Although
cytosine arabinoside (araC) can induce a remission in a majority of patients presenting with
acute myeloblastic leukemia (AML), a minority fail to respond and moreover the
drug has less effect in
acute lymphoblastic leukemia (ALL). The carrier-mediated influx of araC into purified blasts from patients with AML, ALL, and acute undifferentiated
leukemia (AUL) has been compared to that of normal lymphocytes and polymorphs. Blasts showed a larger mediated influx of araC than mature cells, since mean influxes for myeloblasts and lymphoblasts were 6- and 2.3-fold greater than polymorphs and lymphocytes, respectively. Also, the mean influx for myeloblasts was fourfold greater than the mean for lymphoblasts. The number of
nucleoside transport sites was estimated for each cell type by measuring the equilibrium binding of [(3)H]nitrobenzylthioinosine (
NBMPR), which inhibits
nucleoside fluxes by binding with high affinity to specific sites on the transport mechanism. The mean binding site numbers for myeloblasts and lymphoblasts were 5- and 2.8-fold greater, respectively, than for the mature cells of the same maturation series. The mean number of
NBMPR binding sites for myeloblasts was fourfold greater than for lymphoblasts. Patients with AUL were heterogeneous since blasts from some gave values within the myeloblastic range and others within the lymphoblastic range. The araC influx correlated closely with the number of
NBMPR binding sites measured in the same cells on the same day. Transport parameters were measured on blasts from 15 patients with AML or AUL who were then treated with standard induction
therapy containing araC. Eight patients entered complete remission, while seven failed
therapy, among whom were the three patients with the lowest araC influx (<0.4 pmol/10(7) cells per min) and
NBMPR binding (<3,000 sites/cell) for the treated group. In summary, myeloblasts have both higher araC transport rates and more
nucleoside transport sites than lymphoblasts and this factor may contribute to the greater sensitivity of AML to this
drug. AraC transport varied >10-fold between leukemic blasts and normal leukocytes, but transport capacity related directly to the number of
nucleoside transport sites on the cell. Finally, low araC transport rates or few
NBMPR binding sites on blasts were observed in a subset of patients with acute
leukemia who failed to achieve remission with
drug combinations containing araC.