FLT-3 Ligand Provides Hematopoietic Protection From Total Body Irradiation in Rabbits

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 765-769 ◽  
Author(s):  
A. Gratwohl ◽  
L. John ◽  
H. Baldomero ◽  
J. Roth ◽  
A. Tichelli ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Cell Counts ◽  
Hematopoietic Recovery ◽  
Co60 Source ◽  
New Zealand White Rabbits ◽  
White Blood Cell Counts ◽  
Total Body ◽  
American Society ◽  
Clinical Potential ◽  
Stimulating Factor

Several hematopoietic cytokines have been investigated for their potential to provide protection from the lethal consequences of bone marrow aplasia after total body irradiation (TBI). Some can increase the dose of irradiation tolerated by the animals; none allow endogenous recovery after doses such as administered in clinical blood or marrow transplantation. We tested the radioprotective potential of FLT-3 ligand, an early acting hematopoietic cytokine, alone and in combination with a late acting cytokine, granulocyte-colony stimulating factor (G-CSF). Adult outbred New Zealand White rabbits were submitted to TBI of 1,200 or 1,400 cGy by a Co60 source. Recombinant human (rh) FLT-3 ligand at a dose of 500 μg/kg and/or rhG-CSF at a dose of 10 μg/kg were administered for 14 days subcutaneously daily, beginning either 2 days before or the day after TBI. All control animals given no growth factors died of aplasia at day 10 (range, 5 to 16). All 8 animals given G-CSF had severe aplasia and 7 died at day 8 (range, 5 to 10); 1 animal survived, with G-CSF being administered before TBI. In contrast, 11 of 12 animals given FLT-3 ligand, with or without G-CSF, survived. Radioprotection was best in the group given FLT-3 ligand together with G-CSF before TBI. In these animals median platelet counts were never <10 × 109/L and median white blood cell counts never <0.5 × 109/L. These data show that hematopoietic recovery can occur after 1,400 cGy TBI in rabbits, if protected by FLT-3 ligand, and suggest a radioprotective clinical potential of this cytokine. © 1998 by The American Society of Hematology.

FLT-3 Ligand Provides Hematopoietic Protection From Total Body Irradiation in Rabbits

Blood ◽  
1998 ◽  
Vol 92 (3) ◽  
pp. 765-769 ◽  
Author(s):  
A. Gratwohl ◽  
L. John ◽  
H. Baldomero ◽  
J. Roth ◽  
A. Tichelli ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Cell Counts ◽  
Hematopoietic Recovery ◽  
Co60 Source ◽  
New Zealand White Rabbits ◽  
White Blood Cell Counts ◽  
Total Body ◽  
American Society ◽  
Clinical Potential ◽  
Stimulating Factor

Abstract Several hematopoietic cytokines have been investigated for their potential to provide protection from the lethal consequences of bone marrow aplasia after total body irradiation (TBI). Some can increase the dose of irradiation tolerated by the animals; none allow endogenous recovery after doses such as administered in clinical blood or marrow transplantation. We tested the radioprotective potential of FLT-3 ligand, an early acting hematopoietic cytokine, alone and in combination with a late acting cytokine, granulocyte-colony stimulating factor (G-CSF). Adult outbred New Zealand White rabbits were submitted to TBI of 1,200 or 1,400 cGy by a Co60 source. Recombinant human (rh) FLT-3 ligand at a dose of 500 μg/kg and/or rhG-CSF at a dose of 10 μg/kg were administered for 14 days subcutaneously daily, beginning either 2 days before or the day after TBI. All control animals given no growth factors died of aplasia at day 10 (range, 5 to 16). All 8 animals given G-CSF had severe aplasia and 7 died at day 8 (range, 5 to 10); 1 animal survived, with G-CSF being administered before TBI. In contrast, 11 of 12 animals given FLT-3 ligand, with or without G-CSF, survived. Radioprotection was best in the group given FLT-3 ligand together with G-CSF before TBI. In these animals median platelet counts were never &lt;10 × 109/L and median white blood cell counts never &lt;0.5 × 109/L. These data show that hematopoietic recovery can occur after 1,400 cGy TBI in rabbits, if protected by FLT-3 ligand, and suggest a radioprotective clinical potential of this cytokine. © 1998 by The American Society of Hematology.

