Combinations of tetrahydrouridine and cytosine arabinoside in mouse tumors.
Thirteen experimental mouse neoplasms were tested by cytidine (CR)-deaminase and deoxycytidine (dCR)-kinase levels. Four neoplasms, Sarcoma T241, Adenocarcinoma E0771, Lewis lung carcinoma (LL), and Sarcoma 180 Japan (S180J), considered to have high deaminase and sufficient dCR-kinase activities, were tested in vivo for combination chemotherapy with cytosine arabinoside (ara-C) and the CR-deaminase inhibitor, tetrahydrouridine (THU). THU did not significantly improve the growth inhibition of ara-C in a wide range of combinations in T241, E0771, LL, and the solid form of S180J, but more than doubled the survival time of the S180J ascites-bearing animals. Toxicity in the form of weight loss and toxic deaths was observed in some but not all groups, especially at high dosages of ara-C and THU. Tissue distribution of [3H]-ara-C and [14C]-THU in T241-bearing mice revealed an accelerated clearance of ara-C-derived radioactivity under the influence of THU in the tumor and five host tissues, but not in the small intestines. With the exception of the small intestines, clearance of THU-derived radioactivity was faster in all tissues studied compared to the clearance of [3H]-ara-C-derived radioactivity. Intracellular CR-deaminase levels were inhibited significantly, ie, dose dependent, in tumor and host kidney after a single ip injection of THU to E0771--bearing mice. In the solid S180J, with or without simultaneous ip administration of THU, [3H]-ara-C was not converted to 5'-di- and tri-phosphates at all. In mice bearing the ascites form of S180J, [3H]-ara-C was extensively converted to ara-C 5'-di- and tri-phosphates. THU increased both overall ara-C-derived radioactivity and the relative amounts of ara-C 5'-di- and tri-phosphates.
D000230:Adenocarcinoma / Q000188:drug therapy*; D000818:Animals; D003561:Cytarabine / Q000378:metabolism / Q000627:therapeutic use*; D003564:Cytidine Deaminase / Q000037:antagonists & inhibitors / Q000378:metabolism; D003641:Deamination; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005260:Female; D008175:Lung Neoplasms / Q000188:drug therapy*; D051379:Mice; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000201:enzymology; D010770:Phosphotransferases / Q000378:metabolism; D012513:Sarcoma, Experimental / Q000188:drug therapy; D013767:Tetrahydrouridine / Q000378:metabolism / Q000627:therapeutic use*; D014316:Tritium / Q000378:metabolism; D014529:Uridine / Q000031:analogs & derivatives*
D003561:Cytarabine; D014316:Tritium; D013767:Tetrahydrouridine; D010770:Phosphotransferases; D003564:Cytidine Deaminase; D014529:Uridine