Genzyme Corporation, Framingham, MA 01701, USA.
Leuk Lymphoma. 2012 Jan;53(1):130-8. doi: 10.3109/10428194.2011.601698. Epub 2011 Aug 18.
The interaction between CXCR4 on the surface of tumor cells and CXCL12 in the stroma is believed to contribute to tumor cell survival and protection against drug treatment. Inhibition of stromal survival signals by CXCR4 antagonists has been reported to render tumor cells more sensitive to chemotherapy, but little is known about potential synergy with monoclonal antibodies. In this study, administration of the small molecule CXCR4 antagonists plerixafor and GENZ-644494 was found to enhance the anti-tumor activity of the monoclonal antibodies alemtuzumab and rituximab in disseminated lymphoma models. The observed enhancement in therapeutic efficacy by CXCR4 antagonists appeared to involve several factors, including interference with the tumor-promoting signals delivered by CXCL12, disruption of the tumor/stroma interaction and mobilization of effector neutrophils capable of mediating antibody-dependent cell-mediated cytotoxicity. The involvement of neutrophils was further supported by the observed reversal in therapeutic benefit upon neutrophil depletion.
肿瘤细胞表面的 CXCR4 与基质中的 CXCL12 之间的相互作用被认为有助于肿瘤细胞的存活和对药物治疗的抵抗。据报道，CXCR4 拮抗剂抑制基质存活信号可使肿瘤细胞对化疗更敏感，但对于与单克隆抗体的潜在协同作用知之甚少。在这项研究中，小分子 CXCR4 拮抗剂plerixafor 和 GENZ-644494 的给药被发现增强了单克隆抗体阿仑单抗和利妥昔单抗在播散性淋巴瘤模型中的抗肿瘤活性。CXCR4 拮抗剂增强治疗效果的观察结果似乎涉及多个因素，包括干扰 CXCL12 传递的肿瘤促进信号、破坏肿瘤/基质相互作用以及动员能够介导抗体依赖性细胞介导的细胞毒性的效应中性粒细胞。中性粒细胞的参与进一步得到了观察到的中性粒细胞耗竭后治疗益处逆转的支持。
