Liau M C, Smith D W, Hurlbert R B
Cancer Res. 1975 Sep;35(9):2340-9.
The literature indicates that some mechanism other than the interferon or host-mediated immune enhancement might also be responsible for an antitumor effect of polyinosinate-polycytidylate [poly(I)-poly(C)]. We have examined the effect of this drug on the synthesis of ribosomes and other macromolecules in a rat tumor, the Novikoff ascites hepatoma. The nucleolus was one of the primary targets affected by the administration of poly(I)-poly(C) in vivo. A progressive decline of the activity of nucleolar ribosomal RNA methylases began within 2 hr, followed by a decline of the nucleolar RNA content. The activity of nucleolar RNA polymerase was inhibited only at later time intervals. Labeling of tumor macromolecules in vivo revealed that the methylation of ribosomal RNA and the production of ribosomes, particularly in the small subunits, were immediately and progressively affected, followed by inhibition of the synthesis of DNA, RNA, and protein at later times. In addition, poly(I)-poly(C) also induced disaggregation of polyribosomes and restricted the movements of nuclear RNA to cytoplasm and of cytoplasmic protein to nucleus. These in vivo effects of poly(I)-poly(C) on tumor cells was observed neither on the host livers nor on livers of normal rats. Studies on isolated nucleoli showed that the in vitro addition of polyinosinate and several other compounds actively inhibited tumor ribosomal RNA methylases but were devoid of inhibitory effect against liver ribosomal RNA methylases; these results augment other studies in the literature in suggesting a selective effect of the polyinosinate moiety on tumor cells. We conclude from this study that initial impairment of the methylation of ribosomal precursor RNA, following exposure of tumor cells to poly(I)-poly(C), is responsible for the destruction of ribosomes, preferentially the small subunits, during the maturation processes. Failure to provide new ribosomes thus triggers the events limiting the growth of tumor cells.
文献表明，聚肌苷酸 - 聚胞苷酸[poly(I)-poly(C)]的抗肿瘤作用可能由干扰素或宿主介导的免疫增强以外的某些机制引起。我们研究了这种药物对大鼠肿瘤诺维科夫腹水肝癌核糖体和其他大分子合成的影响。核仁是体内给予poly(I)-poly(C)后受影响的主要靶点之一。核仁核糖体RNA甲基化酶的活性在2小时内开始逐渐下降，随后核仁RNA含量下降。核仁RNA聚合酶的活性仅在较晚的时间间隔受到抑制。体内肿瘤大分子的标记显示，核糖体RNA的甲基化和核糖体的产生，特别是小亚基的核糖体，立即并逐渐受到影响，随后在较晚时间DNA、RNA和蛋白质的合成受到抑制。此外，poly(I)-poly(C)还诱导多核糖体解聚，并限制核RNA向细胞质的移动以及细胞质蛋白向细胞核的移动。poly(I)-poly(C)对肿瘤细胞的这些体内作用在宿主肝脏或正常大鼠肝脏中均未观察到。对分离核仁的研究表明，体外添加聚肌苷酸和其他几种化合物可有效抑制肿瘤核糖体RNA甲基化酶，但对肝脏核糖体RNA甲基化酶没有抑制作用；这些结果进一步证明了文献中的其他研究，表明聚肌苷酸部分对肿瘤细胞具有选择性作用。我们从这项研究中得出结论，肿瘤细胞暴露于poly(I)-poly(C)后，核糖体前体RNA甲基化的初始损伤导致核糖体在成熟过程中被破坏，优先是小亚基。无法提供新的核糖体从而引发限制肿瘤细胞生长的事件。
