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纳米化疗颗粒与米非司酮联合使用的有效性取决于乳腺癌临床前模型中的PR异构体比例。

The effectiveness of nano chemotherapeutic particles combined with mifepristone depends on the PR isoform ratio in preclinical models of breast cancer.

作者信息

Sequeira Gonzalo, Vanzulli Silvia I, Rojas Paola, Lamb Caroline, Colombo Lucas, May Maria, Molinolo Alfredo, Lanari Claudia

机构信息

Institute of Experimental Biology and Medicine, IBYME-CONICET, Buenos Aires, Argentina.

出版信息

Oncotarget. 2014 May 30;5(10):3246-60. doi: 10.18632/oncotarget.1922.

DOI:10.18632/oncotarget.1922
PMID:24912774
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4102807/
Abstract

There is clinical and experimental evidence suggesting that antiprogestins might be used for the treatment of selected breast cancer patients. Our aim was to evaluate the effect of albumin-bound paclitaxel (Nab-paclitaxel) and pegylated doxorubicin liposomes (PEG-LD) in combination with mifepristone (MFP) in experimental breast cancer models expressing different ratios of progesterone receptor (PR) isoforms A and B. We used two antiprogestin-responsive (PRA>PRB) and two resistant (PRA<PRB) murine mammary carcinomas growing in BALB/c, GFP-BALB/c or nude mice, along with human T47D-YA and T47D-YB xenografts growing in immunocompromised NSG mice. MFP improved the therapeutic effects of suboptimal doses of Nab-paclitaxel or PEG-LD in murine and human carcinomas with higher levels of PRA than PRB. MFP induced tissue remodeling in PRA-overexpressing tumors, increasing the stromal/tumor cell ratio and the number of functional vessels. Accordingly, an increase in nanoparticles and drug accumulation was observed in stromal and tumor cells in MFP-treated tumors. We conclude that MFP induces an increase in vessels during tissue remodeling, favoring the selective accumulation of nanoparticles inside the tumors. We propose that antiprogestins have the potential to enhance the efficacy of chemotherapy in breast tumors with a high PRA/PRB ratio.

摘要

有临床和实验证据表明，抗孕激素可能用于治疗特定的乳腺癌患者。我们的目的是评估在表达不同比例孕激素受体（PR）同工型A和B的实验性乳腺癌模型中，白蛋白结合型紫杉醇（纳米白蛋白紫杉醇）和聚乙二醇化阿霉素脂质体（PEG-LD）与米非司酮（MFP）联合使用的效果。我们使用了两种抗孕激素反应性（PRA>PRB）和两种抗性（PRA<PRB）的小鼠乳腺癌，它们在BALB/c、GFP-BALB/c或裸鼠中生长，以及在免疫缺陷的NSG小鼠中生长的人T47D-YA和T47D-YB异种移植瘤。在PRA水平高于PRB的小鼠和人癌中，MFP提高了次优剂量纳米白蛋白紫杉醇或PEG-LD的治疗效果。MFP在PRA过表达的肿瘤中诱导组织重塑，增加基质/肿瘤细胞比例和功能性血管数量。因此，在MFP处理的肿瘤的基质和肿瘤细胞中观察到纳米颗粒和药物积累增加。我们得出结论，MFP在组织重塑过程中诱导血管增加，有利于纳米颗粒在肿瘤内的选择性积累。我们提出，抗孕激素有潜力提高PRA/PRB比值高的乳腺肿瘤的化疗疗效。

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