Vukanovic J, Isaacs J T
Johns Hopkins Oncology Center, Baltimore, MD 21231.
Cancer Res. 1995 Apr 1;55(7):1499-504.
Linomide, a quinoline-3-carboxamide, has the ability to inhibit the growth of prostatic cancer in vivo but not in vitro (T. Ichikawa et al., Cancer Res., 52: 3022-3028, 1992). The reason for this discrepancy is that linomide inhibits tumor growth not directly but indirectly in vivo via its ability to inhibit the angiogenic response induced within the growing prostatic cancer (J. Vukanovic, et al., Cancer Res., 53: 1833-1837, 1993). Tumor associated macrophages can stimulate angiogenesis via their ability to secrete various cytokines, particularly tumor necrosis factor alpha (TNF-alpha). Treatment of rats with linomide decreases significantly (P < 0.05), by more than 50%, the number of tumor associated macrophages within both locally invasive (i.e., from 20-40 to 10 macrophages/high power field) and highly metastatic primary prostatic cancers (i.e., from 60-70 to 15-37 macrophages/high power field). Monocytes/macrophages isolated from linomide treated rats had a decreased ability to secrete TNF-alpha when challenged in vitro with the bacterial endotoxin, lipopolysaccharide [i.e., 702 +/- 76 (SEM) ng of TNF-alpha/10(5) monocytes/macrophages from control versus 401 +/- 2 ng of TNF-alpha/10(5) monocytes/macrophages from linomide treated rats]. In addition, when rats were treated with linomide and than challenged with lipopolysaccharide in vivo, the resulting elevation in serum TNF-alpha was inhibited by approximately 50% (i.e., 4.56 +/- 1.8 ng/ml of TNF-alpha in control versus 2.9-2.2 ng/ml depending upon the dose of linomide). The ability of linomide to decrease monocyte/macrophage secretion of TNF-alpha is not immediate, however, since the secretion of TNF-alpha induced by lipopolysaccharide challenge of monocytes/macrophages isolated from untreated animals is not decreased by acute (i.e., < 4 h) linomide treatment in vitro. These results demonstrate that the ability of linomide to inhibit the secretion of TNF-alpha by monocytes/macrophages requires either additional time or host factors. To test if natural killer (NK) cells might be one of the additional host factors required for the in vivo abilities of linomide, prostatic cancer bearing rats were treated with appropriate antiserum to deplete NK cells and then tested for their response to linomide treatment. These studies demonstrated that the antitumor, antimetastatic, and antimacrophage effects of linomide were unaffected by NK cell depletion.(ABSTRACT TRUNCATED AT 400 WORDS)
林诺酰胺是一种喹啉 - 3 - 甲酰胺，它能够在体内抑制前列腺癌生长，但在体外却没有这种作用（T. 市川等人，《癌症研究》，52: 3022 - 3028, 1992）。这种差异的原因在于，林诺酰胺并非直接抑制肿瘤生长，而是通过抑制生长中的前列腺癌内部诱导的血管生成反应在体内间接发挥作用（J. 武卡诺维奇等人，《癌症研究》，53: 1833 - 1837, 1993）。肿瘤相关巨噬细胞可通过分泌多种细胞因子，特别是肿瘤坏死因子α（TNF - α）来刺激血管生成。用林诺酰胺处理大鼠后，局部浸润性（即从每高倍视野20 - 40个巨噬细胞降至10个巨噬细胞）和高转移性原发性前列腺癌（即从每高倍视野60 - 70个巨噬细胞降至15 - 37个巨噬细胞）内肿瘤相关巨噬细胞的数量显著减少（P < 0.05），降幅超过50%。从用林诺酰胺处理的大鼠中分离出的单核细胞/巨噬细胞，在用细菌内毒素脂多糖进行体外刺激时，分泌TNF - α的能力下降[即对照组每10⁵个单核细胞/巨噬细胞分泌702 ± 76（标准误）纳克TNF - α，而用林诺酰胺处理的大鼠每10⁵个单核细胞/巨噬细胞分泌401 ± 2纳克TNF - α]。此外，当大鼠用林诺酰胺处理后再在体内用脂多糖进行刺激时，血清TNF - α的升高被抑制了约50%（即对照组为4.56 ± 1.8纳克/毫升TNF - α，取决于林诺酰胺剂量，用林诺酰胺处理的大鼠为2.9 - 2.2纳克/毫升）。然而，林诺酰胺降低单核细胞/巨噬细胞分泌TNF - α的能力并非即时起效，因为从未经处理动物分离出的单核细胞/巨噬细胞经脂多糖刺激诱导分泌的TNF - α，在体外进行急性（即< 4小时）林诺酰胺处理时并未减少。这些结果表明，林诺酰胺抑制单核细胞/巨噬细胞分泌TNF - α的能力需要额外的时间或宿主因素。为了测试自然杀伤（NK）细胞是否可能是林诺酰胺体内作用所需的额外宿主因素之一，给患有前列腺癌的大鼠注射适当的抗血清以耗尽NK细胞，然后测试它们对林诺酰胺处理的反应。这些研究表明，林诺酰胺的抗肿瘤、抗转移和抗巨噬细胞作用不受NK细胞耗竭的影响。（摘要截短至400字）
