Dran G, Luthy I A, Molinolo A A, Montecchia F, Charreau E H, Pasqualini C D, Lanari C
División Medicina Experimental, Instituto de Investigaciones Hematológicas, Academia Nacional de Medicina, Buenos Aires, Argentina.
Breast Cancer Res Treat. 1995 Aug;35(2):173-86. doi: 10.1007/BF00668207.
The effect of progesterone (Pg), medroxyprogesterone acetate (MPA), estradiol (E2), dihydrotestosterone (DHT) and dexamethasone (DEXA) was studied on the in vitro growth rate of a progestin-dependent (PD), estrogen-sensitive mammary tumor line originated in an MPA-treated BALB/c mouse (C4-HD), and on its estrogen-resistant variant (C4-HDR). The specificity of hormone action was further investigated using the anti-hormones RU-486 and hydroxyflutamide (FLU). Cell growth was evaluated in epithelial and fibroblast-enriched cultures using 3H-thymidine and/or autoradiography and immunocytochemistry. The results indicate that cell growth is directly stimulated by MPA and Pg at concentrations ranging from 10(-11) to 10(-7) M. RU486 prevented MPA-induced stimulation in concentrations 10 to 100 fold lower than those of MPA. When used alone, it inhibited cell proliferation only in concentrations higher than 10(-11) M. At nM concentrations, neither DEXA nor DHT stimulated 3H-thymidine uptake except DEXA at 100 nM. MPA-induced stimulation was not reverted by micromolar concentrations of FLU. As for E2 (10(-7)-10(-9) M) it prevented MPA stimulation only in cultures of estrogen-sensitive tumors. Progesterone receptors (PR) (475 +/- 115 fmoles/10(5) cells, n = 5) and estrogen receptors (ER) (ND-115 fmoles/10(5) cells, n = 5) were detected only in epithelial-enriched cultures. Serum from 7 day-MPA-treated mice induced a significant increase of 3H-thymidine uptake; an increase was also obtained with serum from untreated ovariectomized animals to which 1 nM-100 nM concentrations of MPA had been added. The stimulatory effect of the exogenous MPA was much lower than that of the serum obtained from MPA-treated animals. It is concluded that MPA stimulates cell growth of primary cultures of MPA-induced PD tumors via PR. The results provide support for a direct effect of MPA which may be mediated or potentiated by serum factors.
研究了孕酮（Pg）、醋酸甲羟孕酮（MPA）、雌二醇（E2）、双氢睾酮（DHT）和地塞米松（DEXA）对源自经MPA处理的BALB/c小鼠（C4-HD）的孕激素依赖性（PD）、雌激素敏感乳腺肿瘤细胞系及其雌激素抗性变体（C4-HDR）体外生长速率的影响。使用抗激素RU-486和氟他胺（FLU）进一步研究了激素作用的特异性。使用3H-胸腺嘧啶核苷和/或放射自显影及免疫细胞化学技术，在富含上皮细胞和成纤维细胞的培养物中评估细胞生长。结果表明，浓度范围为10^(-11)至10^(-7) M的MPA和Pg可直接刺激细胞生长。RU486在浓度比MPA低10至100倍时可阻止MPA诱导的刺激。单独使用时，它仅在浓度高于10^(-11) M时抑制细胞增殖。在纳摩尔浓度下，除了100 nM的DEXA外，DEXA和DHT均未刺激3H-胸腺嘧啶核苷摄取。微摩尔浓度的FLU不能逆转MPA诱导的刺激。至于E2（10^(-7)-10^(-9) M），它仅在雌激素敏感肿瘤的培养物中阻止MPA刺激。仅在富含上皮细胞的培养物中检测到孕激素受体（PR）（475±11 fmol/10^5细胞，n = 5）和雌激素受体（ER）（未检测到-115 fmol/10^5细胞，n = 5）。来自经MPA处理7天的小鼠的血清可显著增加3H-胸腺嘧啶核苷摄取；向未处理的去卵巢动物的血清中添加1 nM-100 nM浓度的MPA也可增加摄取。外源性MPA的刺激作用远低于从经MPA处理的动物获得的血清。结论是，MPA通过PR刺激MPA诱导的PD肿瘤原代培养物的细胞生长。结果支持MPA的直接作用可能由血清因子介导或增强的观点。
