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The Metabolism of 9-ß-D-Xylofuranosyl-6-mercaptopurine in Normal and Neoplastic Tissues¹

Life Sciences Research, Stanford Research Institute, Menlo Park, California

9-(ß-D-Xylofuranosyl)-9H-purine-6-thiol (xyl-6-MP)³ and its triacetyl derivative, 9-(2',3',5'-tri-O-acetyl-ß-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.

¹ This work was supported by Contract PH 43-65-575 with the Cancer Chemotherapy National Service Center, National Cancer Institute, NIH.

³ Abbreviations used: 6-MP, 6-mercaptopurine; 6-TG, 6-thioguanine; xyl-6-MP, 9-ß-D-xylofuranosyl-6-mercaptopurine; xyl-6-MP-TAc, 9-(2',3',5'-tri-O-acetyl-ß-D-xylofuranosyl)-6-mercaptopurine; xyl-hypoxanthine-TAc, 9-(2',3',5'-tri-O-acetyl-ß-D-xylofuranosyl)hypoxanthine; PCA, perchloric acid; TCA, trichloracetic acid; PRPP, 5-phosphoribosyl-1-pyrophosphate; R-5-P, ribose-5-phosphate; ATP, adenosine triphosphate.

² Present address: The Research Institute for Tuberculosis, Leprosy and Cancer, Tohoku University, Sendai, Japan.

Received 7/ 6/65. Revised 10/18/65.