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Bryostatin 1, a unique biologic response modifier: anti-leukemic activity
in vitro
RJ Jones, SJ Sharkis, CB Miller, EK Rowinsky, PJ Burke and WS May
Johns Hopkins Oncology Center, Johns Hopkins Medical Institutions,
Baltimore, MD 21205.
Bryostatin 1, a macrocyclic lactone isolated from the marine bryozoan
Bugula neritina, has demonstrated both antineoplastic activity against the
murine P388 leukemia line in vivo and stimulatory activity against mouse
and human hematopoietic progenitors. We studied the effects of bryostatin 1
on the growth of human leukemias in vitro. Bryostatin 1 inhibited 1 to 4
logs of clonogenic leukemia cell growth from three of four leukemia cell
lines. Bryostatin 1 also inhibited, by at least 1 log, the proliferation of
clonogenic acute nonlymphocytic leukemia (ANLL) cells from 10 to 12
patients with newly diagnosed or relapsed ANLL. Maximal inhibition of
leukemic growth occurred at 10(-9) to 10(- 7) mol/L bryostatin 1.
Interestingly, bryostatin 1 also inhibited the growth of hematopoietic
progenitors from eight patients with myelodysplastic syndromes (MDS).
Leukemia cells exposed to bryostatin 1 for up to 96 hours and then washed,
demonstrated no substantial inhibition of clonogenic growth, indicating
that the anti-leukemic effect of bryostatin 1 is cytostatic. The phorbol
ester 12-0- tetradecanoylphorbol-13-acetate (TPA) produced more potent
inhibition of clonogenic leukemia growth, and this inhibition was blocked
by bryostatin 1. Thus, the anti-leukemic activity of bryostatin 1 may be
mediated through activation of protein kinase C. Bryostatin 1 inhibits
clonogenic leukemia cells at concentrations that stimulate normal
hematopoietic progenitors. The differential effects of bryostatin 1 on
normal and abnormal hematopoiesis suggest that bryostatin 1 may have value
in the treatment of leukemias and MDS.
Volume 75,
Issue 6,
pp. 1319-1323,
03/15/1990
Copyright © 1990 by The American Society of Hematology
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