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 malignan cies and causally involved in transformation. High levels of ErbB2 in tumor cells correlate with an unfavorable prognosis. This makes the ErbB2 recept or an interesting target for tumor therapy, and several strategies have bee n designed to direct drugs to ErbB2-expressing cells. We established a nove l cellular model that allows preclinical evaluation of ErbB2-directed drugs in immunocompetent animals. Renal carcinoma (Renca) cells are an establish ed tumor cell line that origined in Balb/c mice. Upon intravenous transplan tation, these cells form pulmonary metastases in Balb/c mice. The transform ing 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 s tructure for specific drugs and with the bacterial lacZ gene to provide a s ensitive means of detection of the tumor cells in the transplanted animals. These genetically modified cells form lung metastasis and can be easily vi sualized on the surface of lung tissue by staining with an X-gal solution. This allows a quantitative analysis of the number of ErbB2-expressing pulmo nary metastasis, We previously used these Renca cells to evaluate the effic acy 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 advanc ed stage of metastasis formation, the ErbB2 specific toxin is able to effic iently reduce the number of pulmonary tumors.