Growth Colony stimulation as chemo suppport

[Rich66]

Medicina (Kaunas). 2009;45(8):600-6.
Safety and efficacy study of the recombinant granulocyte colony-stimulating factor for prevention of neutropenia and neutropenia-related complications in women with metastatic breast cancer receiving docetaxel/doxorubicin

[Article in Lithuanian]
Liutkauskiene S, Sveikata A, Juozaityte E, Characiejus D, Juodzbaliene E, Kregzdyte R, Fokas V.
Department of Oncology, Kaunas University of Medicine, Eiveniu 2, Kaunas 50009, Lithuania. sigitaliu@yahoo.com
BACKGROUND: We evaluated efficacy and safety of recombinant granulocyte-colony stimulating factor (rGCSF) used as primary prophylaxis to prevent neutropenia and neutropenia-related complications induced by docetaxel and doxorubicin chemotherapy in patients with metastatic breast cancer. PATIENTS AND METHODS: Three centers in Lithuania enrolled 36 patients who received rGCSF (5 microg/kg/d) on day 2 of each 21-day chemotherapy with docetaxel 75 mg/m(2) and doxorubicin 50 mg/m(2) (AT) starting in the first cycle. Treatment regimen was repeated for up to six cycles. RESULTS: Leukocytosis, bone pain, and headache were the most frequent adverse events, with incidence rates of 22%, 19%, and 8%, respectively. Adverse events were typical for rGCSF in this patient population. Overall incidence rate of febrile neutropenia was 14%. The mean duration of febrile neutropenia episodes across cycles was 2.14 days. Incidence of chemotherapy delay was 2%. There was no reduction in chemotherapy dose due to expected toxicity or side effects. Intravenous antibiotics for the treatment of febrile neutropenia were needed in 19% of cases. Quality-of-life assessment shows a significant improvement in emotional functioning and a significant decrease in pain score. The efficacy profile of rGCSF observed in the present study was comparable with that of other rGCSF products previously described in the published scientific literature. CONCLUSIONS: The primary prophylaxis of neutropenia and its complications by rGCSF was safe and effective for women with metastatic breast cancer who received chemotherapy with docetaxel and doxorubicin.

PMID: 19773618 [PubMed - in process]

Onkologie. 2009 Oct;32(10):599-604. Epub 2009 Sep 14.
Incidence of febrile neutropenia and myelotoxicity of chemotherapy: a meta-analysis of biosimilar G-CSF studies in breast cancer, lung cancer, and non-Hodgkin's lymphoma.

Engert A, del Giglio A, Bias P, Lubenau H, Gatzemeier U, Heigener D.
Klinik I für Innere Medizin, Klinikum der Universität zu Köln, Cologne, Germany. a.engert@uni-koeln.de
BACKGROUND: The aim of this meta-analysis of 3 clinical studies, conducted with breast cancer, lung cancer, and non-Hodgkin's lymphoma patients, was to compare a new granulocyte colony-stimulating factor (G-CSF) biosimilar, XM02, with filgrastim in terms of its prophylactic effect on the development of febrile neutropenia (FN) during the first chemotherapy cycle in relation to the myelotoxic potency of the applied chemotherapy regimen. PATIENTS AND METHODS: Overall, 608 patients (363 under XM02 and 245 under filgrastim) were included in the meta-analysis. The majority of patients were allocated to the chemotherapy categories docetaxel-doxorubicin (45.4%) and cyclophosphamide-hydroxy daunomycin (adriamycin)-oncovin (vincristine)-prednisolone (CHOP)/platinum(Pt)-vinorelbine or Pt-vinblastine/ Pt-etoposide (43.1%); another 11.5% were allocated to the category Pt-gemcitabine/Pt-docetaxel or Pt-paclitaxel. RESULTS: FN in the XM02 and filgrastim groups was reported for 12.1 and 12.5% of patients, respectively, under docetaxeldoxorubicin, for 13.5 and 11.9% under CHOP/Pt-vinorelbine or Pt-vinblastine/Pt-etoposide, and for 15.6 and 12.0% under Pt-gemcitabine/Pt-docetaxel or Pt-paclitaxel. CONCLUSIONS: The incidence of FN in the first cycle of chemotherapy under primary G-CSF prophylaxis is low (in the range of 12-16%) and not directly correlated with the myelotoxic potency of the applied chemotherapy regimen. XM02 demonstrated to be non-inferior to filgrastim regarding the incidence of FN, irrespective of the myelotoxicity of the chemotherapy regimen. Copyright 2009 S. Karger AG, Basel.

