Antitumor effect of vitamin D-binding protein-derived macrophage activating factor on Ehrlich ascites tumor-bearing mice
Antitumor effect of vitamin D-binding protein-derived macrophage activating factor on Ehrlich ascites tumor-bearing mice
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DOI：
10.1046/j.1525-1373.1999.d01-3.x
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发表时间：
1999-01-01
影响因子：
--
通讯作者：
Yamamoto, N
中科院分区：
文献类型：
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作者：
Koga, Y;Naraparaju, VR;Yamamoto, N
癌细胞分泌α-N-乙酰氨基半乳糖酶（NaGalase）进入血流，导致血清维生素D-3结合蛋白（称为Cc蛋白）的去糖基化，这是巨噬细胞活化因子（RAAF）的前体。CC蛋白与固定化β-半乳糖苷酶和唾液酸酶孵育产生最有效的巨噬细胞活化因子将GcMAF施用于荷癌宿主可绕过灭活的MAF前体并直接作用于巨噬细胞以有效活化。通过存活时间和血清半乳糖醛酸酶活性来评估GcMAF对荷埃利希腹水瘤小鼠的治疗效果，因为血清半乳糖钠酶活性与肿瘤负荷成正比。GcMAF单次给药（100 μ g/小鼠）在移植肿瘤后同一天给予8只小鼠（5 × 10（5）个细胞）显示7只小鼠的平均存活时间为21 +/-3天，其中1只小鼠存活超过60天，而荷瘤对照的平均存活时间为13 +/-2天，在移植后第0天和第4天接受两次GcMAF给药的8只小鼠中有6只存活了31 +/-4天，而其余两只小鼠存活了60天以上。此外，以4天间隔接受三次GcMAF给药的八只小鼠中的六只显示出至少60天的延长存活，并且在整个存活期内血清半乳糖醛酸酶水平与对照小鼠的血清半乳糖醛酸酶水平一样低。用阈下GcMAF治疗（施用一次或两次）治愈荷瘤小鼠似乎是由巨噬细胞介导的杀肿瘤过程引起的炎症引起的持续巨噬细胞活化的结果。因此，由少量GcMAF的几次施用诱导的延长的巨噬细胞活化根除了鼠腹水肿瘤。
Cancerous cells secrete alpha-N-acetylgalactosaminidase (NaGalase) into the blood stream, resulting in deglycosylation of serum vitamin D-3-binding protein (known as Cc protein), which is a precursor for macrophage activating factor (RAAF). Incubation of cc protein with immobilized beta-galactosidase and sialidase generates the most potent macrophage activating factor (designated GcMAF), Administration of GcMAF to cancer-bearing hosts can bypass the inactivated MAF precursor and act directly on macrophages for efficient activation, Therapeutic effects of GcMAF on Ehrlich ascites tumor-bearing mice were assessed by survival time and serum NaGalase activity, because serum NaGalase activity was proportional to tumor burden. A single administration of GcMAF (100 pg/mouse) to eight mice on the same day after transplantation of the tumor (5 x 10(5) cells) showed a mean survival time of 21 +/- 3 days for seven mice, with one mouse surviving more than 60 days, whereas tumor-bearing controls had a mean survival time of 13 +/- 2 days, Six of the eight mice that received two GcMAF administrations, at Day 0 and Day 4 after transplantation, survived up to 31 +/- 4 days whereas, the remaining two mice survived for more than 60 days. Further, six of the eight mice that received three GcMAF administrations with 4-day intervals showed an extended survival of at least 60 days, and serum NaGalase levels were as low as those of control mice throughout the survival period. The cure with subthreshold GcMAF-treatments (administered once or twice) of tumor-bearing mice appeared to be a consequence of sustained macrophage activation by inflammation resulting from the macrophage-mediated tumoricidal process. Therefore, a protracted macrophage activation induced by a few administrations of minute amounts of GcMAF eradicated the murine ascites tumor.