Das Hitzeschockprotein 90 als Ziel der
pharmakologischen Tumortherapie
mit Benzochinon-Ansamycinen

Zusammenfassung

Benzochinon-Ansamycine sind eine neuartige Gruppe von Antitumormedikamenten. Eine gut untersuchtes Beispiel ist Geldanamycin (NSC 122750). In verschiedenen präklinischen Modellen konnte für diese Substanzen in vitro und in vivo antineoplastische Aktivität gezeigt werden. Die Zielmoleküle der zytotoxisch wirksamen Vertreter dieser Gruppe sind Mitglieder der Hitzeschockprotein 90-Familie. Benzochinon-Ansamycine haben Einfluss auf eine Fülle verschiedenster regulatorischer Proteine, von denen einige, unter anderem mutiertes p53, ErbB2, Raf-1 und Fak von genereller onkologischer Bedeutung sind. Diese Proteine haben eine direkte, physische Interaktion mit dem Hitzeschockprotein 90 und werden dadurch in funktionsbereitem Status gehalten. Die Auflösung dieser Bindung führt zur raschen Destabilisierung der Klientenproteine und zum proteolytischen Abbau durch das Proteasom. Ein Benzochinon-Ansamycin mit günstigem Toxizitätsprofil, das 17-(allylamino)-17-demethoxygeldanamycin (NSC 330507), ist zur Zeit in der klinischen Phase I Prüfung.

Abstract

Benzoquinone-ansamycins are a novel group of antitumor drugs. Geldanamycin (NSC 122750) is a well studied example. These compounds demonstrated antineoplastic activity in different preclinical in vitro and in vivo model systems. The target molecules of the cytotoxic agents from this group are the members of the heat shock protein 90-family. Benzoquinone-ansamycins affect a multitude of different regulatory proteins, some of which like mutant p53, ErbB2, Raf-1 and Fak are of general oncological significance. These proteins stand in direct physical interaction with heat shock protein 90 and thus are maintained in a functional state. The dissolution of this binding results in the rapid destabilization of the client proteins and in proteolytic degradation mediated by the proteasome. 17-(allylamino)-17 demethoxygeldanamycin (NSC 330507) is a benzoquinone-ansamycin with a favorable toxicity profile that currently undergoes clinical phase I testing.

Schlüsselwörter

Benzochinon-Ansamycine - Hitzeschockprotein 90 - Geldanamycin - 17-(allylamino)-17-demethoxygeldanamycin

Key words

Benzoquinone-ansamycins - Heat shock protein 90 - Geldanamycin - 17-(allylamino)-17-demethoxygeldanamycin

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