AntiCancer Inc, San Diego, CA, U.S.A.
Graduate School of Medicine, International University of Health and Welfare, Tokyo, Japan.
In Vivo. 2022 Nov-Dec;36(6):2630-2637. doi: 10.21873/invivo.12997.
BACKGROUND/AIM: Dedifferentiated liposarcoma (DDLS) is a type of soft-tissue sarcoma with a poor prognosis due to distant metastasis and resistance to chemotherapy. The antimalarial drug chloroquine (CQ) can induce apoptosis in cancer cells. CQ in combination with rapamycin (RAPA), an mTOR inhibitor, has shown efficacy on osteosarcoma and other types of cancer. In the present study the efficacy of RAPA combined with CQ on the treatment of a DDLS patient-derived orthotopic xenograft (PDOX) model was investigated.
A patient-derived DDLS was transplanted into the left retroperitoneum of nude mice to establish a DDLS PDOX nude-mouse model. The mice were randomly divided as follows: untreated control group; CQ group; RAPA group; combined CQ and RAPA group (n=7 for all groups). During the treatment period, tumor volume was measured every 3-4 days with calipers. After 2 weeks treatment, the mice were sacrificed, and H&E staining was performed for histological evaluation. The TUNEL assay was performed to detect apoptosis.
The combination of CQ and RAPA arrested tumor growth in the DDLS PDOX compared to the untreated control (p=0.009) and was significantly more effective than RAPA alone (p=0.009). RAPA alone slowed tumor growth, but the difference was not statistically significant (p>0.05). CQ was not active alone (p>0.05). The number of apoptotic TUNEL-positive cells was significantly higher in the CQ plus RAPA group than in the other groups (p=0.02).
Combination therapy with CQ and RAPA arrested tumor growth in a DDLS PDOX model by inducing apoptosis.
背景/目的：去分化脂肪肉瘤（DDLS）是一种软组织肉瘤，由于远处转移和化疗耐药，预后较差。抗疟药氯喹（CQ）可诱导癌细胞凋亡。CQ 联合雷帕霉素（RAPA），一种 mTOR 抑制剂，已显示出对骨肉瘤和其他类型癌症的疗效。本研究旨在探讨 RAPA 联合 CQ 治疗 DDLS 患者来源的原位异种移植（PDOX）模型的疗效。
将患者来源的 DDLS 移植到裸鼠左腹膜后，建立 DDLS PDOX 裸鼠模型。将小鼠随机分为以下几组：未治疗对照组；CQ 组；RAPA 组；联合 CQ 和 RAPA 组（每组 n=7）。在治疗期间，每隔 3-4 天用卡尺测量肿瘤体积。治疗 2 周后，处死小鼠，进行 H&E 染色进行组织学评价。进行 TUNEL 检测以检测凋亡。
与未治疗对照组相比，CQ 和 RAPA 联合治疗组在 DDLS PDOX 中抑制肿瘤生长（p=0.009），且明显优于 RAPA 单药组（p=0.009）。RAPA 单药组也能减缓肿瘤生长，但差异无统计学意义（p>0.05）。CQ 单药治疗无明显作用（p>0.05）。CQ 联合 RAPA 组的 TUNEL 阳性细胞凋亡数明显高于其他组（p=0.02）。
CQ 和 RAPA 联合治疗通过诱导凋亡抑制 DDLS PDOX 模型中的肿瘤生长。
