抗雌激素和醋酸甲羟孕酮对他莫昔芬敏感及耐药人乳腺癌细胞克隆形成生长的影响

[Effects of antiestrogens and medroxyprogesterone acetate on the clonogenic growth of tamoxifen-sensitive and resistant human breast cancer cells].

作者信息

Nomura Y, Tashiro H, Takaeko F

出版信息

Gan To Kagaku Ryoho. 1985 Apr;12(4):844-50.

Abstract

Effects of tamoxifen (TAM), nafoxidine (NFA), 4-hydroxytamoxifen (4-OH-TAM), 3-hydroxytamoxifen (3-OH-TAM), and medroxyprogesterone acetate (MPA) on the clonogenic growth of a hormone-responsive human breast cancer cell line (MCF-7) and its tamoxifen-resistant variant (R-27) were studied. TAM, (10(-6)M) showed an inhibitory effect on the colony formation in a plastic dish of MCF-7 cells only in medium containing DDC-treated FCS (E2(-) medium). With the presence of E2 (10(-8)M) in the medium (E2(+) medium), TAM did not show any effect on cell growth. Irrespective of the presence or absence of E2 in the medium, there was no inhibitory effect of TAM on the clonogenic growth of R-27 cells. The ID50 values, expressed as the suppression of plating efficiencies, obtained by adding NFA, 4-OH-TAM, 3-OH-TAM, and MPA to the MCF-7 cells were shown to be 2 X 10(-7)M, less than 10(-8)M, 1 X 10(-7)M, and 4 X 10(-7)M, respectively in the E2 (-) medium, and 2 X 10(-6)M, 2 X 10(-7)M, 2 X 10(-6)M, and 4 X 10(-8)M respectively in the E2 (+) medium. For the R-27 cells, ID50 values obtained by adding NAF, 4-OH-TAM, 3-OH-TAM, and MPA were 7 X 10(-7)M, 5 X 10(-8)M, 4 X 10(-7)M, and 6 X 10(-8)M, respectively in the E2(-) medium, and 2 X 10(-6)M, 2 X 10(-6)M, greater than 5 X 10(-6)M, and 1 X 10(-8)M, respectively in the E2(+) medium. These results suggest that the antiestrogens used produce their suppressive effects on cell growth depending on the E2 concentration in the medium in these estrogen-responsive cell lines, and that the monohydroxytamoxifens are more potent than TAM in suppressing cell growth. The effects of MPA are shown to be different from the antiestrogen used in that MPA inhibited the growth of both TAM-sensitive and-resistant cells, independent of the presence or absence of E2 in the medium. The R-27 cell line, a variant of the MCF-7 cell line, appears to be a good model for studying antiestrogen resistance and for evaluating the effectiveness of agents against endocrine-resistant breast cancer cells.

摘要

研究了他莫昔芬（TAM）、奈福昔定（NFA）、4-羟基他莫昔芬（4-OH-TAM）、3-羟基他莫昔芬（3-OH-TAM）和醋酸甲羟孕酮（MPA）对激素反应性人乳腺癌细胞系（MCF-7）及其他莫昔芬耐药变体（R-27）克隆生长的影响。TAM（10⁻⁶M）仅在含有经DDC处理的胎牛血清的培养基（E2⁻培养基）中对MCF-7细胞在塑料培养皿中的集落形成有抑制作用。当培养基中存在E2（10⁻⁸M）时（E2⁺培养基），TAM对细胞生长无任何影响。无论培养基中是否存在E2，TAM对R-27细胞的克隆生长均无抑制作用。通过向MCF-7细胞中添加NFA、4-OH-TAM、3-OH-TAM和MPA获得的以接种效率抑制表示的ID50值，在E2⁻培养基中分别为2×10⁻⁷M、小于10⁻⁸M、1×10⁻⁷M和4×10⁻⁷M，在E2⁺培养基中分别为2×10⁻⁶M、2×10⁻⁷M、2×10⁻⁶M和4×10⁻⁸M。对于R-27细胞，在E2⁻培养基中添加NAF、4-OH-TAM、3-OH-TAM和MPA获得的ID50值分别为7×10⁻⁷M、5×10⁻⁸M、4×10⁻⁷M和6×10⁻⁸M，在E2⁺培养基中分别为2×10⁻⁶M、2×10⁻⁶M、大于5×10⁻⁶M和1×10⁻⁸M。这些结果表明，所使用的抗雌激素对细胞生长的抑制作用取决于这些雌激素反应性细胞系培养基中的E2浓度，并且单羟基他莫昔芬在抑制细胞生长方面比TAM更有效。MPA的作用与所使用的抗雌激素不同，因为MPA抑制TAM敏感和耐药细胞的生长，与培养基中是否存在E2无关。R-27细胞系作为MCF-7细胞系的变体，似乎是研究抗雌激素耐药性和评估针对内分泌耐药乳腺癌细胞的药物有效性的良好模型。