Studies on the inhibition of growth of Bacillus cereus by 6-mercaptopurine.

Studies on the carcinostatic purine analogue, 6-mercaptopurine, have revealed a variety of effects produced by this drug on biochemical reactions (1, 2). The inhibitory action of the drug on any particular biochemical pathway, however, may not be causally related to the inhibition of cell growth, since the drug effect may not be of vital concern to the cell, or a compensatory pathway may become available to minimize the results of the biochemical blocks produced. Thus, information on the underlying mechanisms by which 6mercaptopurine produces its inhibitory effect on cellular proliferation is still desired. The demonstration that various biochemical actions of 6mercaptopurine are not responsible for the inhibition of growth may help to delineate further that process which is the drug’s principal action. The actions of 6-mercaptopurine that have been suggested as possibly responsible for the growth inhibition include the inhibition of purine synthesis de noso (e.g. see references (3-5)) and interference in the synthesis or function of coenaymes that contain purines (69) and in the interconversion of purines (10). Recently, the demonstration of a specific block by the ribonucleotide of 6-mercaptopurine of the conversion of inosinic acid to adenylic acid (11, 12) and guanylic acid (12) has suggested that the inhibition of these reactions was most detrimental to the growing cell. The importance of this effect was underlined by the observation by Brockman (13) that 6-mercaptopurine ribonucleotide was formed only by cells susceptible to the action of the drug, in contrast to resistant cells. The present study was designed to determine the effects that 6-mercaptopurine produced on the synthesis of two cofactors, coenzyme I and coenzyme A, as well as on the formation of polynucleotides. Information is also presented concerning the relative efficacies of the natural purines in reversing the effects of 6-mercaptopurine on the growth of Bacillus cereus. The possibility of competition between 6-mercaptopurine and hypoxanthine at the site of entry into the cell was also examined. A report of some of this work has been presented (14).