PMID: 19816079 [PubMed - in process]



Angiogenesis problem???:


Blood. 2011 Jun 17. [Epub ahead of print]
G-CSF supplementation with chemotherapy can promote revascularization and subsequent tumor regrowth: prevention by a CXCR4 antagonist.

Voloshin T, Gingis-Velitski S, Bril R, Benayoun L, Munster M, Milsom C, Man S, Kerbel RS, Shaked Y.

LINK

Source

Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion - Israel Institute of Technology, Haifa, Israel;

Abstract

Recombinant G-CSF is used to accelerate recovery from chemotherapy-induced myelosuppression. G-CSF has been recently shown to stimulate angiogenesis mediated by several types of bone-marrow derived cell populations. To investigate whether G-CSF may alter tumor response to therapy, we studied Lewis lung and EMT/6 breast carcinomas, in mice treated with paclitaxel (PTX) chemotherapy in combination with G-CSF. We compared the results obtained to mice treated with PTX and AMD3100, a small molecule drug antagonist of CXCR4 which like G-CSF can be used to mobilize hematopoietic cells. We show that PTX+G-CSF treatment facilitates revascularization, leading to an improvement in blood perfusion in LLC tumors, and a decrease in hypoxia in EMT/6 tumors, thus enhancing tumor growth in comparison to PTX or PTX+AMD3100 therapies. We found that hemangiocytes but not Gr-1+/CD11b+ cells colonize EMT/6 tumors following treatment with PTX+G-CSF but not PTX+AMD3100, and therefore may contribute to angiogenesis. However, increases in hemangiocyte colonization were not observed in LLC PTX+G-CSF-treated tumors, suggesting distinct mechanisms of tumor revascularization following G-CSF. Overall, our observations suggest that despite its known considerable clinical benefits, G-CSF might contribute to tumor revascularization by various mechanisms, and diminish the anti-tumor activity of chemotherapy, an effect that can be prevented by AMD3100.

PMID:

21685373

[PubMed - as supplied by publisher]

Cancer Res. 2009 Oct 1;69(19):7524-8. Epub 2009 Sep 8.
Contribution of granulocyte colony-stimulating factor to the acute mobilization of endothelial precursor cells by vascular disrupting agents.

Shaked Y, Tang T, Woloszynek J, Daenen LG, Man S, Xu P, Cai SR, Arbeit JM, Voest EE, Chaplin DJ, Smythe J, Harris A, Nathan P, Judson I, Rustin G, Bertolini F, Link DC, Kerbel RS.
Department of Molecular Pharmacology, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel. yshaked@tx.technion.ac.il
Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

PMID: 19738066 [PubMed - in process]


Int Immunol. 2006 Jan;18(1):1-9. Epub 2005 Dec 13.
Granulocyte colony-stimulating factor promotes tumor angiogenesis via increasing circulating endothelial progenitor cells and Gr1+CD11b+ cells in cancer animal models.

