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The macrocyclic lactone protein kinase C activator, bryostatin 1, either
alone, or in conjunction with recombinant murine granulocyte- macrophage
colony-stimulating factor, protects Balb/c and C3H/HeN mice from the lethal
in vivo effects of ionizing radiation
S Grant, R Traylor, GR Pettit and PS Lin
Department of Pharmacology, Medical College of Virginia, Richmond 23298.
We have examined the in vivo radioprotective effects of the macrocyclic
lactone protein kinase C (PK-C) activator, bryostatin 1, administered
either alone or in conjunction with recombinant murine granulocyte-
macrophage colony-stimulating factor (rmGM-CSF), in Balb/c and C3H/HeN mice
subjected to lethal total body irradiation (TBI). When administered alone
on a divided dose schedule (24 hours and 30 minutes before TBI), rmGM-CSF
(20 micrograms/kg) was ineffective in increasing survival in either strain.
However, in Balb/c mice, bryostatin 1 alone (1 microgram) permitted the
long-term survival (60 days) of 70% of the animals following TBI, and 80%
when administered in conjunction with rmGM-CSF. Bryostatin 1 administered
alone according to this schedule exerted minimal radioprotective effects in
C3H/HeN mice, but, when combined with a subeffective dose of rmGM-CSF,
allowed 50% of the animals to survive. Treatment of Balb/c mice with
bryostatin 1 administered as a single dose 4 hours before TBI resulted in a
20% survival rate, and 45% when administered with rmGM-CSF; corresponding
values for the C3H/HeN strain were 60% and 40%, respectively. Lastly, the
survival rates of Balb/c mice treated with bryostatin 1 administered as a
single dose 4 hours following TBI was 20%, and 25% with rmGM-CSF;
corresponding values were 50% and 25% for C3H/HeN mice. These findings
indicate that the PK-C activator bryostatin 1 exhibits intrinsic in vivo
radioprotective effects in lethally irradiated Balb/c and C3H/HeN mice, and
may, under some circumstances, augment the radioprotective capacity of
rmGM-CSF. They also underscore the critical role that strain differences
and scheduling considerations play in determining the in vivo
radioprotective capacity of bryostatin 1, as well as its interactions with
rmGM-CSF.
Volume 83,
Issue 3,
pp. 663-667,
02/01/1994
Copyright © 1994 by The American Society of Hematology
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