COMBINATIONS OF TETRAHYDROURIDINE AND CYTOSINE-ARABINOSIDE IN MOUSE TUMORS

  • 1 January 1977
    • journal article
    • research article
    • Vol. 61  (7) , 1355-1364
Abstract
Thirteen experimental mouse neoplasms were tested for 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 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 5 host tissues, but not in the small intestine. With the exception of the small intestine, 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; i.e., dose dependent, in tumor and host kidney after a single i.p. injection of THU to E0771-bearing mice. In the solid S180J, with or without simultaneous i.p. administration of THU, [3H]-ara-C was not converted to 5''-di- and triphosphates at all. In mice bearing the ascites form of S180J, [3H]-ara-C was extensively converted to ara-C 5''-di- and triphosphates. THU increased overall ara-C-derived radioactivity and the relative amounts of ara-C 5''-di- and triphosphates.