Mobilization of primitive and committed hematopoietic progenitors in nonhuman primates treated with defibrotide and recombinant human granulocyte colony-stimulating factor.
OBJECTIVE
The aim of this study was to evaluate the capacity of defibrotide in enhancing cytokine-induced hematopoietic mobilization in rhesus monkeys.


METHODS
Animals received recombinant human granulocyte colony-stimulating factor (rhG-CSF, 100 microg/kg/day SC for 5 days) and, after a 4- to 6-week washout period, were remobilized with defibrotide (15 mg/kg/hour continuous intravenous for 5 days) plus rhG-CSF. Hematopoietic mobilization was evaluated by complete blood counts, differential counts, as well as frequency and absolute numbers of colony-forming cells (CFCs), high-proliferative potential CFCs (HPP-CFCs), and long-term culture-initiating cells (LTC-ICs).


RESULTS
Compared to baseline values, rhG-CSF increased circulating CFCs, HPP-CFCs, and LTC-ICs by 158-, 125-, and 67-fold, respectively; the same figures for defibrotide/rhG-CSF were 299-, 1452-, and 295-fold, respectively. Defibrotide/rhG-CSF treatment compared to rhG-CSF alone increased CFCs, HPP-CFCs, and LTC-ICs by 1.4- (35,089 vs 25,825, p< or =0.02), 6- (4358 vs 748, p< or =0.02), and 5-fold (884 vs 168, p< or =0.04), respectively. We then evaluated the effects of a 2-day defibrotide treatment associated with a 5-day rhG-CSF treatment. Compared to rhG-CSF, defibrotide/rhG-CSF increased the mobilization of CFCs, HPP-CFCs, and LTC-ICs by 2- (31,128 vs 15,527, p< or =0.05), 8- (5361 vs 660, p< or =0.01), and 8-fold (954 vs 119, p< or =0.01), respectively.


CONCLUSIONS
Our data demonstrate that in nonhuman primates: 1) defibrotide enhances rhG-CSF-elicited mobilization of primitive and committed progenitors; and 2) a 2-day defibrotide injection is as effective as a 5-day injection.
Carlo-Stella
Carmelo
C
"Cristina Gandini" Medical Oncology Unit, Istituto Nazionale Tumori, Milano, Italy. carmelo.carlostella@unimi.it
Di Nicola
Massimo
M
Longoni
Paolo
P
Milani
Raffaella
R
Milanesi
Marco
M
Guidetti
Anna
A
Haanstra
Krista
K
Jonker
Margaret
M
Cleris
Loredana
L
Magni
Michele
M
Formelli
Franca
F
Gianni
Alesssandro M
AM
D000818:Animals; D001772:Blood Cell Count; D016179:Granulocyte Colony-Stimulating Factor / Q000494:pharmacology*; D019650:Hematopoietic Stem Cell Mobilization; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D008253:Macaca mulatta; D008297:Male; D011089:Polydeoxyribonucleotides / Q000494:pharmacology*; D011994:Recombinant Proteins
D011089:Polydeoxyribonucleotides; D011994:Recombinant Proteins; D016179:Granulocyte Colony-Stimulating Factor; C036901:defibrotide