Further studies on the mechanism of action of 6-thioguanine.

Evidence reported earlier, indicating that the tumor-inhibitory properties of 6thioguanine resulted from the incorporation of this guanine analog into the nucleic acids of the tumor, was supported by the following additional findings: (a) susceptible tumors showed maximum response to treatment initiated at any time during the rapidgrowth phase; (b) incorporation of thioguanine into tumor-cell nucleic acids was much greater in young, rapidly growing cell populations than in older populations; (c) maximum incorporation of thioguanine into the tumor-cell nucleic acids of susceptible tumors was reached with three treatments; multiple treatments of a resistant tumor did not increase the incorporation; (d) three treatments with thioguanine were sufficient to produce an essentially maximum tumor inhibition; (e) in susceptible tumors, a large part of the incorporation was in I)NA; in two resistant tumors, the small incorporation observed was largely in RNA; (f) in tumor cells labeled with thioguanineC TM and transferred to unlabeled hosts the radioactivity in DNA was completely retained over the time studied (in excess of twice the intermitotic time); retention was also almost complete in RNA. Such cells appear to remain viable but be unable to grow. The evidence all supports the concept that the tumor-inhibitory properties of 6-thioguanine result from its incorporation into the nucleic acids, probably specifically the DNA, with the result that the cells cannot reduplicate this material.