Effect of onapristone and medroxyprogesterone acetate on the proliferation and hormone receptor concentration of human breast cancer cells.
We studied the influence of the antiprogestin onapristone (ZK 98.299) and the progestin medroxyprogesterone acetate (MPA) on the proliferation and hormone receptor levels of the following human breast cancer cell lines: the oestrogen receptor (ER) and progesterone receptor (PR) negative cell line MDA-MB-231 and the ER- and PR-positive cell lines T47-D and SK-BR-3. MPA and onapristone both bind to the cellular PR and can inhibit the proliferation of hormone-dependent cells; PR-negative MDA-MB-231 cells are not inhibited. The growth inhibition of the ER- and PR-positive tumour cells induced by onapristone is accompanied by a significant accumulation of cells in the G0/G1 phase and a reduction of S-phase cells, while MPA does not change the distribution of the cell cycle phases. However, MPA reduces the cellular ER content by 27% and the PR content by more than 80%. Conversely, onapristone does not significantly affect ER and PR levels. The extent of growth inhibition by both drugs differs considerably: onapristone inhibits growth of both receptor positive cell lines (T47-D:39%; SK-BR-3:17%), while MPA affected growth in only SK-BR-3 (61%). These results indicate that even though the two drugs act through the PR, the inhibitory effect on the three cell lines of MPA may depend on ER concentration and its down-regulation, while the inhibitory effect of onapristone is mainly correlated to the PR concentration without significantly affecting ER levels. Since tumour cells with low ER concentration are growth suppressed by onapristone, but not by MPA, it remains to be examined whether antiprogestins should preferably be used in PR-positive tumours with a low ER concentration.
GSF-Forschungszentrum für Umwelt und Gesundheit, Ludwig-Maximilians-Universität München, Germany.
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Classen
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Possinger
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Pelka-Fleischer
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Wilmanns
D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002453:Cell Cycle / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D004273:DNA, Neoplasm / Q000378:metabolism; D005434:Flow Cytometry; D006067:Gonanes / Q000494:pharmacology*; D006801:Humans; D017258:Medroxyprogesterone Acetate / Q000494:pharmacology*; D011960:Receptors, Estrogen / Q000378:metabolism; D011965:Receptors, Glucocorticoid / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D011987:Receptors, Steroid / Q000187:drug effects / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D004273:DNA, Neoplasm; D006067:Gonanes; D011960:Receptors, Estrogen; D011965:Receptors, Glucocorticoid; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D017258:Medroxyprogesterone Acetate; C053238:onapristone