IMMUNOTOKSYNY - CHARAKTERYSTYKA I ZASTOSOWANIE
Michał Kamiński1, Radosław Stachowiak1,*, Jacek Bielecki1
1Zakład Mikrobiologii Stosowanej, Instytut Mikrobiologii, Wydział Biologii UW
00-096 Warszawa, ul. Miecznikowa 1
Wpłynęło w lipcu 2010 r.
1. Wstęp. 2. Toksyny białkowe. 2.1. Toksyny bakteryjne. 2.1.1. Toksyna błonicza Corynebacterium diptheriae (DT). 2.1.2. Egzo-toksyna A Pseudomonas aeruginosa (PE). 2.2. Toksyny roślinne. 2.3. Toksyny zwierzęce. 2.4. Toksyny grzybowe. 3. Cząsteczki nośnikowe. 3.1. Przeciwciała i ich pochodne. 3.2. Cytokiny, czynniki wzrostowe oraz hormony. 4. Skutki uboczne immunotoksyn. 4.1. Zespół przesiękania naczyniowego (VLS). 4.2. Hepatotoksyczność. 4.3. Zespół hemolityczno-mocznicowy (HUS). 4.4. Inne skutki uboczne. 5. Próby zastosowania immunotoksyn. 5.1. Testy przedkliniczne. 5.1.1. Immunotoksyny oparte o PE. 5.1.2. Immunotoksyny oparte o DT. 5.2. Testy kliniczne. 5.2.1. Immunotoksyny oparte o PE. 5.2.2. Immunotoksyny oparte o DT. 6. Podsumowanie
Immunotoxins characteristics and applications
Abstract: Immunotoxins are a new group of therapeutics of potential use in targeted tumor therapy. The research has been conducted for the past 30-40 years but finding specific surface structures on targeted cells remains a major problem. Immunotoxins consist of two main fragments: protein toxin, which kills target cell after internalization, and carrier molecules which specifically identify and bind cancer cells.
Toxins used for immunotoxin preparation have various origin (plant, bacterial, fungal and animal). The most popular among them are: exotoxin A derived from Pseudomonas aeruginosa (PE), diphtheria toxin from Corynebacterium diphtheriae (DT) and ricin from Ricinus communis. The induction of cell death depends on the protein synthesis inhibition due to interactions with various targets such as a ribosomes or EF-2. Monoclonal antibodies, growth factors or cytokines are used as carrier molecules. The specificity of tumor antigen binding determines the type and severity of side effects, occurring due to immunotoxins binding with non-cancerous cells. Unfortunately, the majority of antibodies currently used for immunotoxins preparation recognize antigens that are expressed in both neoplastic and normal cells. Most common side effects include vascular leak syndrome (VLS) and hepatotoxicity.
A wide variety of immunotoxins have recently been tested in preclinical and clinical trials. Some of them show promising results, bringing hope for treatment of chemoresistant cancers.
1. Introduction. 2. Protein toxins. 2.1. Bacterial toxins. 2.1.1. Diphtheria toxin from Corynebacterium diptheriae (DT). 2.1.2. Egzotoxin A from Pseudomonas aeruginosa (PE). 2.2. Plant toxins. 2.3. Animal toxins. 2.4. Fungal toxins. 3. Carrier molecules. 3.1. Antibodies and antibody derivatives. 3.2. Cytokines, growth factors and hormones. 4. Immunotoxins side effects. 4.1. Vascular-leak syndrome (VLS). 4.2. Hepatotoxicity. 4.3. Hemolytic uremic syndrome (HUS). 4.4. Other side effects. 5. Immunotoxin trials. 5.1. Preclinical trials. 5.1.1. PE based immunotoxins. 5.1.2. DT based immunotoxins. 5.2. Clinical trials. 5.2.1. PE based immunotoxins. 5.2.2. DT based immunotoxins 6. Summary
Słowa kluczowe: immunotoksyny, DT, PE, VLS, denileukin diftitox
Key words: immunotoxins, DT, PE, VLS, denileukin diftitox
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