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

Abstract

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.

The Role of Protein Kinase C Activity in the Killing of Chinese Hamster Ovary Cells by Ionizing Radiation and Photodynamic Treatment

“…In summary, the present results underscore that PKC modulation may be a very useful adjuvant in cancer therapy, as suggested in several recent studies (22,31,36,38). However, the efficiency of PKC modulation may not only depend on the characteristics of different tumor cells, but also on the nature of the cytotoxic treatment, used in combination with PKC modulation.…”

The Role of Protein Kinase Activators and ZFN in Reducing the Harmful Effects of Total Body Irradiation

“…The mechanism by which protein kinase activators enhance radiation protection is that the activation of accessory cells by bryostatin causes the release of growth factors, such as G-CSF, IL-1 and IL-6 which have a clear role in radiation protection. Bryostatin may modify the action of GM-CSF Granulocyte-macrophage colony-stimulating factor [20].…”

“…Activating of Pk-C signals by bryostatin may also contribute to the expression of certain oncogenes, such as c-jun tumor genes, which interfere with the cell's protection from radiation harm [20]. Bryostatin enhances the development of advanced stem cells in mouse bone marrow, i.e.…”

Progress in the Discovery of Biosynthetic Anticancer Drugs

“…We were able to crystallize this substance and complete the X-ray crys-tallographic structural determination. Bryostatin 1 was found to be a remarkable macrocyclic lactone. − …”

“…Subsequently, we were greatly stimulated by the experiments of Dr. P. Blumberg 110,111 in the NCI, where bryostatin 1 was shown to be a powerful antitumor promoter and either an inhibitor or stimulator of protein kinase C. In fact, it has a tremendous effect on the signal transduction pathway. Later, bryostatin 1 ( 42 ) was found to promote the normal growth of bone marrow progenitor cells. , One consequence of the hematopoietic progenitor effects was found when mice, given 1 μg of bryostatin 1, followed by a lethal dose of radiation, were found to survive. , Furthermore, bryostatin 1 was found to be an immune stimulant, , and it also stimulates the normal production of interleukin 2 and interferon.…”