Summary. The effects of the protein kinase C activator bryostatin 1, either with or without recombinant granulocyte‐macrophage colony stimulating factor (rGM‐CSF) were examined with respect to the in vitro metabolism of ara‐C in leukaemic myeloblasts obtained from 10 patients with acute myelogenous leukaemia (AML). Coincubation of cells with 12·5 × 10−9m bryostatin 1 and 10−5m ara‐C for 4 h resulted in a significant increase in ara‐CTP formation (compared to controls) in 6/10 specimens (mean increase 106%: range 38–255%), and no change in the remainder. In contrast, coincubation of cells with 1·25 ng/ml rGM‐CSF resulted in a significant increase in only one specimen, and decreases in two. Bryostatin 1 also significantly increased ara‐C DNA incorporation in 6/9 evaluable samples, including two which did not display an increase in ara‐CTP formation. Coincubation of cells with both bryostatin 1 and rGM‐CSF did not lead to a further increase in ara‐CTP formation or ara‐C DNA incorporation compared to values obtained with either agent alone. Finally, exposure of blasts to bryostatin 1 for 24 h before ara‐C led to an increase in ara‐CTP formation in 3/8 additional specimens, and a decrease in one sample displaying evidence of bryostatin 1 ‐induced macrophage differentiation. Incubation of cells with both rGM‐CSF and bryostatin 1 for this period resulted in ara‐CTP levels equivalent to those obtained with bryostatin 1 alone. These studies indicate that while bryostatin 1 exerts a heterogeneous effect on ara‐C metabolism in leukaemic myeloblasts, it is capable of potentiating ara‐C phosphorylation in a subset of patient samples, including some that do not exhibit an increase in response to rGM‐CSF. They also raise the possibility that bryostatin 1‐induced potentiation of ara‐C metabolism in some leukaemic cells may contribute, at least in part, to the antileukaemic efficacy of this drug combination.
|Original language||English (US)|
|Number of pages||7|
|Journal||British Journal of Haematology|
|State||Published - Nov 1992|
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