- Email: [email protected]
Reply to Hérodin and Drouet: “Myeloprotection Following Cytotoxic Damage: The Sooner the Better”
Experimental Hematology 2008;36:771–772
REPLY TO LETTER TO THE EDITOR
Reply to He´rodin and Drouet: ‘‘Myeloprotection Following Cytotoxic Damage: The Sooner the Better’’ We appreciate the opportunity to respond to the letter to the editor ‘‘Myeloprotection Following Cytotoxic Damage: The Sooner the Better,’’ by Francis He´rodin and Michel Drouet, which addressed our article entitled ‘‘Efficacy of Delayed Administration of Postchemotherapy Granulocyte Colony-Stimulating Factor: Evidence from Murine Studies of Bone Marrow Cell Kinetics’’ [1]. We appreciate the authors’ comments on our article, but the issues raised are distinct from the central focus of our article. Drs. Herodin and Drouet discuss the effects of cytokines on survival of irradiated mice first demonstrated by Tanikawa et al. [2]. We agree with their comments as they relate to survival of animals and blood count recovery following administration of various growth factors and cytokines after myeloablative treatment. However, they are not germane to the results reported in our article. Thus, in contrast to the results alluded to in the letter by Drs. Herodin and Drouet, our results describe changes in blood cell populations following use of a single specific growth factor, i.e., nonpegylated granulocyte colony-stimulating factor (G-CSF), to ameliorate the neutropenic periods seen after nonmyeloablative chemotherapyda situation more commonly encountered in clinical practice. ‘‘Short-acting’’ cycle-active cytotoxic agents like cyclophosphamide administered in conventional doses affect actively dividing bone marrow precursor cells and do not affect stem cells. Consequently, the myelosuppression is typically short-lasting [3]. This is fundamentally different from radiation-induced myelosuppression (especially total body irradiation), where the damage is deeper to the level of stem cells and the period of bone marrow recovery is much longer. Clearly, G-CSFassociated shortening of postchemotherapy neutropenia is a result of increased amplification of immature granuloid cells (due to increased cycling and reduced transit time [3]), while the cytokine-associated rescue from the lethal doses of irradiation could be a result of prevention of apoptosis and shortening the period of GO residence of the stem cells [2]. The cytokines mentioned in their letter (stem cell factor, interleukin-3, Flt3 ligand, thrombopoietin,
Offprint requests to: Maxim Yankelevich, M.D., NN Blokhin Russian Cancer Research Center, Institute for Pediatric Oncology and Hematology, 24 Kashirskoye shosse, Moscow 115478, Russian Federation.
pegylated G-CSF) have different properties from G-CSF, are not used in clinic, or have limited application. G-CSFrelated thrombocytopenia is a well-known phenomenon. Drop in platelet counts in healthy donors are seen by day 8 [4,5]. The mechanism of G-CSFrelated thrombocytopenia is not exactly clear. G-CSF may directly act on bone marrow megakaryocytes and decrease platelet production, directly act on platelets (platelets have been shown to have G-CSF receptors), or produce thrombocytopenia through development of hypersplenism. The latter may be more pronounced in mice vs humans or other primates. In fact, depending on the stimulation schedule, the spleen weights after G-SCF stimulation in our experiments were two to three times higher than the chemotherapy-only regimen (unpublished data). Our model, like many animal models, has some limitations, but the statement that ‘‘one can wonder whether such a model is appropriate to evaluate the kinetic effects of GCSF administration in a context of myelosuppressive chemotherapy’’ is not based on any specific issues raised in their letter. The speed of hematopoiesis in mice is indeed about twice as fast as humans, due to the differences in interphase duration, consequently, the neutropenic nadirs in mice develop sooner and the neutrophil recovery time is shorter; however, one still has 7 to 10 days to follow kinetics of recovery in mice compared to 14 to 20 days in humans. Finally, we studied the colony-forming units in culture in spleens because the stem and progenitor cells seed this organ after mobilization in mice, however, we agree with Drs. Herodin and Drouet that the murine colony-forming unit mobilization data are difficult to translate to humans. Maxim Yankelevich, M.D. NN Blokhin Russian Cancer Research Center Institute for Pediatric Oncology and Hematology Moscow, Russian Federation E-mail: [email protected] Margaret A. Goodell, Ph.D. Baylor College of Medicine Center for Cell and Gene Therapy Houston, TX Joseph Kaplan, M.D., Ph.D. Wayne State University Department of Pediatrics Detroit, MI
0301-472X/08 $–see front matter. Copyright Ó 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. doi: 10.1016/j.exphem.2008.02.006
772
M. Yankelevich et al./ Experimental Hematology 2008;36:771–772
References 1. Yankelevich M, Goodell MA, Kaplan J. Efficacy of delayed administration of postchemotherapy granulocyte colony-stimulating factor: evidence from murine studies of bone marrow cell kinetics. Exp Hematol. 2008;36:9–16. 2. Tanikawa S, Nose M, Aoki Y, Tsuneoka K, Shikita M, Nara N. Effects of recombinant human granulocyte colony-stimulating factor on the hematologic recovery and survival of irradiated mice. Blood. 1990;76:445–449. 3. Kim SK, Demetri GD. Chemotherapy and neutropenia. Hematol Oncol Clin North Am. 1996;10:377–395.
