PEG-Filgrastim activity on granulocyte functions

Fazzi, Rita; Orciuolo, Enrico; Trombi, Luisa; Mattii, Letizia; Battola, B; Riccioni, R; Carulli, Giovanni; Galimberti, Sara; Petrini, Mario

doi:10.1016/j.leukres.2006.11.016

Cited by 9 publications

(10 citation statements)

References 14 publications

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“…It is conceivable that such abnormalities are due to specific pegfilgrastim-induced cytoskeleton activation rather than to accelerated bone marrow transit with the release of structurally immature neutrophils [28, 41, 42]. In fact, strong neutrophil activation after pegfilgrastim as well as a neutrophil functional ‘paralysis’ related to a hyperactivation state has already been reported [36]. Even our data, which showed a significant increase in LAP activity, suggest activation of cells rather than their immaturity.…”

Section: Discussionmentioning

confidence: 66%

“…However, a recent study showed a trend towards the superiority of pegfilgrastim over filgrastim or lenograstim in reducing the frequency of febrile neutropenia in patients treated with taxane and epirubicin chemotherapy regimens for breast cancer [33]. Since data on the biological effects of pegfilgrastim on neutrophils from healthy subjects or from patients exposed to chemotherapy are limited to a few studies [34,35,36], we evaluated apoptosis, actin polymerization and LAP scores of neutrophils from patients treated with a dose-dense chemotherapy regimen supported by pegfilgrastim.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several studies have reported such changes in neutrophils stimulated in vivoby filgrastim [28, 41, 42] and also pegfilgrastim [36], and these modifications are likely to be responsible for the reduced chemotaxis of filgrastim-primed neutrophils [28, 41, 42]. It is conceivable that such abnormalities are due to specific pegfilgrastim-induced cytoskeleton activation rather than to accelerated bone marrow transit with the release of structurally immature neutrophils [28, 41, 42].…”

Section: Discussionmentioning

confidence: 99%

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Biological Effects of Pegfilgrastim on Circulating Neutrophils in Breast Cancer Patients Undergoing Dose-Dense Chemotherapy

et al. 2008

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Pegfilgrastim is a covalent conjugate of filgrastim and polyethylene glycol that has proved to be effective in supporting myelopoiesis during chemotherapy. Since very limited information is available on the biological effects of pegfilgrastim on neutrophils exposed to chemotherapy, we analyzed the following parameters in neutrophils of patients undergoing dose-dense chemotherapy for breast cancer: apoptosis, by a TUNEL technique; actin polymerization, using FITC-labeled phalloidin, and alkaline phosphatase activity by cytochemistry. Peripheral blood buffy coat smears were obtained before starting treatment and immediately before each chemotherapy course. After pegfilgrastim stimulation we observed the following: (1) stability of the absolute neutrophil count for the whole duration of treatment and no infectious events; (2) a reduction in the neutrophil constitutive apoptosis rate in comparison with that observed in control patients treated with standard chemotherapy courses with no growth factor support; (3) persistent abnormalities of actin assembly in neutrophils, indicative of changes in cytoskeletal organization, and (4) a significant increase in the activity of leukocyte alkaline phosphatase, a sensitive marker of the later stages of neutrophil maturation. In conclusion, these results suggest that pegfilgrastim improves the neutrophil functions in patients exposed to chemotherapy by inhibition of constitutive apoptosis, thereby prolonging the survival of these cells.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Biological Effects of Pegfilgrastim on Circulating Neutrophils in Breast Cancer Patients Undergoing Dose-Dense Chemotherapy

et al. 2008

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“…A slight reduction in neutrophil ROS production was observed after treatment with all three forms of rG-CSF (47). Two other studies suggested that there could be changes in neutrophil chemotaxis with pegfilgrastim treatment, as evidenced by the observed abnormalities in actin polymerization in breast cancer patients undergoing chemotherapy and treated with pegfilgrastim (48, 49). However, it is not clear whether this effect was due to chemotherapy or to pegfilgrastim treatment, since decreased neutrophil chemotaxis, which is associated with defects in actin polymerization (48), has also been reported with chemotherapy alone (50).…”

Section: Discussionmentioning

confidence: 97%

Kinetics of Neutrophils in Mice Exposed to Radiation and/or Granulocyte Colony-Stimulating Factor Treatment

et al. 2013

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Astronauts have the potential to develop the hematopoietic syndrome as a result of exposure to radiation from a solar particle event (SPE) during exploration class missions. This syndrome is characterized by a reduction in the number of circulating blood cells (cytopenias). In the present study the effects of SPE-like proton and γ radiation on the kinetics of circulating neutrophils were evaluated during a one-month time period using mice as a model system. The results revealed that exposure to a 2 Gy dose of either SPE-like proton or γ radiation significantly decreased the number of circulating neutrophils, with two nadirs observed on day 4 and day 16 postirradiation. Low circulating neutrophil count (neutropenia) is particularly important because it can increase the risk of astronauts developing infections, which can compromise the success of the mission. Thus, two granulocyte colony-stimulating factors (G-CSFs), filgrastim and pegfilgrastim were evaluated as countermeasures for this endpoint. Both forms of G-CSF significantly increased neutrophil counts in irradiated mice, however, the effect of pegfilgrastim was more potent and lasted longer than filgrastim. Using the expression of CD11b, CD18 and the production of reactive oxygen species (ROS) as markers of neutrophil activation, it was determined that the neutrophils in the irradiated mice treated with pegfilgrastim were physiologically active. Thus, these results suggest that pegfilgrastim could be a potential countermeasure for the reduced number of circulating neutrophils in irradiated animals.

