TARGETING 6-THIOGUANINE TO THE KIDNEY WITH S-(GUANIN-6-YL)-L-CYSTEINE

Recently, S-(purin-6-yl)-L-cysteine (GC) was shown to be a kidney-sele ctive prodrug of 6-mercaptopurine. In the present study, for further d evelopment of kidney-selective chemotherapeutic agents, GC was synthes ized, and its metabolism was examined in the rat by cysteine conjugate beta-lyase (beta-lyase) to yield the antitumor and immunosuppressant drug, 6-thioguanine (6-TG). The apparent K-m values obtained with rena l mitochondrial and cytosolic beta-lyases were similar, but the V-max value obtained with renal mitochondrial beta-lyase was approximately 4 5-fold higher than the V-max value obtained with renal cytosolic beta- lyase. After rats were administered GC (400 mu mol/kg), the concentrat ions of GC in the kidney, liver and plasma at 30 min were higher than the corresponding values at 15 or 60 min. GC concentrations in plasma and kidney were, however, 3- and 5-fold higher than that in liver, res pectively. Although GC metabolites were not detected in plasma, they w ere detectable in liver and kidney; metabolite concentrations at 30 mi n were higher than those at 15 or 60 min. Renal 6-TG concentration at 30 min was nearly 4-fold higher than hepatic 6-TG concentration; hepat ic and renal 6-thioxanthine and 6-thiouric acid concentrations were si milar. The amount of GC metabolites excreted in urine within 24 hr was linearly proportional to the administered GC dose. Rats administered GC (400 mu mol/kg) excreted nearly 5-fold the amount of metabolites as rats given an equimolar dose of 6-chloroguanine, a GC precursor. Thes e results and the finding that renal 6-TG concentrations after GC trea tments were in excess of the ED(50) of 6-TG (0.5-1.0 mu M) in two huma n renal carcinoma cell lines (A-498 and CAKI-1) suggest that GC may ha ve clinical usefulness as a prodrug of 6-TG.