The selectivity of action of 1-beta-D-arabinofuranosylcytosine (
ara-C) against leukemic cells was studied in vivo. Dynamic state tissue levels of
ara-C and of its mono-, di-, and
triphosphate (
ara-CTP) were measured in L1210 leukemic cells and in C57BL x DBA/2 F1 host tissues at different times after various doses of the agent. The levels were correlated with inhibition of
thymidine incorporation into
DNA and with cytocidal effects as measured by loss of isotopically prelabeled
DNA.
ara-CTP levels, but not those of the mono- and
diphosphates of
ara-C, were higher in leukemic cells and in host cell renewal systems than in other host tissues.
DNA synthesis was equally inhibited by similar levels of
ara-CTP in ascitic L1210 cells, in leukemic infiltrates in liver, and in small intestine. However, L1210 cells accumulated higher levels of
ara-CTP for longer periods than did small intestine, and correspondingly the inhibition of
DNA synthesis was greater and more prolonged in leukemic cells.
ara-C caused greater losses of prelabeled
DNA in
ascites cells and in infiltrated liver than in host small intestine. It appears that the differential net tissue level of
ara-CTP and its duration are the determinants of chemotherapeutic efficacy of
ara-C against
L1210 leukemia.
ara-C was the predominant
nucleoside present in hydrolysates of
ara-CTP fractions. By contrast, 1-beta-D-arabinofuranosyluracil predominated in hydrolysates of monophosphate
nucleotide fractions from
ascites cells, liver, small intestine, and blood. Monophosphate
nucleotide was also present in
ascites fluid and plasma.