Verbik D J, Stinson W W, Brunda M J, Kessinger A, Joshi S S
Department of Cell Biology, University of Nebraska Medical Center, Omaha, USA.
Clin Exp Metastasis. 1996 May;14(3):219-29. doi: 10.1007/BF00053895.
Despite considerable advancement in anticancer therapy, minimal residual disease (MRD) is still a major problem in the clinical management of cancer, including lymphoma. In this report, we have studied the antitumor effects of interleukin-12 (IL-12) against an aggressive liver metastatic murine RAW117-H10 lymphoma. Our results using three different doses of IL-12 (0.175, 0.35 and 0.7 micrograms/mouse) showed that a 0.35 micrograms dose is the most efficacious against lymphoma grown in intact mice. Furthermore, we have evaluated the therapeutic effects of IL-12 against residual lymphoma in a transplantation setting. BALB/c mice were treated with high-dose therapy (HDT) and transplanted with syngeneic bone marrow cells added with a known number of RAW117-H10 lymphoma cells to mimic the clinical situation of MRD. The mice were then treated with IL-12 (0.25 micrograms/mouse/day) alone or IL-12 plus activated cytotoxic effector cells. Our results showed that IL-12 had a significant (P < 0.05) antitumor therapeutic effect against liver metastatic lymphoma grown in intact mice as well as in lymphoma-bearing mice treated with HDT followed by stem cell transplantation as determined by survival period. The therapeutic effect of IL-12 was also demonstrated by a very significant decrease (P < 0.05) in the tumor burden in livers from the IL-12-treated mice. Mice that were treated with IL-12 following HDT and hematopoietic stem cell transplantation had a significant decrease in circulating white blood cells (P < 0.05), a significant increase in spleen weight and cellularity (P < 0.05), and hematopoietic progenitor cells (P < 0.05), a significant increase in the number of splenocytes expressing IL-2 alpha-chain receptor (P < 0.05), and an increase in the frequency of natural killer cells in their spleens. These studies suggest that cytokines such as IL-12 may have the potential to mediate antitumor effects against residual lymphoma without compromising lymphohematopoietic recovery.
尽管抗癌治疗取得了长足进展，但微小残留病（MRD）仍是癌症（包括淋巴瘤）临床管理中的一个主要问题。在本报告中，我们研究了白细胞介素-12（IL-12）对侵袭性肝转移性小鼠RAW117-H10淋巴瘤的抗肿瘤作用。我们使用三种不同剂量的IL-12（0.175、0.35和0.7微克/小鼠）的结果表明，0.35微克的剂量对完整小鼠体内生长的淋巴瘤最有效。此外，我们评估了IL-12在移植环境中对残留淋巴瘤的治疗效果。用高剂量疗法（HDT）治疗BALB/c小鼠，并移植添加了已知数量RAW117-H10淋巴瘤细胞的同基因骨髓细胞，以模拟MRD的临床情况。然后，小鼠单独接受IL-12（0.25微克/小鼠/天）治疗或IL-12加活化的细胞毒性效应细胞治疗。我们的结果表明，根据生存期测定，IL-12对完整小鼠体内生长的肝转移性淋巴瘤以及接受HDT后进行干细胞移植的荷瘤小鼠具有显著（P<0.05）的抗肿瘤治疗效果。IL-12治疗组小鼠肝脏中的肿瘤负荷也非常显著地降低（P<0.05），这也证明了IL-12的治疗效果。接受HDT和造血干细胞移植后用IL-12治疗的小鼠循环白细胞显著减少（P<0.05），脾脏重量和细胞数量显著增加（P<0.05），造血祖细胞显著增加（P<0.05），表达IL-2α链受体的脾细胞数量显著增加（P<0.05），脾脏中自然杀伤细胞的频率增加。这些研究表明，诸如IL-12之类的细胞因子可能有潜力介导针对残留淋巴瘤的抗肿瘤作用，而不会损害淋巴造血功能的恢复。
