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.