The importance of intracellular purine salvage was examined. Adenine is salvaged from methylthioadenosine (MTA), a by-product of polyamine biosynthesis, in all normal cells and most tumor cells. It has been suggested that this salvage pathway be blocked in order to render the cells more sensitive to purine de novo synthesis inhibitors. Two cell lines, L1210 and L5178Y are similar in many parameters except the ability to salvage adenine from MTA. The basal rates of purine synthesis are similar in these two lines as is the sensitivity of the de novo pathways to 6-diaza-5-oxo-L-norleucine (DON). There is no difference in the ability of DON to inhibit growth in these two cell lines. Thus, from this limited study, developing blockers of salvage from MTA to use in combination with inhibitors of de novo purine synthesis is not a valid approach. Inhibitors of nucleoside transport (e.g. dipyridamole) and inhibitors of uridine kinase were evaluated for possible use in combination with inhibitors of de novo pyrimidine synthesis. Dipyridamole had only limited effectiveness in inhibiting nucleoside salvage in vivo, whereas 3-deazauridine was an effective inhibitor. Cyclopentenyl uracil, an effective inhibitor, was found to have many advantages over other compounds tested and will be studied in depth as supplies of this agent are made available.