scholarly journals Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1308-1313 ◽  
Author(s):  
FG Schuening ◽  
R Storb ◽  
S Goehle ◽  
TC Graham ◽  
FR Appelbaum ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Peripheral Leukocyte ◽  
Hematopoietic Recovery ◽  
Blood Neutrophils ◽  
Leukocyte Counts ◽  
Total Body ◽  
Marrow Infusion ◽  
Stimulating Factor

This study was designed to test whether recombinant human G-CSF (rh G- CSF) affects hematopoiesis in normal dogs and, if so, to test the effects of G-CSF in dogs given otherwise lethal total body irradiation (TBI). Rh G-CSF given subcutaneously at 10 or 100 micrograms/kg/d for 14 days to two normal dogs increased peripheral blood neutrophils eight to tenfold and monocytes four to sixfold above controls. Lymphocyte counts remained unchanged at the lower dose and increased threefold at the higher dose of rh G-CSF. No significant changes were observed in eosinophil, platelet, reticulocyte, or hematocrit levels. After 2 weeks of treatment with rh G-CSF, bone marrow displayed myeloid hyperplasia and left-shifted granulocytopoiesis. After discontinuation of rh G-CSF, peripheral leukocyte counts returned to control levels within three days. Five dogs administered 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow infusion or growth factor, all developed profound pancytopenia and died between 17 and 23 days after TBI with infections secondary to marrow aplasia. Four of five dogs treated within two hours after 400 cGy TBI with 100 micrograms rh G- CSF/kg/d subcutaneously twice a day for 21 days showed complete and sustained endogenous hematopoietic recovery. In contrast, five dogs irradiated with 400 cGy TBI and treated with 100 micrograms rh G- CSF/kg/d starting on day 7 after TBI, all died between days 17 and 20 after TBI with infections secondary to marrow aplasia. Rh G-CSF, if administered shortly after irradiation, can reverse the otherwise lethal myelosuppressive effect of radiation exposure.

scholarly journals Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 20-26 ◽  
Author(s):  
FG Schuening ◽  
FR Appelbaum ◽  
HJ Deeg ◽  
M Sullivan-Pepe ◽  
TC Graham ◽  
...  
Keyword(s):  
Stem Cell ◽  
Total Body Irradiation ◽  
Stem Cell Factor ◽  
Combined Treatment ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Platelet Recovery ◽  
Hematopoietic Recovery ◽  
Total Body ◽  
Stimulating Factor

The effects of recombinant canine stem cell factor (rcSCF) on hematopoiesis were studied in normal dogs and in dogs given otherwise lethal total body irradiation (TBI) without marrow transplant. Results were compared with previous and concurrent data with recombinant granulocyte colony-stimulating factor (rG-CSF). Four normal dogs received 200 micrograms rcSCF per kilogram body weight daily either by continuous intravenous infusion for 28 days (n = 2) or by subcutaneous (SC) injection in two divided doses for 20 days (n = 2). All dogs showed at least a twofold increase in peripheral blood neutrophil counts starting approximately 7 days after the initiation of treatment. Hematocrit level and monocyte, lymphocyte, eosinophil, reticulocyte, and platelet counts were not elevated. Marrow sections after rcSCF treatment showed panhyperplasia. The only toxicity was facial edema during the first few days of rcSCF administration, presumably caused by mast cell stimulation. Ten dogs were given 400 cGy TBI at 10 cGy/min from two opposing 60Co sources. They were given no marrow infusion and received 200 micrograms/kg/d rcSCF SC in two divided doses for 21 days starting within 2 hours of TBI. Five of the 10 dogs showed complete and sustained hematopoietic recovery and survived as compared with 1 of 28 control dogs not receiving growth factor (P < .005). RcSCF treatment allowed for hematopoietic recovery in two of seven dogs administered 500 cGy of TBI but in none of five dogs given 600 cGy of TBI. Results with rcSCF are similar to those obtained with rG-CSF. The rate of neutrophil recovery in rcSCF-treated dogs after 400 cGy TBI was not different from that of rG-CSF-treated dogs (P = .65), but the rate of platelet recovery was faster (P = .06) in the rcSCF-treated animals. Combined treatment with rcSCF and rcG-CSF after 500 cGy TBI did not result in strongly improved survival as compared with results obtained with either factor alone.

