Basic Biochemical Effects and Mechanism of Action of 6-thioguanine.

resistance to 6-thioguanine (6-TG) of some cell lines resistant to 6-mercaptopurine (6-MP) have led some investigators to assume that 6-TG and 6-MP havesimilar or identicalmetaboliceffects. This cross-resistance can probably be explained on the basis of the resistance mechanism, which has been so thoroughly investigated by Brock man and his associates (2). Since it now ap pears that both 6-MP and 6-TG are active in the nucleotide form and that both reach this form by way of the guanine pyrophosphorylase, loss of the latter enzyme results in resistance to both agents. However, a 6-TG-resistant line of Ehrlich car cinoma cells was found to be sensitive to 6-MP (6), and a sensitive line of Ehrlich cells responded better to treatment with combinations of 6-MP and 6-TG than to any dose of either drug alone (4). As will be reported, our investigations on 6-TG all support the concept that the incorporation of 6TGintodeoxyribonucleic acid(DNA) isclosely linked to the toxicity produced in normal or neo plastic cells. Such was not the case when 6-MP was studied by Bieber et al. (1) ; incorporation of 6-MP into DNA was greater in a 6-MP-resistant line. The data presented in Table 1 illustrate the rela tionship between incorporation to 6-TG into nucleic acids and response to therapy with the drug in a series of ascites cell mouse tumors and in growing tissues of the mouse. Therapy was routinely by intraperitoneal injection twice daily for 6 days at 0.5 mg/kg. Incorporation was measured 2 hours after injection with a single dose of 10 mg/kg. Further support for the concept of a direct relationship between the incorporation of 6-TG into cellularDNA and toxicity to the cells has been reported by LePage and Jones (7). It was established that : (a) susceptible tumors showed maximum response to treatment initiated at any time during the rapid-growth phase ; (b) incorpora tion of 6-TG into tumor-cell nucleic acids was much greater in young, rapidly growing cell popu lations than in older populations; (c) maximum in corporation of 6-TG 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 6-TG were sufficient to pro duce an essentially maximum tumor inhibition; (e) in susceptible tumors, a large part of the in corporation was in DNA; in two resistant tumors, the small incorporation observed was largely in RNA; (I) in tumor cells labeled with thioguanine C'4 and transferred to unlabeledhosts the radio activity in DNA was completely retained over the