Okazaki T, Ebihara S, Asada M, Kanda A, Sasaki H, Yamaya M.
Department of Geriatric and Respiratory Medicine, Tohoku University School of Medicine, Seiryo-machi 1-1, Aoba-ku, Sendai 980-8574, Japan. tatsuma@geriat.med.tohoku.ac.jp
Recombinant granulocyte colony-stimulating factor (G-CSF) is used for cancer patients with myelosuppression induced by chemotherapy. G-CSF has been reported to progress tumor growth and angiogenesis, but the precise mechanism of tumor angiogenesis activated by G-CSF has not been fully clarified. N-terminal-mutated recombinant human G-CSF administration increased WBCs and neutrophils in peripheral blood and reduced bone marrow stromal cell-derived factor-1 in mice, indicating its biological relevance. Mice were inoculated with Lewis lung carcinoma cells (LLCs) or KLN205 cells and treated with G-CSF. G-CSF accelerated tumor growth and intratumoral vessel density, while it did not accelerate proliferation of LLCs, KLN205 cells or human umbilical vein endothelial cells in vitro. In the absence of tumors, G-CSF did not increase circulating cells that displayed phenotypic characteristics of endothelial progenitor cells (EPCs). In the presence of tumors, G-CSF increased circulating EPCs. In addition, G-CSF treatment increased immune suppressor and endothelial cell-differentiating Gr1+CD11b+ cells in tumor-bearing mice. We conclude that G-CSF promotes tumor growth by activating tumor angiogenesis via increasing circulating EPCs and Gr1+CD11b+ cells in cancer animal models.

PMID: 16352631 [PubMed - indexed for MEDLINE]


ALTERNATIVES?


Cancer Immunol Immunother. 2010 Jun;59(6):885-97. Epub 2010 Feb 6.
Maitake beta-glucan promotes recovery of leukocytes and myeloid cell function in peripheral blood from paclitaxel hematotoxicity.

Lin H, de Stanchina E, Zhou XK, Hong F, Seidman A, Fornier M, Xiao WL, Kennelly EJ, Wesa K, Cassileth BR, Cunningham-Rundles S.

LINK

Source

Cellular Immunology Laboratory, Division of Hematology/Oncology, Department of Pediatrics, Weill Medical College of Cornell University, 1300 York Avenue, New York, NY 10065, USA.

Abstract

Bone marrow myelotoxicity is a major limitation of chemotherapy. While granulocyte colony stimulating factor (G-CSF) treatment is effective, alternative approaches to support hematopoietic recovery are sought. We previously found that a beta-glucan extract from maitake mushroom Grifola frondosa (MBG) enhanced colony forming unit-granulocyte monocyte (CFU-GM) activity of mouse bone marrow and human hematopoietic progenitor cells (HPC), stimulated G-CSF production and spared HPC from doxorubicin toxicity in vitro. This investigation assessed the effects of MBG on leukocyte recovery and granulocyte/monocyte function in vivo after dose intensive paclitaxel (Ptx) in a normal mouse. After a cumulative dose of Ptx (90-120 mg/kg) given to B6D2F1mice, daily oral MBG (4 or 6 mg/kg), intravenous G-CSF (80 microg/kg) or Ptx alone were compared for effects on the dynamics of leukocyte recovery in blood, CFU-GM activity in bone marrow and spleen, and granulocyte/monocyte production of reactive oxygen species (ROS). Leukocyte counts declined less in Ptx + MBG mice compared to Ptx-alone (p = 0.024) or Ptx + G-CSF treatment (p = 0.031). Lymphocyte levels were higher after Ptx + MBG but not Ptx + G-CSF treatment compared to Ptx alone (p < 0.01). MBG increased CFU-GM activity in bone marrow and spleen (p < 0.001, p = 0.002) 2 days after Ptx. After two additional days (Ptx post-day 4), MBG restored granulocyte/monocyte ROS response to normal levels compared to Ptx-alone and increased ROS response compared to Ptx-alone or Ptx + G-CSF (p < 0.01, both). The studies indicate that oral MBG promoted maturation of HPC to become functionally active myeloid cells and enhanced peripheral blood leukocyte recovery after chemotoxic bone marrow injury.

PMID:

20140432

[PubMed - indexed for MEDLINE]