Studies on the mode of action of 6-mercaptopurine and its ribonucleoside on mammalian cells in culture.

The biological activity of 6mercaptopurine, an analogue of hypoxanthme, has been the subject of extensive studies, but the mechanism of its action has remained unclear. This drug inhibits the growth of bacteria (l-3) and mammalian cells (4, 5) in vitro and the proliferation of experimental tumors and leukemias in tiuo (6-9). It has been suggested that it interferes with the synthesis of nucleic acid purines by preventing the conversion of some hypoxanthine derivative to adenine or guanine derivatives (lO-12), or by interfering with the function and synthesis of purine-containing coenzymes (3). The incorporation of formate and of hypoxanthine, but not of adenine, into nucleic acids of various tissues of tumor-bearing mice in Go (10) and into nucleic acids of tumor cells in vitro (13, 14) was prevented by 6-mercaptopurine. In mouse liver, it also inhibited the synthesis of reduced diphosphopyridine nucleotide associated with the administration of nicotinamide (15). The synthesis of inosinic acid de nouo from glycine by soluble enzymes of avian liver was not inhibited by the ribonucleotide of 6-mercaptopurine (16). In the present study Eagle’s medium (17, 18) and modiications of this medium (19) have been used to analyze the mode of action of 6-mercaptopurine and its ribonucleoside on the growth of S-1801 and HeLa cells. Evidence is presented that suggests that both of these compounds exert their action as the ribonucleotide by interfering competitively with the conversion of inosinic acid to adenylic acid. A preliminary report on these studies has been presented (20).