Altered expression of P-glycoprotein and cellular adhesion molecules on human multi-drug-resistant tumor cells does not affect their susceptibility to NK- and LAK-mediated cytotoxicity
✍ Scribed by Rik J. Scheper; William S. Dalton; Thomas M. Grogan; Arno Schlosser; William T. Bellamy; Charles W. Taylor; Phil Scuderi; Catherine Spier
- Publisher
- John Wiley and Sons
- Year
- 1991
- Tongue
- French
- Weight
- 819 KB
- Volume
- 48
- Category
- Article
- ISSN
- 0020-7136
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✦ Synopsis
Drug resistance has been associated with resistance to NKand LAK-cell-mediated cytotoxicity. We evaluated this issue in human cell lines, using multiple myeloma cells (8226) and 2 multi-drug-resistant (MDR) sublines selected using doxorubicin (8226/Dox40) and mitoxantrone (8226lMR40). In parallel, we studied the human breast carcinoma cell line series MCF7, MCF7/D40 and MCF7IMitox. Unlike the sensitive parental cell lines, all 4 sublines display MDR-patterns of resistance, with the P-glycoprotein pump (P-170) detected only in the doxorubicin-selected sublines. Flow cytornetric and immunocytochemical analyses showed expression of cellular adhesion molecules ICAM-I and LFA-3, and MHC-Class4 (MCF7ID40 only), to be decreased in the doxorubicin-selected MDRsublines, whereas expression of CD56 (Leu 19) was strongly up-regulated in 8226/Dox40. lysis of P-170-positive MDR tumor cells by NK or LAK cells was, however, unaffected by these alterations, suggesting redundancy in effect0r:targetcell adhesion pathways. Mitoxantrone-selected tumor cells did not display P-170, nor did they show altered expression of cellular adhesion molecules. Their susceptibility to N K or LAK cytolysis was also unimpaired as compared to the parental cell lines. Clinically, these results imply that immunotherapeutic modalities aiming at increased natural killer functions deserve full consideration even in patients who have become refractory to further cytostatic drug treatment. 'IC,, values for the parental cell l i e s . The IC,, refers to the drug concentration that results in a 50% reduction in colony fomation.-*Resistance factors determined by dividing the IC,, for the multi-drug-resistant sublines by the IC,, for the respective parent cell line~.-~Taylor er al., 1991.-4Dalton et d., 1989.-,Data not shown.