Level of Flt3-ligand in plasma: a possible new bio-indicator for radiation-induced aplasia

Bertho, Jean-Marc; Demarquay, Christelle; Frick, Johanna; Joubert, Christophe; Arenales, S; Jacquet, N.; Sorokine-Durm, I.; Chau, Q.; Lopez, M.; Aigueperse, Jocelyne; Gorin, Norbert‐Claude; Gourmelon, P.

doi:10.1080/09553000110043711

Cited by 86 publications

(70 citation statements)

References 27 publications

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“…It has been shown that bone marrow recovery after TBI is mediated in large part by hematopoietic cytokines and growth factor release (20,(38)(39)(40)(41). Several hematopoietic growth factors and cytokines have been demonstrated to generate reactive oxygen species (ROS) as part of their signaling cascade in hematopoietic cells, including stem cells (42,43).…”

Section: Discussionmentioning

confidence: 99%

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

et al. 2008

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The purpose of this study was to determine whether a dietary supplement consisting of Lselenomethionine, vitamin C, vitamin E succinate, α-lipoic acid and N-acetyl cysteine could improve the survival of mice after total-body irradiation. Antioxidants significantly increased the 30-day survival of mice after exposure to a potentially lethal dose of X rays when given prior to or after animal irradiation. Pretreatment of animals with antioxidants resulted in significantly higher total white blood cell and neutrophil counts in peripheral blood at 4 and 24 h after 1 Gy and 8 Gy. Antioxidants were effective in preventing peripheral lymphopenia only after low-dose irradiation. Antioxidant supplementation was also associated with increased bone marrow cell counts after irradiation. Supplementation with antioxidants was associated with increased Bcl2 and decreased Bax, caspase 9 and TGF-β1 mRNA expression in the bone marrow after irradiation. Maintenance of the antioxidant diet was associated with improved recovery of the bone marrow after sublethal or potentially lethal irradiation. Taken together, oral supplementation with antioxidants appears to be an effective approach for radioprotection of hematopoietic cells and improvement of animal survival, and modulation of apoptosis is implicated as a mechanism for the radioprotection of the hematopoietic system by antioxidants.

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Section: Discussionmentioning

confidence: 99%

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

et al. 2008

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“…Previous studies have shown that FL levels rise and then fall after aplasia-inducing therapy. 25,26 From the Cephalon 204 trial, we also had plasma samples collected on or around day 42 with which we were able to examine FL levels in individual patients during recovery from a single course of chemotherapy. Results from these samples ( Figure 1C) indicate that in many cases FL levels remain elevated for weeks after initiation of therapy.…”

Section: Plasma Flt3 Ligand Levels Are Elevated After Chemotherapymentioning

confidence: 99%

“…19,20 Furthermore, it has previously been shown that plasma FL levels rise during periods of bone marrow aplasia induced by chemotherapy or radiation. [21][22][23][24][25][26][27] Given that in both of these trials lestaurtinib was administered after intensive chemotherapy, we decided to examine FL levels in the plasma samples available to us. To derive an estimate of FL levels in newly diagnosed AML patients, we tested plasma from 7 consecutive AML patients presenting to our institution at diagnosis.…”

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FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo

Sato

Yang

Knapper

et al. 2011

Blood

225

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We examined in vivo FLT3 inhibition in acute myeloid leukemia patients treated with chemotherapy followed by the FLT3 inhibitor lestaurtinib, comparing newly diagnosed acute myeloid leukemia patients with relapsed patients. Because we noted that in vivo FLT3 inhibition by lestaurtinib was less effective in the relapsed patients compared with the newly diagnosed patients, we investigated whether plasma FLT3 ligand (FL) levels could influence the efficacy of FLT3 inhibition in these patients. After intensive chemotherapy, FL levels rose to a mean of 488 pg/mL on day 15 of induction therapy for newly diagnosed patients, whereas they rose to a mean of 1148 pg/mL in the relapsed patients. FL levels rose even higher with successive courses of chemotherapy, to a mean of 3251 pg/mL after the fourth course. In vitro, exogenous FL at concentrations similar to those observed in patients mitigated IntroductionAcute myeloid leukemia (AML) patients who harbor the FLT3/ITD mutation have an exceptionally poor prognosis. 1,2 During the past decade, efforts have been underway to develop FLT3 inhibitors in the hopes of improving outcomes for these patients. 3 Several agents have now been studied as monotherapy for this disease, and the results have been only modestly successful. Although there have been a few remissions reported, the responses are usually limited to clearance of peripheral blasts, with persistence of disease in the marrow. In light of this, attention has turned to incorporating these agents into existing chemotherapy regimens, on the hypothesis that FLT3 inhibition will synergize with chemotherapy in inducing cytotoxicity. 4 Alternately, others have postulated that mobilizing the leukemia cells from the marrow might enhance the efficacy of FLT3 inhibition and have therefore tested FLT3 inhibitors in combination with CXCR4 inhibition. 5 Several large trials of chemotherapy administered in combination with FLT3 inhibitors are either actively accruing or have recently completed accrual. Because chemotherapy may alter the pharmacokinetics of FLT3 inhibitors and therefore affect target inhibition in vivo, we examined FLT3 inhibition in patients receiving lestaurtinib, an indolocarbazole FLT3 inhibitor, from 2 separate trials in which the agent was combined with chemotherapy. We noted a discrepancy in the degree of FLT3 inhibition, as measured by a plasma inhibitory activity assay, between the 2 groups of patients. We hypothesized that high levels of FLT3 ligand (FL), a cytokine that is known to increase after myelosuppressive therapy, could be interfering with FLT3 inhibition in these trials. We have therefore examined FL levels in response to chemotherapy and FLT3 inhibition, as well as the effect of FL levels on the efficacy of FLT3 inhibitors in vitro and in vivo. Our findings may explain why blasts in the bone marrow are more resistant to FLT3 inhibitors and furthermore have important implications both for FLT3 mutant AML as a disease as well as for efforts to incorporate FLT3 inhibitors into AML therapy. Methods ...

