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Effects Of Antiestrogens On The Activity Of Lymphokine Activated Killer (LAK) Cells Reactive To Autologous Breast Cancer Cells: Effects On Estrogen Receptor (ER) Negative Tumor Cells.
1Mohammed Samy Afifi and, 2Mohamed Ibrahim Abu-Deba.
Departments of 1Immunology and 2Surgery, Medical Research Institute, Alexandria University, Egypt.

The non-steroidal estrogen antagonist tamoxifen (TX) which is currently used for treatment of estrogen-dependent (ER) breast carcinomas and some other hormone-dependent tumors was observed to have a beneficial effect on patients with estrogen receptor negative tumors. The reason for this is not clear up till now. Since killer cells and especially lymphokine activated killer (LAK) cells are one of the main effectors responsible for immunosurveillance, it is possible that the observed beneficiary effect of TX in patients with ER negative tumor might have resulted from stimulation of LAK cells. To test the hypothesis, surgically resected breast tumor cells and their in vitro generated autologous LAK cells were either pretreated with TX prior to or during the cytotoxicity assay. TX doses were chosen to the equivalent of the different physiological levels of estrogen. A four-hour pretreatment of effector cells with TX had no effect on the activity of LAK cells against their autologous breast cancer cells irrespective of their ER state. However, pretreatment of ER positive tumor cells with TX (10 and 100 nM) rendered them significantly more sensitive to LAK cell-mediated lysis as compared to untreated cells in a 4-hour 51Cr release assay. Moreover, The degree of susceptibility to lysis was in direct correlation of the dose to TX used, suggesting a direct mode of action. On the other hand, TX pretreatment of ER negative breast cancer cells did not affect their sensitivity to LAK-cell mediated lysis, suggesting a differential effect of TX on ER positive and negative tumor cells. In fact, enhanced LAK cell mediated lysis of ER negative tumor cells was only observed when TX was included in the assay and only at very low level (1 nM). This selective stimulation might have resulted from a mediator release with antiproliferative effect, possibly, interferon beta and /or tumor necrosis factor rather than simultaneous stimulation of LAK cells. Taken together, our results suggest a dual mechanism of action of tamoxifen, one direct, which is evident against ER positive tumor cells while the other is indirect through the release of immune mediators. This might explain the beneficiary effect observed with anti-estrogens in ER negative tumor patients.

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Copyright 2002 Egyptian Association of Immunologists .
Last modified: January 21, 2003 .