scholarly journals Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1963-1970
Author(s):  
RA Nash ◽  
FG Schuening ◽  
K Seidel ◽  
FR Appelbaum ◽  
T Boone ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Control Group ◽  
Colony Stimulating Factor ◽  
Platelet Counts ◽  
Hematopoietic Recovery ◽  
Significant Difference ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Total Body ◽  
Stimulating Factor

Recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) was studied in normal dogs and in dogs receiving otherwise lethal total body irradiation (TBI) without marrow transplant. Five normal dogs receiving 25 micrograms/kg of rcGM-CSF by subcutaneous (SC) injection twice daily (BID) for 14 days showed increases in peripheral blood neutrophil counts of three to five times the baseline. Platelet counts decreased during administration of rcGM-CSF to a mean nadir of 52,800. Ten dogs received 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow graft. Within 2 hours of TBI, rcGM-CSF was begun at a dose of 50 micrograms/kg SC BID for 5 doses and then continued at 25 micrograms/kg SC BID for 21 days. Only 1 of the 10 dogs receiving rcGM-CSF survived with complete and sustained recovery of hematopoiesis. One of 13 historical control dogs survived after 400 cGy with no hematopoietic growth factor or marrow infusion. Results with rcGM-CSF were compared with previous and concurrent data with G-CSF studied in the same model. Of 10 dogs receiving G-CSF, 8 survived with complete and sustained hematopoietic recovery, a significantly better survival than that seen with rcGM-CSF (P = .006). Neutrophil counts were sustained at higher levels after TBI for the first 18 days in the G-CSF group (P < .016) and the neutrophil nadirs were higher. No differences in neutrophil nadirs were noted between the rcGM-CSF and control groups. Dogs treated with rcGM-CSF experienced a more rapid decline of platelet counts than G-CSF-treated or control dogs over the first 18 days (P < .001). The nadir of the platelet count was higher in the control group than in either the G-CSF or rcGM-CSF group and no significant difference was observed between the G-CSF and rcGM-CSF groups. After otherwise lethal TBI (400 cGy) in dogs, rcGM-CSF was not effective in promoting hematopoietic recovery or improving survival.

scholarly journals Effect of recombinant human granulocyte colony-stimulating factor on hematopoiesis of normal dogs and on hematopoietic recovery after otherwise lethal total body irradiation

Blood ◽  
1989 ◽  
Vol 74 (4) ◽  
pp. 1308-1313 ◽  
Author(s):  
FG Schuening ◽  
R Storb ◽  
S Goehle ◽  
TC Graham ◽  
FR Appelbaum ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Peripheral Leukocyte ◽  
Hematopoietic Recovery ◽  
Blood Neutrophils ◽  
Leukocyte Counts ◽  
Total Body ◽  
Marrow Infusion ◽  
Stimulating Factor

