STUDIES ON DRUG RESISTANCE .1. DISTRIBUTION OF 1-BETA-D-ARABINOFURANOSYLCYTOSINE CYTIDINE AND DEOXYCYTIDINE IN MICE BEARING ARA-C-SENSITIVE AND -RESISTANT P815 NEOPLASMS

A study of the physiological distribution of tritiated-1-β-d-arabinofuranosylcytosine (3H-ara-C) in mice, carrying bilateral implants of ara-C-sensitive and -resistant tumors, indicated a selective, specific and prolonged accumulation of radio-activity in the sensitive tumor compared with the resistant tumor, liver, kidneys, spleen, lungs, blood, small intestines and brain of the host. Although the patterns of the brain and sensitive tumor tissues were similar, the brain accumulated much less radioactivity. The main difference of uptake of ara-C in the sensitive tumor compared with the resistant tumor was the presence of a large amount of ara-C nucleotide in the sensitive tumor and its negligible content in the resistant tumor. Deoxycytidine (CdR)-derived radioactivity was present, but not protracted, in all the above mentioned tissues. 3H-cytidine (3H-CR) was taken up equally in the sensitive and resistant tumors. In the liver its level was high and long-lasting. The relative values of uptake in sensitive and resistant tumors were 6-8:1 for ara-C; 2-4:1 for CdR; and 1:1 for CR 48 hr after injection. Determination in vitro of ara-C, CR and CdR deamination by tissue homogenates indicated no sizeable amounts of such nucleoside deaminases in the liver and two tumors. On the other hand, high levels of these substrates were deaminated by the kidney tissue. Of several naturally occurring CR- and CdR-nucleotides and ara-CMP, only deoxycytidine-5'-diphosphate (dCDP) and deoxycytidine-5'-triphosphate (dCTP) were comparably deaminated by both tumors. Liver, kidney and both tumor tissues in vitro phosphorylated CR to the same degree. Ara-C and CdR were phosphorylated readily in the sensitive tumor and to a lesser extent in the liver; the kidney and resistant tumor showed only minor kinase activity. Cytidine-5'-diphosphate-reductase activity was about equal in both tumors. © 1969.