A novel animal model for the evaluation of the efficacy of drugs directed against the ErbB2 receptor on metastasis formation.
The ErbB2 receptor tyrosine kinase is often overexpressed in human malignancies and causally involved in transformation. High levels of ErbB2 in tumor cells correlate with an unfavorable prognosis. This makes the ErbB2 receptor an interesting target for tumor therapy, and several strategies have been designed to direct drugs to ErbB2-expressing cells. We established a novel cellular model that allows preclinical evaluation of ErbB2-directed drugs in immunocompetent animals. Renal carcinoma (Renca) cells are an established tumor cell line that originated in Balb/c mice. Upon intravenous transplantation, these cells form pulmonary metastases in Balb/c mice. The transforming genetic lesions in these cells are not fully characterized, but do not seem to involve alterations in ErbB2 gene expression. We transfected Renca cells with the gene encoding the human ErbB2 receptor to provide a target structure for specific drugs and with the bacterial lacZ gene to provide a sensitive means of detection of the tumor cells in the transplanted animals. These genetically modified cells form lung metastasis and can be easily visualized on the surface of lung tissue by staining with an X-gal solution. This allows a quantitative analysis of the number of ErbB2-expressing pulmonary metastasis. We previously used these Renca cells to evaluate the efficacy of an ErbB2-specific tumor toxin on pulmonary metastases in an adjuvant and a palliative treatment setting. In both cases, we achieved a dramatic reduction of disseminated lung lesions. Here we show that even at an advanced stage of metastasis formation, the ErbB2-specific toxin is able to efficiently reduce the number of pulmonary tumors.
Maurer-Gebhard
M
M
Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Schmidt
M
M
Azemar
M
M
Stöcklin
E
E
Wels
W
W
Groner
B
B
D000818:Animals; D002292:Carcinoma, Renal Cell / Q000276:immunology / Q000473:pathology / Q000628:therapy; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000276:immunology / Q000378:metabolism*; D005069:Evaluation Studies as Topic; D006801:Humans; D007121:Immunocompetence; D007150:Immunohistochemistry; D000922:Immunotoxins / Q000627:therapeutic use*; D007680:Kidney Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy; D007763:Lac Operon; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000276:immunology / Q000517:prevention & control / Q000556:secondary*; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D014162:Transfection; D014407:Tumor Cells, Cultured
D066246:ErbB Receptors; D000922:Immunotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases