MODULATION OF DOXORUBICIN SENSITIVITY AND LEVEL OF P-GLYCOPROTEIN EXPRESSION IN HUMAN COLON-CARCINOMA CELLS BY ECTOPIC AND ORTHOTOPIC ENVIRONMENTS IN NUDE-MICE

The purpose of the study was to determine whether the organ environmen t can influence the response of colon cancer cells to chemotherapy. Th e highly metastatic human colon cancer cell line KM12L4, previously se lected for production of liver metastases in nude mice, was injected i nto the cecal wall and into the spleen to produce liver metastases, an d into the subcutis of nude mice. Doxorubicin (DOX) at 10 mg/kg or sal ine (control) was injected intravenously on days 7 and 16 after tumor cell injection. The in vivo response of tumors growing in the cecum, l iver, and subcutaneous (s.c.) sites as well as the DOX sensitivity of cell lines established from liver and s.c. tumors were compared. Colon cancers growing s.c. were more sensitive to DOX than tumors growing i n the cecal wall or liver of nude mice. The difference in response to DOX between s.c. tumors (sensitive) and liver tumors (resistant) was n ot due to selection of cell populations with different sensitivity to DOX, or differences in DOX distribution. PKC activity was lower in tum ors of the liver and the cecum than in s.c. tumors. The expression of P-glycoprotein as determined by flow cytometric analysis of tumor cell s harvested from lesions in different organs correlated inversely with their sensitivity to DOX. Increased levels of P-glycoprotein correlat ed with mdr-1, mdr-3 mRNA expression as determined by Northern analysi s. Collectively, the data show that the organ environment influences t he response of human colon carcinoma cells to DOX and recommend that a nimal models of this disease for experimental therapeutic studies empl oy orthotopic implantation of tumor cells.