Systemic treatment with a recombinant erbB-2 receptor-specific tumor toxin efficiently reduces pulmonary metastases in mice injected with genetically modified carcinoma cells.

Abstract

Receptor-mediated targeted tumor therapy is an important applied consequence of the studies on the genetic causes of cancer. These therapy concepts have to be evaluated in novel animal models that reflect the molecular aberrations found in human tumors. Here we introduce an animal model that allows the evaluation of drugs directed against a surface receptor that is frequently altered in primary human adenocarcinomas. Tumor toxins are polypeptides in which a tumor cell-specific recognition domain and a toxic effector domain have been joined by DNA recombination in vitro. Tumor cell recognition is contributed by a single-chain antibody domain specific for the extracellular domain of the erbB-2 receptor [scFv(FRP5)] and cytotoxicity by the enzymatically active domain of a bacterial exotoxin (exotoxin A from Pseudomonas aeruginosa). The erbB-2 receptor is overexpressed in many primary human cancer cells and is a favorable target for directed tumor therapy. The fusion protein scFv(FRP5)-exotoxin A has previously been shown to be able to efficiently and specifically kill erbB-2 receptor-expressing tumor cells. We have investigated the potential of this tumor toxin to detect and eliminate metastasizing tumor cells upon systemic administration. Murine renal carcinoma cells genetically modified with human erbB-2 receptor and bacterial beta-galactosidase genes form large pulmonary metastases when injected into the tail vein of BALB/c mice. Administration of the tumor toxin over a 10-day time period starting 1 day after tumor cell transplantation totally suppressed the formation of metastases. The treatment of animals 11 days after tumor cell transplantation, allowing the establishment of many pulmonary metastases, led to a drastic reduction in their number and size.

• Authors: M Maurer-Gebhard, M Schmidt, M Azemar, U Altenschmidt, E Stöcklin, W Wels, B Groner
• Journal: Cancer research (Cancer Res) Vol. 58 Issue 12 Pg. 2661-6 (Jun 15 1998) ISSN: 0008-5472 [Print] United States
• PMID: 9635594 (Publication Type: Journal Article)

Chemical References

• Bacterial Toxins
• Exotoxins
• Recombinant Proteins
• Virulence Factors
• ADP Ribose Transferases
• Pseudomonas aeruginosa exotoxin A
• Receptor, ErbB-2

Topics

• ADP Ribose Transferases
• Animals
• Bacterial Toxins
• Carcinoma, Renal Cell (secondary)
• Exotoxins (therapeutic use)
• Female
• Genetic Engineering
• Genetic Therapy
• Humans
• Lung Neoplasms (pathology, secondary, therapy)
• Mice
• Mice, Inbred BALB C
• Neoplasm Invasiveness
• Receptor, ErbB-2 (drug effects)
• Recombinant Proteins (therapeutic use)
• Transfection
• Tumor Cells, Cultured
• Virulence Factors