toremifene and Leukemia--Myeloid

Oestrogens can regulate immune functions, and due to this females have more effective immune responses than males. Oestrogens and anti-oestrogens enhance T-cell-dependent antibody production of B cells in vitro. The cytokine mediators which are behind oestrogen and anti-oestrogen induced effects are not yet known. The authors studied whether anti-oestrogens (tamoxifen and toremifene) can regulate PMA-induced cytokine production of B-, T- or myeloid cell lines. Anti-oestrogens, tamoxifen and toremifene, stimulated overall cytokine production on a B-cell line (Ball), whereas on a T-cell line (Molt-4) tamoxifen stimulated IL-1 beta, IL-6 and IFN-gamma production and toremifene inhibited it. Anti-oestrogens did not have any significant effect on cytokine production of myeloid cells.

Topics: B-Lymphocytes; Cell Line; Cytokines; Estrogen Antagonists; Humans; Leukemia-Lymphoma, Adult T-Cell; Leukemia, Myeloid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; T-Lymphocytes; Tamoxifen; Toremifene; Tumor Cells, Cultured

The reversing effect of toremifene, a new tamoxifen derivative, on multidrug resistance in a K562 subline and its mechanism were studied. K562 cells were cultured in serially increasing concentrations up to 1.0 microM daunorubicin (DNR), and were found to be 28 times more resistant to DNR in comparison to the parent cells. In the resistant cell line (K562/D1-9), intracellular accumulation of DNR was less than that of the parent cell line, and P-glycoprotein was overexpressed. The resistance was reversed by addition of toremifene in a dose-dependent manner in K562/D1-9, while toremifene had no effect in K562. DNR accumulation was also reversed by toremifene in K562/D1-9, but not in K562. However, there was no significant difference of toremifene retention between K562/D1-9 and K562, and neither verapamil nor DNR increased toremifene accumulation in K562/D1-9. Moreover, toremifene and verapamil did not show an additive effect on intracellular DNR accumulation. These results suggested that the reversing mechanism of toremifene is different from that of verapamil, and this compound could be a good candidate for overcoming multidrug resistance.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Carrier Proteins; Chemical Phenomena; Chemistry, Physical; Daunorubicin; Drug Resistance; Drug Screening Assays, Antitumor; Humans; Leukemia, Myeloid; Membrane Glycoproteins; Phenotype; Solubility; Toremifene; Tumor Cells, Cultured; Verapamil