The effects of cyclosporin A, tamoxifen, and medroxyprogesterone acetate on the enhancement of Adriamycin cytotoxicity in primary cultures of human breast epithelial cells
The effects of cyclosporin A, tamoxifen, and medroxyprogesterone acetate on the enhancement of Adriamycin cytotoxicity in primary cultures of human breast epithelial cells
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DOI：
10.1007/bf01807156
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发表时间：
1996-01-01
影响因子：
3.8
通讯作者：
Emerman, JT
中科院分区：
文献类型：
--
作者：
Claudio, JA;Emerman, JT
阿霉素 (Adr) 是用于治疗乳腺癌的单一最活跃的药物，但由于多药耐药 (MDR) 肿瘤的发展，随着治疗的进展，阿霉素 (Adr) 可能会变得无效。与 MDR 相关的一个主要机制是 P-糖蛋白 (Pgp) 表达增加。本研究检验了抗雌激素他莫昔芬 (TAM) 和孕激素醋酸甲羟孕酮 (MPA) 以及已知的耐药调节剂环孢菌素 A (CsA) 增强 Adr 对原代培养物中人乳腺上皮细胞 (HBEC) 的细胞毒性作用的能力。分别使用单克隆抗体 C219 和 H222 Sp gamma 通过免疫细胞化学测定测定每种培养物中的 Pgp 和雌激素受体 (ER) 表达。 Adr 敏感的 Pgp-、ER+ MCF-7 细胞系和 Adr 抗性、Pgp+、ER-MCF7-AdrR 细胞系用作对照。原代培养物被分类为来自接受过或未接受过化疗的组织的 HBEC。在来自先前未接受化疗的组织的 15 个细胞培养物中的 1 个中检测到了 Pgp，在来自先前接受过化疗的组织的 6 个细胞培养物中的 5 个中检测到了 Pgp。与 CsA 或 MPA 加 Adr 一起孵育可增强 Pgp+ 细胞培养物中的 Adr 毒性，但不会增强 Pgp- 细胞培养物中的毒性，而 TAM 对任何培养物的敏感性均无影响。在 21 个 HBEC 原代培养物中，3 个为 ER+。 Adr细胞毒性的增强与ER状态之间没有相关性。数据表明 MPA 以及 CsA 可用作克服 Pgp 相关多药耐药性的修饰剂。
Adriamycin (Adr), the single most active agent used in the treatment of breast cancer, may become ineffective as treatment progresses due to the development of multidrug resistant (MDR) tumors. A major mechanism associated with MDR is increased P-glycoprotein (Pgp) expression. This study examined the abilities of the anti-estrogen tamoxifen (TAM) and the progestin medroxyprogesterone acetate (MPA) as well as cyclosporin A (CsA), a known resistance modifier, to enhance the cytotoxic effects of Adr on human breast epithelial cells (HBEC) in primary culture. Pgp and estrogen receptor (ER) expression were determined in each of the cultures by immunocytochemical assays using the monoclonal antibodies C219 and H222 Sp gamma, respectively. The Adr-sensitive, Pgp-, ER+ MCF-7 cell line and the Adr-resstant, Pgp+, ER-MCF7-AdrR cell line were used as controls. Primary cultures were categorized as HBEC from tissues with or without previous chemotherapy. Pgp was detected in 1 of the 15 cell cultures from tissues without previous chemotherapy and in 5 of the 6 cell cultures from tissues previously exposed to chemotherapy. Incubation with either CsA or MPA plus Adr enhanced Adr toxicity in Pgp+ but not Pgp- cell cultures, whereas TAM had no effect on the sensitivity of any of the cultures. Of the 21 primary cultures of HBEC, 3 were ER+. There was no correlation between the enhancement of Adr cytotoxicity and ER status. The data suggest that MPA as well as CsA may be useful as modifying agents in overcoming Pgp-associated multidrug resistance.