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.
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.
Grant
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S
Department of Pharmacology, Medical College of Virginia, Richmond 23298.
Traylor
R
R
Pettit
G R
GR
Lin
P S
PS
D000818:Animals; D054713:Bryostatins; D004357:Drug Synergism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology*; D007783:Lactones / Q000494:pharmacology*; D018942:Macrolides; D051379:Mice; D008807:Mice, Inbred BALB C; D008809:Mice, Inbred C3H; D011493:Protein Kinase C / Q000378:metabolism; D011837:Radiation-Protective Agents / Q000494:pharmacology*; D011994:Recombinant Proteins / Q000494:pharmacology; D014916:Whole-Body Irradiation
D054713:Bryostatins; D007783:Lactones; D018942:Macrolides; D011837:Radiation-Protective Agents; D011994:Recombinant Proteins; C046785:bryostatin 1; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D011493:Protein Kinase C