Thymidine as a kinetic and biochemical modulator of 1-beta-D-arabinofuranosylcytosine in human acute nonlymphocytic leukemia.

We have carried out a clinical trial in which patients with relapsed leukemia were treated with thymidine (dThd) prior to and concomitantly with the administration of 1-beta-D-arabinofuranosylcytosine (ara-C) in an effort to kinetically and biochemically modulate the leukemic cells with two objectives: (a) to increase the S-phase fraction before giving ara-C; and (b) to increase the uptake and phosphorylation of ara-C. Six patients with acute nonlymphocytic leukemia who had relapsed after conventional or experimental therapy were given continuous i.v. infusions of dThd in conjunction with ara-C. dThd was started at 75 g/sq m/day (producing 1 mM plasma levels) and was given for 5 to 8 days until the proportion of bone marrow cells in S-phase (measured by autoradiography and flow cytometry) had increased and/or stabilized; then ara-C at 200 mg/sq m/day was begun. Twenty-four hr after initiation of ara-C therapy, the dThd dose was reduced to 30 g/sq m/day (plasma dThd, 0.1 to 0.6 mM). Both drugs were continued for 6 to 12 days until marrow aplasia or unacceptable toxicity occurred. Four patients with a base-line labeling index lower than 30% experienced a sustained increase in the S-phase fraction; two patients with a base-line labeling index higher than 30% experienced a reduction in the S-phase compartment during dThd infusion, in one case followed by an increase. The degree of S-phase arrest did not correlate with remission induction. In 5 patients, the flash incorporation of labeled ara-C into nucleoside triphosphate and deoxycytidine into DNA of bone marrow cells was measured. Three patients had a significant increase in the incorporation of deoxycytidine into DNA. Two of them achieved a complete remission. Increases in ara-C uptake were less impressive. A new technique was used to measure the absolute number of blasts present in the bone marrow. A decrease in leukemic cells between 0.9 and 2.6 logs10/mm was found at the end of the infusions. Three patients experienced greater than 2-log reduction. Two of them entered complete remission that lasted 6 weeks and 3 months, respectively. These correlations should be interpreted with caution because of the small number of patients treated. This study suggests that dThd, although of very limited therapeutic value by itself, may have potentiated the antitumor activity of ara-C to some extent. Whether this effect is of significance can only be determined by further studies.