Haematopoietic Growth Factors in the Treatment of Therapeutic and Accidental Irradiation-induced Bone Marrow Aplasia

Abstract

Bone marrow aplasia is one of the main syndromes following a high dose accidental exposure of ionizing radiation. Although both transfusion and bone marrow transplantation have been used with some success since the first treatments of patients, other therapeutic strategies are needed. The strategies involving haematopoietic growth factors for the treatment of radiation victims have been explored in vivo mainly in animal models and it is hoped that new therapeutic regimens will be elucidated from such approaches. The growth factors stimulate proliferation and/or differentiation of haematopoietic progenitor cells and possible stem cells. Furthermore, they act on the functions of mature cells. They now have specific uses in haematology, related to their role in the regulation of growth and differentiation of haematopoietic progenitor cells. The results of the clinical trials, performed with numerous patients and often randomized bring important clues about what to expect from growth factor therapy. Other factors are only entering the preclinical or clinical trials now. Although numerous in vitro or in vivo experiments suggest a benefit from their effects, their possible uses in therapy are still questionable. Some growth factors have already been used for the treatment of accidental radiation-induced aplasia and lessons have been learned from their medical management and follow-up.

Short-term injection of antiapoptotic cytokine combinations soon after lethal γ-irradiation promotes survival

“…7,26 In most preclinical trials, HGF administration starts from the day after myeloablative injury, and the duration of treatment covers 15 to 21 days until neutrophil or platelet recovery. [2][3][4][5][6]27 Few combinations have been used despite promising studies in myeloablated nonhuman primates that entailed 2 cytokines 4-6 or synthetic dual cytokine receptor agonists. 3,27 Thus far, nuclear accident victims have been treated with GM-CSF and IL-3 28 or G-CSF ϩ GM-CSF.…”

“…1 Numerous studies have shown the efficacy of hematopoietic growth factors (HGFs) in stimulating neutrophil and platelet recovery in animals and humans after myeloablation. 2 Granulocyte-colony-stimulating factor (G-CSF), granulocyte macrophage-colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), IL-11, and thrombopoietin (TPO) are among the most efficient cytokines. 3 These molecules have primarily been evaluated as monotherapy, but the simultaneous or sequential administration of 2 complementary cytokines has resulted in better patterns of hematologic recovery.…”

Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: long-term follow-up of hematopoiesis

“…1 The rationale of HGF treatment is the presence of residual hematopoietic stem and progenitor cells (HSPCs) in BM areas after total body irradiation (TBI) due to the constitutive heterogeneity of dose distribution involving notably the attenuation related to body thickness. 2,3 These "underexposed" HSPCs represent useful targets in order to accelerate hematopoietic recovery in addition to intrinsic radio-resistant stem cells.…”

Le Flt3-ligand plasmatique, un bio-indicateur pronostique de l'atteinte radio-induite à la moelle osseuse

“…Cette difficulté est essentiellement due au manque de bio-indicateurs de l'étendue des dommages radio-induits et en particulier des dommages au système hématopoïétique. En effet, le choix entre différents traitements du syndrome hématopoïétique, c'est-à-dire thérapie de soutien, injection de cytokines (Butturini et al, 1988 ; Mac Vittie et Monroy, 1990 ; Thierry et al, 1995) ou greffe de moelle osseuse (Mathé et al, 1964 ;Baranov et al, 1989 ;Gale et Butturini, 1991), est surtout basé sur l'estimation de la dose reçue par la victime plutôt que sur l'étendue des dommages radio-induits à la moelle osseuse (Gale, 1988). Cependant, l'étude des accidents d'irradiation passés montre clairement que dans la plupart des cas, l'irradiation est hétérogène (Bond et al, 1953 ;Nénot, 1998).…”