Mechanism of action of inosine dialdehyde (NSC 118994) in the inhibition of proliferation of tumor cells in culture.

Inosine dialdehyde (INOX), the periodate oxidation product of inosine, inhibited the proliferation of various tumor cell lines in suspension culture in a concentration-dependent manner. A concentration of about 1 mM was required to completely inhibit the proliferation of Novikoff rat hepatoma and mouse L-cells, whereas about 0.1 mM completely inhibited the proliferation of L1210 and P388 mouse leukemia and Chinese hamster ovary cells. INOX inhibited in a similar time- and concentration-dependent manner the synthesis of protein, RNA, and DNA, as measured by the incorporation of labeled amino acid, uridine, and thymidine, into acid-insoluble material, without significantly affecting the incorporation of these precursors into the acid-soluble pool. Flow microfluorometric analyses showed that many of the INOX-treated cells became arrested in G2 + M. The results are consistent with the view that INOX affects multiple metabolic steps. The effects of INOX were quite different from those caused by typical inhibitors of ribonucleotide reductase, hydroxyurea, and 2,3-dihydro-1H-pyrazolo(2,3-a)imidazole, which very rapidly inhibited DNA synthesis and caused arrest of the cells in G1, with minimal effects on RNA and protein synthesis.