Division of Gynecologic Surgery, Mayo Clinic, Rochester, USA.
Department of Experimental Pathology, Mayo Clinic, Rochester, USA.
Gynecol Oncol. 2017 Jul;146(1):187-195. doi: 10.1016/j.ygyno.2017.04.022. Epub 2017 May 22.
Generate preclinical data on the effect of quinacrine (QC) in inhibiting tumorigenesis in endometrial cancer (EC) in vitro and explore its role as an adjunct to standard chemotherapy in an EC mouse model.
Five different EC cell lines (Ishikawa, Hec-1B, KLE, ARK-2, and SPEC-2) representing different histologies, grades of EC, sensitivity to cisplatin and p53 status were used for the in vitro studies. MTT and colony formation assays were used to examine QC's ability to inhibit cell viability in vitro. The Chou-Talalay methodology was used to examine synergism between QC and cisplatin, carboplatin or paclitaxel. A cisplatin-resistant EC subcutaneous mouse model (Hec-1B) was used to examine QC's role as maintenance therapy.
QC exhibited strong synergism in vitro when combined with cisplatin, carboplatin or paclitaxel with the highest level of synergism in the most chemo-resistant cell line. Neither QC monotherapy nor carboplatin/paclitaxel significantly delayed tumor growth in xenografts. Combination treatment (QC plus carboplatin/paclitaxel) significantly augmented the antiproliferative ability of these agents and was associated with a 14-week survival prolongation compared to carboplatin/paclitaxel. Maintenance with QC resulted in further delay in tumor progression and survival prolongation compared to carboplatin/paclitaxel. QC was not associated with weight loss and the yellow skin discoloration noted during treatment was reversible upon discontinuation.
QC exhibited significant antitumor activity against EC in vitro and was successful as maintenance therapy in chemo-resistant EC mouse xenografts. This preclinical data suggest that QC may be an important adjunct to standard chemotherapy for patients with chemo-resistant EC.
生成关于氯喹（QC）在体外抑制子宫内膜癌（EC）肿瘤发生的临床前数据，并探索其在 EC 小鼠模型中作为标准化疗辅助剂的作用。
使用 5 种不同的 EC 细胞系（Ishikawa、Hec-1B、KLE、ARK-2 和 SPEC-2）代表不同的组织学、EC 分级、对顺铂的敏感性和 p53 状态，进行体外研究。MTT 和集落形成测定用于检查 QC 抑制细胞活力的体外能力。Chou-Talalay 方法用于检查 QC 与顺铂、卡铂或紫杉醇之间的协同作用。使用顺铂耐药的 EC 皮下小鼠模型（Hec-1B）检查 QC 作为维持治疗的作用。
QC 与顺铂、卡铂或紫杉醇联合使用时在体外表现出很强的协同作用，在最具化疗耐药性的细胞系中协同作用最强。QC 单药治疗或卡铂/紫杉醇均不能显著延缓异种移植物中的肿瘤生长。联合治疗（QC 加卡铂/紫杉醇）显著增强了这些药物的抗增殖能力，并与卡铂/紫杉醇相比延长了 14 周的存活期。与卡铂/紫杉醇相比，QC 的维持治疗导致肿瘤进展进一步延迟和存活期延长。QC 不伴有体重减轻，治疗过程中出现的黄皮肤变色在停药后可逆转。
QC 在体外对 EC 表现出显著的抗肿瘤活性，并在化疗耐药的 EC 小鼠异种移植中成功作为维持治疗。这些临床前数据表明，QC 可能是化疗耐药 EC 患者标准化疗的重要辅助剂。
