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Modulation of Interferon Receptor Expression during Combination ß_ser-Interferon and -Interferon Treatment of Human Colon Carcinoma Cells¹

The University of Wisconsin Clinical Cancer Center, Madison, Wisconsin 53792; The William S. Middleton Memorial Veterans Administration Hospital, Madison, Wisconsin 53705; and Laboratory of Biochemical Physiology, Biological Response Modifiers Program, Division of Cancer Treatment and Biological Carcinogenesis Development Program, Program Resources, Inc., National Cancer Institute-Frederick Cancer Research Facility, Frederick, Maryland 21701

Combination treatment of SKCO1 human colon carcinoma cells with ß_ser-interferon (IFN-ß_ser) and -interferon (IFN-) results in a synergistic antiproliferative effect. The role of IFN-ß_ser and IFN- receptor modulation was investigated as a possible mechanism for this response. IFN- (0.05–50 ng/ml) pretreatment of SKCO1 cells for 24 h decreased specific binding of ¹²⁵I-IFN-ß_ser by 35–60%. Scatchard analysis of binding data obtained following 24-h treatment with 5 ng/ml IFN- showed that this reduction in binding was due to a decreased receptor affinity (control cells, K_d = 46 ± 1.6 pM; IFN--treated cells, K_d = 106 ± 6 pM, n = 2) rather than a significant change in receptor number (receptor number/control cell = 1214 ± 471, receptor number/IFN- treated cell = 1118 ± 153, n = 2). In contrast, pretreatment of SKCO1 cells with IFN-ß_ser (5 ng/ml) resulted in slight (10–35%) increases in ¹²⁵I-IFN--specific binding. Scatchard analysis of binding data obtained following 24-h treatment with 5 ng/ml IFN-ß_ser showed a decrease in binding affinity (control cells, K_d = 28 ± 7 pM; IFN-ß_ser-treated cells, K_d = 38 ± 7 pM, n = 2) and a 32% increase in IFN- receptor sites (receptor number/control cell = 4257 ± 464, receptor number/IFN-ß_ser-treated cell = 5570 ± 730; n = 2). ¹²⁵I-IFN- internalization studies performed at 37°C confirmed the cell surface binding assays; IFN-ß_ser-treated cells internalized 30–50% more labeled IFN- than untreated cells. However, it is unlikely that differences in binding and internalization of this magnitude play a primary role in the synergistic antiproliferative effect of IFN- with IFN-ß_ser in SKCO1 cells. Biochemical modulation at sites distal to the ligand receptor interaction should be investigated.

¹ This project has been funded, in part, with Federal funds from the Department of Health and Human Services under contract number NO1-CO-74102 with Program Resources, Inc. The content of this publication does not necessarily reflect the views or policies of the Department of Health and Human Services, nor does mention of trade names, commercial products, or organizations imply endorsement by the U. S. Government.

² Recipient of an American Cancer Society Clinical Oncology Career Development Award. Partially supported by the Veterans Administration.

³ To whom requests for reprints should be addressed, at the University of Wisconsin Clinical Cancer Center, K4/666, CSC, 600 Highland Avenue, Madison, WI 53792.

Received 11/ 7/88. Revised 7/ 7/89. Accepted 9/29/89.

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