Cytostatic effect of antiestrogens in lymphoid cells: relationship to high affinity antiestrogen-binding sites and cholesterol.
The antiproliferative effect of 10(-6) M antiestrogens in an estrogen receptor-negative lymphoid cell line (K36) was enhanced in lipoprotein-poor growth medium. The enhancement was not due to increased bioavailability because cellular uptake of [3H]tamoxifen was not increased and the lipoprotein fraction of serum had negligible [3H]tamoxifen-binding capacity. Cholesterol and lipoproteins, but not mevalonate, reversed the cytostatic effect of antiestrogens. Reversal by cholesterol was dose-related (10(-7) M to 10(-5) M), while that by lipoproteins could also be demonstrated in medium undepleted of lipoproteins. The cytostatic efficacy of a series of ten compounds correlated well with their relative binding affinities for solubilized antiestrogen-binding sites from K36 cells when log IC50 values (concentration required to reduce [3H]thymidine incorporation by 50%) were plotted against log RBA50 values (concentration required to reduce [3H]tamoxifen binding by 50%) (correlation coefficient 0.94). Transmission electron microscopy of antiestrogen-treated cells showed evidence of disordered cytokinesis which was partially reversed by cholesterol. These observations implicate the antiestrogen-binding protein in the antiproliferative effect of antiestrogens in nonestrogen target cells.
Tang
B L
BL
Department of Biochemistry, National University of Singapore.
Teo
C C
CC
Sim
K Y
KY
Ng
M L
ML
Kon
O L
OL
D002455:Cell Division / Q000187:drug effects; D002784:Cholesterol / Q000494:pharmacology*; D002996:Clomiphene / Q000494:pharmacology; D003470:Culture Media; D004965:Estrogen Antagonists / Q000494:pharmacology*; D015458:Leukemia, T-Cell; D008074:Lipoproteins / Q000494:pharmacology; D008798:Mevalonic Acid / Q000494:pharmacology; D008854:Microscopy, Electron; D011955:Receptors, Drug; D011960:Receptors, Estrogen / Q000378:metabolism*; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism / Q000648:ultrastructure; D013629:Tamoxifen / Q000378:metabolism / Q000494:pharmacology; D014407:Tumor Cells, Cultured
D003470:Culture Media; D004965:Estrogen Antagonists; D008074:Lipoproteins; D011955:Receptors, Drug; D011960:Receptors, Estrogen; D013629:Tamoxifen; D002996:Clomiphene; D002784:Cholesterol; D008798:Mevalonic Acid