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 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 were 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.
This work was supported by American Cancer Society Grant NP-97B and National Cancer Institute Grant CA-15086-01.