Biochemical approaches to enhancement of antitumor drug selectivity: selective protection of cells from 6-thioguanine and 6-mercaptopurine by adenosine.
The cytotoxicity of 6-thioguanine and 6-mercaptopurine to cultured lymphoblasts and fibroblasts was strongly antagonized by pretreatment of the cells with 100 microM adenosine. Administration of adenosine 2 hours after the antipurine agent did not cause antagonism. In two rat hepatoma cell lines, adenosine pretreatment did not protect cells from the antipurines. Treatment of lymphoblasts or fibroblasts with 100 microM adenosine gave increases up to 150% in cellular ATP and ADP and decreases greater than 80% in UTP and UDP. In the hepatoma lines, adenine nucleotides did not increase by greater than 45%, and uridine nucleotides did not decrease by greater than 40% following adenosine treatment. The selective protection of the normal cells from 6-thioguanine and 6-mercaptopurine was probably the consequence of phosphoribosylpyrophosphate (PRPP) depletion, since adenosine pretreatment decreased PRPP pools by greater than 90% in the normal cells but by only 30% in the malignant hepatoma cells. In the absence of PRPP the antipurines would not be metabolically activated. The selectivity of the adenosine and antipurine combinations was probably attributable to the low activity of adenosine kinase and high activities of adenosine deaminase and PRPP synthetase characteristic of malignant hepatomas.
D000241:Adenosine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D002452:Cell Count; D002460:Cell Line; D004347:Drug Interactions; D004351:Drug Resistance; D008114:Liver Neoplasms, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015122:Mercaptopurine / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D010754:Phosphoribosyl Pyrophosphate / Q000378:metabolism; D051381:Rats; D013866:Thioguanine / Q000037:antagonists & inhibitors / Q000627:therapeutic use*; D014530:Uridine Diphosphate / Q000378:metabolism; D014544:Uridine Triphosphate / Q000378:metabolism
D014530:Uridine Diphosphate; D000244:Adenosine Diphosphate; D010754:Phosphoribosyl Pyrophosphate; D000255:Adenosine Triphosphate; D015122:Mercaptopurine; D013866:Thioguanine; D000241:Adenosine; D014544:Uridine Triphosphate