PURPOSE: The biologic behavior of tumor cells is partially controlled by the microenvironment. We investigated the expression levels of several genes involved in metastasis and drug response in RENCA cells growing in ectopic (skin) and orthotopic (kidney) sites. MATERIALS AND METHODS: Murine renal carcinoma cells were injected into kidney (orthotopic) and subcutis (ectopic) of syngeneic mice. Mice were treated with doxorubicin (DXR) (8 mg/kg) on days 8 and 15 after tumor cell implantation. Drug response was measured both in vivo and ex vivo by measuring tumor size and MTT assay. We also performed an in situ mRNA hybridization to estimate the expression levels of mdr (multidrug resistance), EGFR (epidermal growth factor receptor) and type IV collagenase. RESULTS: RENCA cells growing in the kidney of syngeneic mice produced metastatic lesions in the lung (57% of mice), while the same cells growing in the subcutis did not. Tumors growing in the kidney were more resistant to DXR than tumors growing in the subcutis. MTT assays revealed that tumor cells derived from kidney were more resistant to DXR than those cells from subcutis. In situ hybridization analyses showed that transcripts of EGFR and type IV collagenase genes in kidney tumors were higher than those of subcutaneous tumors but mdr expression showed no difference between the two tumors. CONCLUSION: These results demonstrate that the organ environment influences the drug responsive ness and the expression of EGFR and type IV collagenase genes in murine renal cell carcinoma cells.