Growth Control of Normal and Malignant Lymphocytes – Cell Death Research from Basic Concepts to Signal Pathways and Translation into the Clinic

Abstract

Twenty years ago the fist bona fide death receptor, APO-1/FAS/CD95 was discovered along with the pathways that regulate programmed cell death or apoptosis. From the very beginning, this research was considered to have substantial impact on diseases and to provide a rational strategy for therapeutic intervention. In particular cell death research proved to be the key for the development of novel strategies for cancer therapy. In the past two decades, deregulated apoptosis in tumors has been delineated and possible targets for therapeutic intervention have been identified. However, it still took a long way until this work could be translated into clinical trials only in the past few years. Current strategies involve modification of apoptosis signalling based on our knowledge of sensitivity and resistance for apoptosis induction rather than the use of individual agents for cytotoxicity. In this review, an overview of the developments in the field from basic discoveries to the recent clinical trials is given.

Zusammenfassung

Vor 20 Jahren wurde Apo-1/Fas/CD95 als erster Rezeptor mit nahezu ausschließlicher Vermittlung von Zelltod gemeinsam mit Elementen der Signalwege, die programmierten Zelltod oder Apoptose regulieren, entdeckt. Sehr früh konnte man davon ausgehen, dass diese Forschung erheblichen Einfluss auf Verständnis und Entwicklung rationaler Strategien zur therapeutischen Behandlung einer Vielzahl von Erkrankungen haben wird. Insbesondere für die Entwicklung neuer Therapiekonzepte in der Krebstherapie hat sich die Erforschung der Zelltodesprogramme als wichtig erwiesen. In den letzten beiden Dekaden wurden die Grundlagen der deregulierten Apoptose in Tumoren charakterisiert und mögliche Zielstrukturen für therapeutische Interventionen identifiziert. Dennoch hat es lange Zeit gedauert, bis diese grundlegenden Erkenntnisse erst in den letzten Jahren in klinische Studien umgesetzt werden konnten. Die gegenwärtigen Strategien entwickeln auf Grundlage unseres Verständnisses von Sensitivität und Resistenz für Apoptoseinduktion Therapiekonzepte zur Modifikation von Apoptosesignalwegen. Die Anwendung einzelner Apoptose induzierender Substanzen steht demgegenüber zukünftig wohl im Hintergrund. In diesem Review wird eine Übersicht insbesondere über die Entwicklung in diesem Forschungsgebiet von den grundlegenden Entdeckungen bis zu den derzeit laufenden klinischen Studien gegeben.

Key words

apoptosis - signal pathways - cancer therapy - sensitivity and resistance in tumors

Schlüsselwörter

Apoptose - Signalwege - Krebstherapie - Sensitivität und Resistenz in Tumoren

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