一种 CXCR4 抑制剂（贝立司他）增强了多西他赛在前列腺癌骨转移小鼠模型中的抗肿瘤活性。
A CXCR4 inhibitor (balixafortide) enhances docetaxel-mediated antitumor activity in a murine model of prostate cancer bone metastasis.
机构信息
Department of Urology, University of Michigan, Ann Arbor, Michigan, USA.
Spexis AG, Allschwil, Switzerland.
出版信息
Prostate. 2023 Sep;83(13):1247-1254. doi: 10.1002/pros.24584. Epub 2023 May 27.
BACKGROUND
Prostate cancer (PCa) bone metastases have been shown to be more resistant to docetaxel than soft tissue metastases. The proinflammatory chemokine receptor CXCR4 has been shown to confer resistance to docetaxel (DOC) in PCa cells. Balixafortide (BLX) is a protein epitope mimetic inhibitor of CXCR4. Accordingly, we hypothesized that BLX would enhance DOC-mediated antitumor activity in PCa bone metastases.
METHODS
PC-3 luciferase-labeled cells were injected into the tibia of mice to model bone metastases. Four treatment groups were created: vehicle, DOC (5 mg/kg), BLX (20 mg/kg), and combo (receiving both DOC and BLX). Mice were injected twice daily subcutaneously with either vehicle or BLX starting on Day 1 and weekly intraperitoneally with DOC starting on Day 1. Tumor burden was measured weekly via bioluminescent imaging. At end of study (29 days), radiographs were taken of the tibiae and blood was collected. Serum levels of TRAcP, IL-2, and IFNγ levels were measured using ELISA. Harvested tibiae were decalcified and stained for Ki67, cleaved caspase-3, and CD34 positive cells or microvessels were quantified.
RESULTS
Tumor burden was lower in the combo group compared to the DOC alone group. Treatment with the combination had no impact on the number of mice with osteolytic lesions, however the area of osteolytic lesions was lower in the combo group compared to the vehicle and BLX groups, but not the DOC group. Serum TRAcP levels were lower in the combo compared to vehicle group, but not the other groups. No significant difference in Ki67 staining was found among the groups; whereas, cleaved caspase-3 staining was lowest in the Combo group and highest in the BLX group. The DOC and combo groups had more CD34+ microvessels than the control and BLX groups. There was no difference between the treatment groups for IL-2, but the combo group had increased levels of IFNγ compared to the DOC group.
CONCLUSIONS
Our data demonstrate that a combination of BAL and DOC has greater antitumor activity in a model of PCa bone metastases than either drug alone. These data support further evaluation of this combination in metastatic PCa.
背景
已经表明，与软组织转移相比，前列腺癌（PCa）骨转移对多西紫杉醇的耐药性更强。促炎性趋化因子受体 CXCR4 已被证明可赋予 PCa 细胞对多西紫杉醇（DOC）的耐药性。巴利昔芬（BLX）是 CXCR4 的蛋白表位模拟抑制剂。因此，我们假设 BLX 会增强 PCa 骨转移中 DOC 介导的抗肿瘤活性。
方法
将带有荧光素酶标记的 PC-3 细胞注入小鼠胫骨中以建立骨转移模型。创建了四个治疗组：载体，DOC（5mg/kg），BLX（20mg/kg）和联合组（同时接受 DOC 和 BLX）。从第 1 天开始，每天两次通过皮下注射载体或 BLX 开始治疗，每周一次通过腹腔内注射 DOC 开始治疗。每周通过生物发光成像测量肿瘤负担。在研究结束时（29 天），对胫骨进行 X 光检查并采集血液。使用 ELISA 测量血清 TRAcP、IL-2 和 IFNγ 水平。对收获的胫骨进行脱钙并对 Ki67、cleaved caspase-3 和 CD34 阳性细胞或微血管进行染色，并对其进行量化。
结果
与单独使用 DOC 相比，联合组的肿瘤负担较低。联合治疗对溶骨性病变的小鼠数量没有影响，但是联合组的溶骨性病变面积低于载体和 BLX 组，但与 DOC 组没有差异。与载体组相比，联合组的血清 TRAcP 水平较低，但与其他组没有差异。各组之间 Ki67 染色无明显差异；而 cleaved caspase-3 染色在联合组中最低，在 BLX 组中最高。DOC 和联合组的 CD34+微血管多于对照组和 BLX 组。治疗组之间的 IL-2 没有差异，但联合组的 IFNγ 水平高于 DOC 组。
结论
我们的数据表明，BAL 和 DOC 的联合使用在 PCa 骨转移模型中比单独使用任何一种药物具有更强的抗肿瘤活性。这些数据支持在转移性 PCa 中进一步评估这种联合用药。
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