MODULATION OF TUMOR-CELL RESPONSE TO CHEMOTHERAPY BY THE ORGAN ENVIRONMENT

The outcome of cancer metastasis depends on the interaction of metasta tic cells with various host factors. The implantation of human cancer cells into anatomically correct (orthotopic) sites in nude mice can be used to ascertain their metastatic potential. While it is clear that vascularity and local immunity can retard or facilitate tumor growth, we have found that the organ environment also influences tumor cell fu nctions such as production of degradative enzymes. The organ microenvi ronment can also influence the response of metastases to chemotherapy. It is not uncommon to observe the regression of cancer metastases in one organ and their continued growth in other sites after systemic che motherapy. We demonstrated this effect in a series of experiments usin g a murine fibrosarcoma, a murine colon carcinoma, and a human colon c arcinoma. The tumor cells were implanted subcutaneously or into differ ent visceral organs. Subcutaneous tumors were sensitive to doxorubicin (DXR), whereas lung or liver metastases were not. In contrast, sensit ivity to 5-FU did not differ between these sites of growth. The differ ences in response to DXR between s.c. tumors (sensitive) and lung or l iver tumors (resistant) were not due to variations in DXR potency or D XR distribution. The expression of the multidrug resistance-associated P-glycoprotein as determined by flow cytometric analysis of tumor cel ls harvested from lesions in different organs correlated inversely wit h their sensitivity to DXR: increased P-glycoprotein was associated wi th overexpression of mdr1 mRNA. However, the organ-specific mechanism for upregulating mdr1 and P-glycoprotein has yet to be elucidated.