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“…De plus, aucune variation significative du niveau du FL n'a été détectée en fonction de l'âge et du sexe des animaux, ni en fonction du cycle circadien ( Fig. 1) (Bertho et al, 2001 Différentes expériences d'irradiation de primates ont été réalisées, et ont permis de suivre l'évolution de la concentration plasmatique du FL en fonction de la configuration d'irradiation (homogène ou hétérogène), de la dose d'irradiation (de 2 à 8 Gy), ou du traitement du syndrome hématopoïétique mis en place. Les résultats montrent que chez tous les animaux irradiés, il y a une élévation de la concentration plasmatique de FL dans la première semaine qui suit l'irradiation.…”

Section: éTudes Chez Le Primate Non-humain : Un Modèle Pré-cliniqueunclassified

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

Bertho¹,

Frick²,

Demarquay³

et al. 2001

Radioprotection

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À la suite d'une irradiation accidentelle, le choix entre différents traitements du syndrome hématopoïétique dépend essentiellement de l'estimation de l'étendue des dommages radio-induits h la moelle osseuse. Récemment, il a été montré que la concentration dans le sérum du Flt3-Ligand (FL), une cytokine agissant sur les cellules immatures de la moelle osseuse, est fortement augmentée lors des aplasies médullaires induites ou acquises. Ceci nous a suggéré que le FL pourrait être un hioindicateur de l'atteinte radio-induite à la moelle osseuse. Afin de vérifier cette hypothèse, un ensemble de travaux a été initié, aussi bien dans un modèle de primate uon-humain que chez des patients traités par radio-ou chimiothérapie. Les résultats montrent que la concentration de FL dans le plasma, dans les 5 premiers jours après irradiation, permet de prédire l'évolution du syndrome hématopoïétique chez l'animal. Des résultats similaires sont retrouvés chez l'homme. L'ensemble de ces études devrait permettre à terme, de disposer d'un bio-indicateur de l'atteinte radioinduite à la moelle osseuse en situation d'irradiation accidentelle. RÉSUMÉABSTRACT Plasma Flt3-ligand as a prognostic hio-indicator of radiation-induced bone marrow damage.Following an accidental irradiation, the choice between different therapeutic strategies mainly depends upon the estimated radiation-induced bone marrow damage. It was shown receutly that the serum concentration of FIt3-ligand (FL), a cytokine mainly acting on immature haemopoietic cells, is highly elevated in either acquired or induced bone marrow aplasia. This suggested to us that FL measurement could he used as a hio-indicator of radiation-induced houe marrow damage. In order to verify this hypothesis, studies were conducted in a non humau primate mode1 as well as in humans undergoing radio a n a o r chemotherapy. Resultsshowed that the increase in FL concentration on day 5 after irradiation is predictive of the evolution of the haemopoietic syndrome. Similar results were obîained in humans. Overall these results suggested that FI, measurement could he used as a reliahle hio-iudicator of radiation-induced bone marrow damage in accidental irradiation situations.

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Level of Flt3-ligand in plasma: a possible new bio-indicator for radiation-induced aplasia

Abstract: Monitoring plasma FL concentration can be used as an indicator of radiation-induced marrow aplasia, and this may be of use in accidental irradiation situations.

Cited by 86 publications

References 27 publications

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

Dietary Antioxidants Protect Hematopoietic Cells and Improve Animal Survival after Total-Body Irradiation

FLT3 ligand impedes the efficacy of FLT3 inhibitors in vitro and in vivo

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

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