Dinney C P, Bucana C D, Utsugi T, Fidler I J, von Eschenbach A C, Killion J J
University of Texas M.D. Anderson Cancer Center, Department of Cell Biology, Houston 77030.
Cancer Res. 1991 Jul 15;51(14):3741-7.
Current therapies for renal cell carcinoma have been limited by the unresponsiveness of metastatic disease to conventional treatments. Although the use of biological response modifiers as adjuvant therapy has generally not been successful against disseminated disease, in situ activation of macrophages to a tumoricidal state by liposome-encapsulated immunomodulators has been shown to eradicate metastatic cancer in murine tumor models. We, therefore, designed experiments to evaluate the ability of a new macrophage activator, CGP 31362, a synthetic bacterial cell wall analogue, to cause regression of spontaneous lung metastases in mice whose primary renal adenocarcinoma was removed by nephrectomy. Delivery of the CGP 31362 to the lungs was accomplished by its encapsulation in multilamellar phospholipid liposomes (MLV-CGP 31362). Therapy with repeated i.v. injections of MLV-CGP 31362 significantly reduced the number of lung metastases in nephrectomized mice. Therapeutic efficacy of MLV-CGP 31362 was influenced by the encapsulation ratio of CGP 31362 to total phospholipid, the dose of injected liposomes, and the frequency of administration. Optimal therapy was achieved by combining the use of i.v. MLV-CGP 31362 with the s.c. injection of recombinant murine gamma interferon. Administration of MLV-CGP 31362 prior to removal of the primary tumor and continuing postoperatively was superior to postoperative therapy alone. Several lines of evidence indicate that in situ activation of macrophages was responsible for the therapeutic effects of MLV-CGP 31362: (a) macrophages harvested from the lungs of treated mice had significant tumoricidal activity against cultured renal carcinoma cells, (b) activated macrophages, as defined by the MRP-14 marker, were present in lung tumor nodules of treated mice but not untreated mice, and (c) the in situ activation of alveolar macrophages was consistent with the in vivo deposition of 60% of radiolabeled MLV-CGP 31362 liposomes in the lungs following i.v. injection. The results reported here represent the first in vivo evaluation of MLV-CGP 31362 and offer additional evidence that macrophage combination with therapies that reduce tumor burden.
目前，肾细胞癌的治疗方法受到转移性疾病对传统治疗无反应的限制。尽管使用生物反应调节剂作为辅助治疗通常对播散性疾病并不成功，但脂质体包裹的免疫调节剂可将巨噬细胞原位激活为杀肿瘤状态，这在小鼠肿瘤模型中已显示能根除转移性癌症。因此，我们设计了实验，以评估一种新型巨噬细胞激活剂CGP 31362（一种合成细菌细胞壁类似物）使原发性肾腺癌已通过肾切除术切除的小鼠自发性肺转移灶消退的能力。将CGP 31362包裹在多层磷脂脂质体（MLV-CGP 31362）中实现其向肺部的递送。通过反复静脉注射MLV-CGP 31362进行治疗，可显著减少肾切除小鼠肺部转移灶的数量。MLV-CGP 31362的治疗效果受CGP 31362与总磷脂的包封率、注射脂质体的剂量以及给药频率的影响。通过将静脉注射MLV-CGP 31362与皮下注射重组小鼠γ干扰素联合使用可实现最佳治疗效果。在切除原发性肿瘤之前给予MLV-CGP 31362并在术后持续给药优于单纯术后治疗。多条证据表明，巨噬细胞的原位激活是MLV-CGP 31362治疗效果的原因：（a）从接受治疗小鼠的肺部收获的巨噬细胞对培养的肾癌细胞具有显著的杀肿瘤活性，（b）经MRP-14标记物定义的活化巨噬细胞存在于接受治疗小鼠的肺肿瘤结节中，而未接受治疗的小鼠中则没有，并且（c）肺泡巨噬细胞的原位激活与静脉注射后60%的放射性标记MLV-CGP 31362脂质体在肺部的体内沉积一致。此处报道的结果代表了对MLV-CGP 31362的首次体内评估，并提供了更多证据表明巨噬细胞与减轻肿瘤负荷的疗法联合使用的效果。
