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Targeted toxins

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands

G C de Gast

Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

J H M Schellens

Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands, Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

J H Beijnen

Department of Pharmacy and Pharmacology, The Netherlands Cancer Institute/Slotervaart Hospital, Amsterdam, The Netherlands, Department of Medical Oncology, The Netherlands Cancer Institute/Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands, Division of Drug Toxicology, Faculty of Pharmacy, Utrecht University, Utrecht, The Netherlands

Objective. Current modalities used in the treatment of cancer often cause unacceptable damage to normal tissue. Toxins targeted toward tumor cells by antibodies or growth factors have the potential to selectively kill tumor cells while leaving normal tissue intact. The purpose of this review is to provide background information on targeted toxins and current clinical studies for this new class of anti-cancer compounds.

Data sources. A MEDLINE search was conducted using the term "immunotoxins." Relevant articles were also obtained by the systematic examination of article references.

Data synthesis. The toxins Pseudomonas exotoxin, diphtheria toxin, and ricin toxin are often used as targeted toxins. Deletion or mutation of the binding domains of these toxins decreased binding of the toxins to normal tissues. Antibodies or growth factors can be used as targeting moiety, and the resulting agents are called immunotoxins or fusion proteins, respectively. DNA technology and chemical modifications of the toxin as well as the antibody moiety led to smaller and less immunogenic targeted toxins. Smaller targeted toxins are less toxic and penetrate further into the tumor. The summary of several targeted toxins elicited during clinical trials in this review makes it clear that several targeted toxins are potential agents for the treatment of various cancers, although some problems still need to be overcome. These problems include toxicity, immunogenicity, cross-reactivity of the targeted toxin with life-sustaining tissue, heterogenicity of tumor cells, and limited tumor penetration.

Key Words: Targeted toxins • Pseudomonas • exotoxin • diphtheria toxin • ricin

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