combat Organized Crime adopted by the Ministers for Justice and Home Affairs during the Dutch EU Presidency, submitted some 30 recommendations with respect to greater harmonisation regarding the fight against organised crime in the EU Member States. The author gives a concise summary of the most relevant changes and the structural characteristics per Member State, paying attention to developments in the specific countries and the organisations involved. One of the conclusions reached is that few or no reforms within national investigative and prosecution authorities may be directly traced back to the regulatory impulses of the EU. Although the EU Action Plan has not yet realised a convergence of the systems, the European process of integration has increased the mutual transparency and knowledge of one anothers systems.

Security clouds: Towards an ethical governance of surveillance in Europe

Within the European Union (EU), several instruments have been created at local, national and international level to monitor the movements of persons, goods and systems. The political justification of this vast expansion of surveillance instruments is based on the supposed need for security actors to predict and prevent security voids. In this article, we argue that the emergence of security clouds – the spray of data on individuals that floats between accumulated data-systems and networked surveillance instruments – present a considerable challenge to the governance of surveillance. The formally pronounced objects of combating crime and terror can be conceptualized as emerging forms of governance through surveillance and therefore influence societies deeper than merely in the field of security governance. Data which are fused in the security clouds can be stored for different purposes by different actors, acquire new functionalities and technical applications. The responsibility for surveillance technolog...Within the European Union (EU), several instruments have been created at local, national and international level to monitor the movements of persons, goods and systems. The political justification of this vast expansion of surveillance instruments is based on the supposed need for security actors to predict and prevent security voids. In this article, we argue that the emergence of security clouds – the spray of data on individuals that floats between accumulated data-systems and networked surveillance instruments – present a considerable challenge to the governance of surveillance. The formally pronounced objects of combating crime and terror can be conceptualized as emerging forms of governance through surveillance and therefore influence societies deeper than merely in the field of security governance. Data which are fused in the security clouds can be stored for different purposes by different actors, acquire new functionalities and technical applications. The responsibility for surveillance technologies reaches beyond the scope of traditional scrutiny mechanisms, including parliaments, judicial authorities and civilian oversight bodies. The European, national, vertical and horizontal legal arrangements for transparency, access and data protection lack coherence and consistency. This article advocates a professional security ethic on top of a consolidated legal framework.

Wake-up call for the Lowlands: Dutch counterterrorism from a comparative perspective

The Netherlands is one of the few countries in Western Europe that did not experience massive terrorist attacks and where counterterrorism actions did not feature prominently on the political agenda. Until quite recently, the Netherlands had neither emergency legislation for terrorist incidents nor a specific Act that criminalized terrorist offences. In response to the European Union framework legislation, a bill was produced that penalizes participation in a terrorist organization, flanked by a vast array of other measures. This article analyses the policy, institutional and legislative responses to terrorism in the Netherlands and compares these with responses from other European states. The events of 9/11, as well as the political and public anxiety over the murders of Pim Fortuyn and Theo van Gogh, acted as a firm wake-up call for the Netherlands insofar as the threat of terrorism is concerned. Whilst most countries adopted an incremental approach to countering terrorism, the Netherlands witnessed a radical shift in criminal justice and law enforcement policy following these events.The Netherlands is one of the few countries in Western Europe that did not experience massive terrorist attacks and where counterterrorism actions did not feature prominently on the political agenda. Until quite recently, the Netherlands had neither emergency legislation for terrorist incidents nor a specific Act that criminalized terrorist offences. In response to the European Union framework legislation, a bill was produced that penalizes participation in a terrorist organization, flanked by a vast array of other measures. This article analyses the policy, institutional and legislative responses to terrorism in the Netherlands and compares these with responses from other European states. The events of 9/11, as well as the political and public anxiety over the murders of Pim Fortuyn and Theo van Gogh, acted as a firm wake-up call for the Netherlands insofar as the threat of terrorism is concerned. Whilst most countries adopted an incremental approach to countering terrorism, the Netherlands witnessed a r...

Police, policy and politics in Brussels: scenarios for the shift from sovereignty to solidarity

This article analyses the evolution of European Union (EU) police cooperation on the basis of structural processes in the form of agencification, regulation and standardization, as well as substantive processes in the form of information-sharing and multi-disciplinary cooperation. The Lisbon Treaty holds some key conditions for further integration. The level of integration of police cooperation in the EU is measured by analysing institutional power, the regulatory framework and transnational professionalism. Despite a positive score on each of these levels, member states remain caught between national sovereignty and solidarity. As a consequence, they face an implementation gap and have not embedded European police cooperation in their domestic systems. Building on the pro-integrative moves that have been introduced by virtue of the Lisbon Treaty, improved governance and deeper integration can be achieved by means of more active parliamentary involvement, independent police oversight (both at European and at the national level), the mainstreaming of cooperation mechanisms and a systematic Europe-wide cultivation of police professionalism. Within the realm of internal security cooperation in the EU, a concerted effort is required which demands close consultation between relevant institutional actors and the professional actors in the member states.