The Metabolism of 9-β-d-Xylofuranosyl-6-mercaptopurine in Normal and Neoplastic Tissues¹

9-(β-d-Xylofuranosyl)-9H-purine-6-thiol (xyl-6-MP)³ and its triacetyl derivative, 9-(2′,3′,5′-tri-O-acetyl-β-d-xylofuranosyl)-9H-purine-6-thiol (xyl-6-MP-TAc) produced about 50% prolongation of survival time of mice bearing S-180 ascites tumor cells at 45 mg/kg and 63.9 mg/kg, respectively. The combination of either of these agents with azaserine caused additive effects rather than synergistic effects on the survival time. A 6-thioguanine (6-TG)-resistant cell line showed cross-resistance to xyl-6-MP.

Use of the ³⁵S-labeled compounds showed that little or no nucleoside cleavage and little or no nucleotide formation occurred. Insignificant traces were present in nucleic acids and proteins of S-180 tumor cells.

Both drugs were rapidly cleared from the blood and rapidly excreted in the urine. Paper chromatography of the urine showed that much of xyl-6-MP-³⁵S was excreted unchanged with relatively minor amounts of 3 other ³⁵S-containing compounds, but little or no sulfate-³⁵S. In contrast xyl-6-MP-TAc-³⁵S was excreted mainly as a form of xyl-6-MP-³⁵S and as sulfate-³⁵S. About 35% of either drug was excreted within an hr. Both drugs caused increases in urinary output of a material giving a positive orcinol test in excess of that due to the drug, in an amount equivalent to 75% of that present as drug, which suggests that they caused production of other carbohydrate moieties which were excreted in the urine.

Xyl-6-MP and xyl-6-MP-TAc inhibited the utilization of exogenously administered guanine-8-¹⁴C in vivo after a single dose of 100 mg/kg and 63 mg/kg, respectively, a dose level which caused no inhibition in the utilization of glycine-2-¹⁴C, orotic acid-6-¹⁴C, uracil-2-¹⁴C, or adenine-8-¹⁴C. However, enzymatic nucleotide formation from guanine-8-¹⁴C with a cell-free extract from S-180 cells was not inhibited by the drugs at 1 mm concentration.