Abstract This study was designed to test whether recombinant human G-CSF (rh G- CSF) affects hematopoiesis in normal dogs and, if so, to test the effects of G-CSF in dogs given otherwise lethal total body irradiation (TBI). Rh G-CSF given subcutaneously at 10 or 100 micrograms/kg/d for 14 days to two normal dogs increased peripheral blood neutrophils eight to tenfold and monocytes four to sixfold above controls. Lymphocyte counts remained unchanged at the lower dose and increased threefold at the higher dose of rh G-CSF. No significant changes were observed in eosinophil, platelet, reticulocyte, or hematocrit levels. After 2 weeks of treatment with rh G-CSF, bone marrow displayed myeloid hyperplasia and left-shifted granulocytopoiesis. After discontinuation of rh G-CSF, peripheral leukocyte counts returned to control levels within three days. Five dogs administered 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow infusion or growth factor, all developed profound pancytopenia and died between 17 and 23 days after TBI with infections secondary to marrow aplasia. Four of five dogs treated within two hours after 400 cGy TBI with 100 micrograms rh G- CSF/kg/d subcutaneously twice a day for 21 days showed complete and sustained endogenous hematopoietic recovery. In contrast, five dogs irradiated with 400 cGy TBI and treated with 100 micrograms rh G- CSF/kg/d starting on day 7 after TBI, all died between days 17 and 20 after TBI with infections secondary to marrow aplasia. Rh G-CSF, if administered shortly after irradiation, can reverse the otherwise lethal myelosuppressive effect of radiation exposure.

scholarly journals Effect of recombinant canine granulocyte-macrophage colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

Blood ◽  
1994 ◽  
Vol 83 (7) ◽  
pp. 1963-1970 ◽  
Author(s):  
RA Nash ◽  
FG Schuening ◽  
K Seidel ◽  
FR Appelbaum ◽  
T Boone ◽  
...  
Keyword(s):  
Total Body Irradiation ◽  
Control Group ◽  
Colony Stimulating Factor ◽  
Platelet Counts ◽  
Hematopoietic Recovery ◽  
Significant Difference ◽  
Macrophage Colony Stimulating Factor ◽  
Macrophage Colony ◽  
Total Body ◽  
Stimulating Factor

Abstract Recombinant canine granulocyte-macrophage colony-stimulating factor (rcGM-CSF) was studied in normal dogs and in dogs receiving otherwise lethal total body irradiation (TBI) without marrow transplant. Five normal dogs receiving 25 micrograms/kg of rcGM-CSF by subcutaneous (SC) injection twice daily (BID) for 14 days showed increases in peripheral blood neutrophil counts of three to five times the baseline. Platelet counts decreased during administration of rcGM-CSF to a mean nadir of 52,800. Ten dogs received 400 cGy TBI at 10 cGy/min from two opposing 60Co sources and no marrow graft. Within 2 hours of TBI, rcGM-CSF was begun at a dose of 50 micrograms/kg SC BID for 5 doses and then continued at 25 micrograms/kg SC BID for 21 days. Only 1 of the 10 dogs receiving rcGM-CSF survived with complete and sustained recovery of hematopoiesis. One of 13 historical control dogs survived after 400 cGy with no hematopoietic growth factor or marrow infusion. Results with rcGM-CSF were compared with previous and concurrent data with G-CSF studied in the same model. Of 10 dogs receiving G-CSF, 8 survived with complete and sustained hematopoietic recovery, a significantly better survival than that seen with rcGM-CSF (P = .006). Neutrophil counts were sustained at higher levels after TBI for the first 18 days in the G-CSF group (P < .016) and the neutrophil nadirs were higher. No differences in neutrophil nadirs were noted between the rcGM-CSF and control groups. Dogs treated with rcGM-CSF experienced a more rapid decline of platelet counts than G-CSF-treated or control dogs over the first 18 days (P < .001). The nadir of the platelet count was higher in the control group than in either the G-CSF or rcGM-CSF group and no significant difference was observed between the G-CSF and rcGM-CSF groups. After otherwise lethal TBI (400 cGy) in dogs, rcGM-CSF was not effective in promoting hematopoietic recovery or improving survival.

scholarly journals Effects of recombinant canine stem cell factor, a c-kit ligand, and recombinant granulocyte colony-stimulating factor on hematopoietic recovery after otherwise lethal total body irradiation

