Antiestrogens affect both pathways of killer cell-mediated oncolysis.
BACKGROUND
Our previous studies indicate that antiestrogenic drugs tamoxifen (TX) and toremifene (TO) augment immune oncolysis induced by various killer cells. The underlying mechanism(s), however, have not been fully elucidated.


METHODS
Ovarian carcinoma cells freshly isolated from cancer patients and the human erythroleukemia cell line, K562 were used as targets for killer cells and/or the anti-Fas monoclonal antibody, CH-11 in 51Cr release assays. In a number of experiments, extracellular Ca++ was chelated by EGTA/MgCl2 to distinguish Ca(++)-dependent perforin/granzyme pathway from Fas/FasL pathway. Fas expression was studied by flow cytometry.


RESULTS
Ovarian carcinoma cells were sensitized by antiestrogens towards enhanced cytolysis mediated by autologous cytotoxic lymphocytes. Antiestrogens also significantly augmented the killing of ovarian carcinoma cells triggered by anti-Fas monoclonal antibody. Flow cytometry analyses showed an upregulation of Fas (CD 95/Apo-1) upon TX or TO treatment in a number of cases. By contrast, antiestrogen treatment did not induce Fas expression in the Fas-negative K562 cells; yet, natural killer cell-mediated cytotoxicity against K562 was augmented by antiestrogens and maximal lysis was achieved when both target and effector cells were treated. The presence of Ca++ chelator (EGTA/MgCl2) in the assay abrogated killing of K562 and its antiestrogen--mediated augmentation. This indicates the involvement of the perforin/granzyme pathway.


CONCLUSIONS
Antiestrogens can influence both Fas/FasL and perforin/granzyme pathways of killer cell--mediated oncolysis.
Department of Immunology, Faculty of Medicine, University of Manitoba Winnipeg, Canada.
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SM
Haeryfar
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Nagy
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Baral
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Krepart
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Lotocki
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Berczi
D010450:Endopeptidases / Q000187:drug effects / Q000276:immunology; D020847:Estrogen Receptor Modulators / Q000494:pharmacology*; D053222:Fas Ligand Protein; D005260:Female; D006801:Humans; D020014:K562 Cells; D015979:Killer Cells, Lymphokine-Activated / Q000187:drug effects* / Q000276:immunology; D007694:Killer Cells, Natural / Q000187:drug effects* / Q000276:immunology; D008562:Membrane Glycoproteins / Q000187:drug effects / Q000276:immunology; D010051:Ovarian Neoplasms / Q000473:pathology; D054353:Perforin; D052899:Pore Forming Cytotoxic Proteins; D012697:Serine Endopeptidases; D013602:T-Lymphocytes, Cytotoxic / Q000187:drug effects* / Q000276:immunology; D013629:Tamoxifen / Q000494:pharmacology; D017312:Toremifene / Q000494:pharmacology; D019014:fas Receptor / Q000187:drug effects / Q000276:immunology
D020847:Estrogen Receptor Modulators; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D019014:fas Receptor; D013629:Tamoxifen; D054353:Perforin; D017312:Toremifene; D010450:Endopeptidases; D012697:Serine Endopeptidases