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SYNKAVIT (2-methyl-1,4-naphthaquinol bis disodium phosphate) has been used in the treatment of cancer both as a radiosensitiser and, in tritiated form, as a radioactive drug, and attempts have been made to elucidate the nature of some of the biochemical processes affected by Synkavit (Mitchell and Marrian, 1965). The present paper describes experiments concerned particularly with its effects on the synthesis of nucleic acids. Previously, Synkavit has been shown to inhibit the uptake of formate and glycine into the RNA purines of Ehrlich ascites cells in vivo, but to have no detectable effect on the incorporation into DNA or acid-soluble purine nucleotides (Marrian, 1959). It was suggested, therefore, that Synkavit specifically inhibited RNA synthesis. Many studies on the effect of menadione (2-methyl-1,4-napthaquinone) on mitochondrial respiration in many tissues have revealed that it reduces the extent of oxidative phosphorylation (Slater, Colpa-Boonstra and Links, 1961; Mitchell and Marrian, 1965). Under certain conditions, it may also inhibit both aerobic and anaerobic glycolysis (Tiedemann, Risse and Born, 1958). Thus Synkavit, which is known to be rapidly dephosphorylated enzymically to give menadione (Ramasarma et al., 1959), has been found to reduce the total cellular ATP content of ascites cells (Chipperfield and Marrian, 1962). Therefore, since ATP and other nucleoside triphosphates are the direct precursors of RNA, the reduction in RNA synthesis may be explained by the lowered triphosphate level. However, recent studies investigating the complexing of menadione with DNA by electron-spin resonance techniques have obtained evidence for a complex in unirradiated samples (Nicolau, Korner and Cristea, 1966). Thus, the effect of menadione may be to bind on to the DNA primer and so to inhibit the formation of transcript RNA. It was considered essential, therefore, to study the effect of Synkavit on the synthesis of nucleic acids, to ascertain the precise manner in which it acts, and the conditions under which its effect is maximal. Accordingly, this paper describes experiments with Ehrlich ascites cells in vitro under various conditions, with a more detailed analysis of the intermediate stages of nucleic acid synthesis from nucleoside precursors.

british journal of cancer

Studies of potential radiosensitizing agents. Inhibition of nucleic acid synthesis by Synkavit (2-methyl-1,4-naphthaquinol bis disodium phosphate) in Ehrlich mouse ascites tumour cells