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“…Dal punto di vista quantitativo l'uso di pegfilgrastim come dose singola è analogo a una mediana di 11 somministrazioni giornaliere di filgrastim in termini di riduzione di incidenza e durata della neutropenia, e la molecola è rintracciabile nel circolo ematico fino a circa 16 giorni consecutivamente dopo la singola somministrazione [18]. Dal punto di vista qualitativo, invece, pegfilgrastim (filgrastim long-acting) e filgrastim hanno identico meccanismo di azione e le caratteristiche dei neutrofili indotti dalle due molecole sono sovrapponibili [19][20]. Probabilmente le più recenti evidenze cliniche porteranno a una più approfondita definizione dell' efficacia dei G-CSF, passando dall'attuale semplicistica analisi quantitativa (ANC) alla più plausibile considerazione anche delle qualità funzionali dei neutrofili indotti.…”

Section: Efficaciaunclassified

Appropriate administration of Granulocyte-Colony Stimulating Factors

Rosti¹

2012

RHC

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Chemotherapy-induced febrile neutropenia is a potentially fatal complication of cancer treatment and is also the main reason of dose-reduction and/or delay of chemotherapy regimen. Prophylaxis with G-CSF is applicable to reduce the risk of chemotherapy-induced neutropenia. Two molecules of recombinant G-CSF are available for clinical use: lenograstim, identical to human native G-CSF, that is derived from mammalian cells and filgrastim, different to human native G-CSF, expressed in E. coli and commercialized in normal form and pegilated long-acting form. Neutrophil morphology and expected defense functions are modified by treatment with filgrastim, while they are not affected by lenograstim. These functionality differences observed in vitro are recently confirmed in a clinical trial that shows a lower incidence of febrile episodes with lenograstim compared to filgrastim in presence of G-CSF induced neutrophils. The long-term safety of lenograstim was supported by the results of a prospective, longer-term study involving almost 4,000 healthy donors. Another important question is the respect of timing of administration of G-CSF and chemotherapy. Absolutely in no case the plasma concentration of G-CSF is to be detected 48h before to 24h post chemotherapeutic drugs administration. In fact, this combination could result in an increased risk of mielotoxicity and a potential for an increase in sensitivity of rapidly dividing myeloid cells to cytotoxic-mutagenic chemotherapy potential. Lenograstim and filgrastim shows short half-life time, instead pegfilgrastim shows detectable concentrations for 16 days after a single administration. This is important to be considered, in particular in bi-weekly and tri-weekly adjuvant chemotherapy regimens. Anyway, the use of the lowest effective dose for the shortest adequate time of medications ensures the optimal balance among effectiveness, safety and costs of treatments, in a context that takes into account effectiveness and efficiency.Keywords Granulocyte-Colony Stimulating Factors; Lenograstim; Filgrastim; Pegfilgrastim; G-CSF; Timing; Appropriateness; Guidelines Appropriatezza d'uso dei fattori di crescita granulocitari nella profilassi e nel trattamento della neutropenia febbrile Introduzione Chemioterapia, neutropenia e G-CSFLa chemioterapia antiblastica, anche nell' era delle terapie target, resta il caposaldo del trattamento della maggioranza dei tumori solidi e delle neoplasie ematologiche. A fronte del beneficio clinico, alcuni effetti collaterali sono preminenti, in particolare la mielodepressione e, nell'ambito di questa, soprattutto la neutropenia. Il comparire di neutropenia durante il trattamento può portare una serie di ulteriori complicanze come la neutropenia febbrile e la riduzione della dose intensity, intesa come diminuzione della quantità di dose somministrata nell'unità di tempo. Da ciò deriva un possibile ridotto effetto dei farmaci sul controllo della malattia e quindi un peggiorato outcome [1]. Indubbiamente negli ultimi anni l'impiego in clinica...

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PEG-Filgrastim activity on granulocyte functions

Cited by 9 publications

References 14 publications

Biological Effects of Pegfilgrastim on Circulating Neutrophils in Breast Cancer Patients Undergoing Dose-Dense Chemotherapy

Biological Effects of Pegfilgrastim on Circulating Neutrophils in Breast Cancer Patients Undergoing Dose-Dense Chemotherapy

Kinetics of Neutrophils in Mice Exposed to Radiation and/or Granulocyte Colony-Stimulating Factor Treatment

Appropriate administration of Granulocyte-Colony Stimulating Factors

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