Blood ◽  
1993 ◽  
Vol 81 (1) ◽  
pp. 20-26 ◽  
Author(s):  
FG Schuening ◽  
FR Appelbaum ◽  
HJ Deeg ◽  
M Sullivan-Pepe ◽  
TC Graham ◽  
...  
Keyword(s):  
Stem Cell ◽  
Total Body Irradiation ◽  
Stem Cell Factor ◽  
Combined Treatment ◽  
Granulocyte Colony Stimulating Factor ◽  
Colony Stimulating Factor ◽  
Platelet Recovery ◽  
Hematopoietic Recovery ◽  
Total Body ◽  
Stimulating Factor

Abstract The effects of recombinant canine stem cell factor (rcSCF) on hematopoiesis were studied in normal dogs and in dogs given otherwise lethal total body irradiation (TBI) without marrow transplant. Results were compared with previous and concurrent data with recombinant granulocyte colony-stimulating factor (rG-CSF). Four normal dogs received 200 micrograms rcSCF per kilogram body weight daily either by continuous intravenous infusion for 28 days (n = 2) or by subcutaneous (SC) injection in two divided doses for 20 days (n = 2). All dogs showed at least a twofold increase in peripheral blood neutrophil counts starting approximately 7 days after the initiation of treatment. Hematocrit level and monocyte, lymphocyte, eosinophil, reticulocyte, and platelet counts were not elevated. Marrow sections after rcSCF treatment showed panhyperplasia. The only toxicity was facial edema during the first few days of rcSCF administration, presumably caused by mast cell stimulation. Ten dogs were given 400 cGy TBI at 10 cGy/min from two opposing 60Co sources. They were given no marrow infusion and received 200 micrograms/kg/d rcSCF SC in two divided doses for 21 days starting within 2 hours of TBI. Five of the 10 dogs showed complete and sustained hematopoietic recovery and survived as compared with 1 of 28 control dogs not receiving growth factor (P < .005). RcSCF treatment allowed for hematopoietic recovery in two of seven dogs administered 500 cGy of TBI but in none of five dogs given 600 cGy of TBI. Results with rcSCF are similar to those obtained with rG-CSF. The rate of neutrophil recovery in rcSCF-treated dogs after 400 cGy TBI was not different from that of rG-CSF-treated dogs (P = .65), but the rate of platelet recovery was faster (P = .06) in the rcSCF-treated animals. Combined treatment with rcSCF and rcG-CSF after 500 cGy TBI did not result in strongly improved survival as compared with results obtained with either factor alone.

scholarly journals RRx-001 Radioprotection: Enhancement of Survival and Hematopoietic Recovery in Gamma-Irradiated Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Kimberly J. Jurgensen ◽  
William K. J. Skinner ◽  
Bryan Oronsky ◽  
Nacer D. Abrouk ◽  
Andrew E. Graff ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Total Body Irradiation ◽  
Reduction Factor ◽  
Phase Iii ◽  
Hematopoietic Recovery ◽  
Total Body ◽  
Gamma Irradiated ◽  
Bone Marrow Regeneration ◽  
Marrow Cellularity

The present studies evaluate the in vivo prophylactic radioprotective effects of 1-bromoacetyl-3, 3-dinitroazetidine (RRx-001), a phase III anticancer agent that inhibits c-myc and downregulates CD-47, after total body irradiation (TBI), in lethally and sublethally irradiated CD2F1 male mice. A single dose of RRx-001 was administered by intraperitoneal (IP) injection 24 h prior to a lethal or sublethal radiation dose. When irradiated with 9.35 Gy, the dose lethal to 70% of untreated mice at 30 days (LD70/30), only 33% of mice receiving RRx-001 (10 mg/kg) 24 h prior to total body irradiation (TBI) died by day 30, compared to 67% in vehicle-treated mice. The same pretreatment dose of RRx-001 resulted in a significant dose reduction factor of 1.07. In sublethally TBI mice, bone marrow cellularity was increased at day 14 in the RRx-001-treated mice compared to irradiated vehicle-treated animals. In addition, significantly higher numbers of lymphocytes, platelets, percent hematocrit and percent reticulocytes were observed on days 7 and/or 14 in RRx-001-treated mice. These experiments provide proof of principle that systemic administration of RRx-001 prior to TBI significantly improves overall survival and bone marrow regeneration.

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