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Metabolism and Intracellular Retention of 1-ß-D-Arabinofuranosylcytosine as Predictors of Response of Animal Tumors¹

Departments of Medicine A and of Experimental Therapeutics, Roswell Park Memorial Institute, New York State Department of Health, Buffalo, New York 14263

The uptake, phosphorylation of 1-ß-D-arabinofuranosylcytosine (ara-C), and the intracellular retention of ara-C metabolites, and the plasma levels of intact drug after a single i.v. dose of [5-³H]ara-C were studied in mice bearing i.p. leukemia L1210, P-288, and Taper hepatoma. There were no significant differences in the plasma level kinetics of intact drug, but among the 3 tumor types there were quantitative differences in drug uptake and intracellular retention of drug metabolites. Fifteen min after i.v. administration, the amount of total label was 24- and 8-fold greater in L1210 than in P-288 and Taper hepatoma cells, respectively. At 4 hr the amount of label in L1210 was 5-fold greater than in the other cells. 1-ß-D-arabinofuranosyluracil 5'-monophosphate pools were small and stable over 4 hr; 1-ß-D-arabinofuranosylcytosine 5'-monophosphate pools were also stable but varied in the order of Taper hepatoma > P-288 > L1210. In L1210 cells, 1-ß-D-arabinofuranosylcytosine 5'-triphosphate pools were relatively large, stable, and 23 nmoles/10⁹ cells remained intracellularly at 4 hr; in contrast 2.5 and 1.0 nmoles were found in P-288 and Taper hepatoma cells, respectively. Furthermore, L1210 cells accumulated higher levels of 1-ß-D-arabinofuranosylcytosine 5'-triphosphate for a longer time than did host tissues. In vitro inhibition by ara-C of [¹⁴C]deoxycytidine incorporation into DNA was shown to be dose dependent. In L1210 cells, 0.25 µg of ara-C per ml produced about 81% inhibition, whereas only 33 and 15% inhibition was achieved with P-288 and Taper hepatoma cells, respectively. At a higher ara-C concentration, similar inhibition was achieved in the 3 tumor cell lines.

Mice bearing these tumors were treated with different schedules, and it was found that 20 mg of ara-C per kg every 4 hr for 24 hr was the optimum schedule. The percentage of increases of survival time were 150, 68, and 18 days of L1210, P-288, and Taper hepatoma, respectively, with 60-day survivors (8 of 15) only among L1210-bearing mice.

These data suggest that the differences in sensitivity of these tumors seem related to the differential net tissue levels of 1-ß-D-arabinofuranosylcytosine 5'-triphosphate and its duration of retention at target site.

¹ This work was supported in part by Project Grant CA-18420 and Core Program Grant CA-13038 from the National Cancer Institute, USPHS.

Received 8/24/77. Accepted 11/23/77.