Combinations of tetrahydrouridine and cytosine arabinoside in mouse tumors.

Abstract

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.

• Authors: W Kreis, C Hession, A Soricelli, K Scully
• Journal: Cancer treatment reports (Cancer Treat Rep) Vol. 61 Issue 7 Pg. 1355-64 (Oct 1977) ISSN: 0361-5960 [Print] United States
• PMID: 589601 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cytarabine
• Tritium
• Tetrahydrouridine
• Phosphotransferases
• Cytidine Deaminase
• Uridine

Topics

• Adenocarcinoma (drug therapy)
• Animals
• Cytarabine (metabolism, therapeutic use)
• Cytidine Deaminase (antagonists & inhibitors, metabolism)
• Deamination
• Drug Evaluation
• Drug Therapy, Combination
• Female
• Lung Neoplasms (drug therapy)
• Mice
• Neoplasms, Experimental (drug therapy, enzymology)
• Phosphotransferases (metabolism)
• Sarcoma, Experimental (drug therapy)
• Tetrahydrouridine (metabolism, therapeutic use)
• Tritium (metabolism)
• Uridine (analogs & derivatives)