4. Stroncek DF, Clay ME, Petzoldt ML, et al. Treatment of normal individuals with granulocyte colony-stimulating factor: donor experiences and the effects on peripheral blood CD34þ cell counts and on the collection of peripheral blood stem cells. Transfusion. 1996;36: 601–610. 5. Tassi C, Tazzari PL, Bonifazi F, et al. Short- and long-term hematological surveillance of healthy donors of allogeneic peripheral hematopoietic progenitors mobilized with G-CSF: a single institution prospective study. Bone Marrow Transplant. 2005;36:289–294.
REPLY TO LETTER TO THE EDITOR
Reply to He´rodin and Drouet: ‘‘Myeloprotection Following Cytotoxic Damage: The Sooner the Better’’ We appreciate the opportunity to respond to the letter to the editor ‘‘Myeloprotection Following Cytotoxic Damage: The Sooner the Better,’’ by Francis He´rodin and Michel Drouet, which addressed our article entitled ‘‘Efficacy of Delayed Administration of Postchemotherapy Granulocyte Colony-Stimulating Factor: Evidence from Murine Studies of Bone Marrow Cell Kinetics’’ [1]. We appreciate the authors’ comments on our article, but the issues raised are distinct from the central focus of our article. Drs. Herodin and Drouet discuss the effects of cytokines on survival of irradiated mice first demonstrated by Tanikawa et al. [2]. We agree with their comments as they relate to survival of animals and blood count recovery following administration of various growth factors and cytokines after myeloablative treatment. However, they are not germane to the results reported in our article. Thus, in contrast to the results alluded to in the letter by Drs. Herodin and Drouet, our results describe changes in blood cell populations following use of a single specific growth factor, i.e., nonpegylated granulocyte colony-stimulating factor (G-CSF), to ameliorate the neutropenic periods seen after nonmyeloablative chemotherapyda situation more commonly encountered in clinical practice. ‘‘Short-acting’’ cycle-active cytotoxic agents like cyclophosphamide administered in conventional doses affect actively dividing bone marrow precursor cells and do not affect stem cells. Consequently, the myelosuppression is typically short-lasting [3]. This is fundamentally different from radiation-induced myelosuppression (especially total body irradiation), where the damage is deeper to the level of stem cells and the period of bone marrow recovery is much longer. Clearly, G-CSFassociated shortening of postchemotherapy neutropenia is a result of increased amplification of immature granuloid cells (due to increased cycling and reduced transit time [3]), while the cytokine-associated rescue from the lethal doses of irradiation could be a result of prevention of apoptosis and shortening the period of GO residence of the stem cells [2]. The cytokines mentioned in their letter (stem cell factor, interleukin-3, Flt3 ligand, thrombopoietin,
Offprint requests to: Maxim Yankelevich, M.D., NN Blokhin Russian Cancer Research Center, Institute for Pediatric Oncology and Hematology, 24 Kashirskoye shosse, Moscow 115478, Russian Federation.
pegylated G-CSF) have different properties from G-CSF, are not used in clinic, or have limited application. G-CSFrelated thrombocytopenia is a well-known phenomenon. Drop in platelet counts in healthy donors are seen by day 8 [4,5]. The mechanism of G-CSFrelated thrombocytopenia is not exactly clear. G-CSF may directly act on bone marrow megakaryocytes and decrease platelet production, directly act on platelets (platelets have been shown to have G-CSF receptors), or produce thrombocytopenia through development of hypersplenism. The latter may be more pronounced in mice vs humans or other primates. In fact, depending on the stimulation schedule, the spleen weights after G-SCF stimulation in our experiments were two to three times higher than the chemotherapy-only regimen (unpublished data). Our model, like many animal models, has some limitations, but the statement that ‘‘one can wonder whether such a model is appropriate to evaluate the kinetic effects of GCSF administration in a context of myelosuppressive chemotherapy’’ is not based on any specific issues raised in their letter. The speed of hematopoiesis in mice is indeed about twice as fast as humans, due to the differences in interphase duration, consequently, the neutropenic nadirs in mice develop sooner and the neutrophil recovery time is shorter; however, one still has 7 to 10 days to follow kinetics of recovery in mice compared to 14 to 20 days in humans. Finally, we studied the colony-forming units in culture in spleens because the stem and progenitor cells seed this organ after mobilization in mice, however, we agree with Drs. Herodin and Drouet that the murine colony-forming unit mobilization data are difficult to translate to humans. Maxim Yankelevich, M.D. NN Blokhin Russian Cancer Research Center Institute for Pediatric Oncology and Hematology Moscow, Russian Federation E-mail: [email protected] Margaret A. Goodell, Ph.D. Baylor College of Medicine Center for Cell and Gene Therapy Houston, TX Joseph Kaplan, M.D., Ph.D. Wayne State University Department of Pediatrics Detroit, MI
0301-472X/08 $–see front matter. Copyright Ó 2008 ISEH - Society for Hematology and Stem Cells. Published by Elsevier Inc. doi: 10.1016/j.exphem.2008.02.006
772
M. Yankelevich et al./ Experimental Hematology 2008;36:771–772
References 1. Yankelevich M, Goodell MA, Kaplan J. Efficacy of delayed administration of postchemotherapy granulocyte colony-stimulating factor: evidence from murine studies of bone marrow cell kinetics. Exp Hematol. 2008;36:9–16. 2. Tanikawa S, Nose M, Aoki Y, Tsuneoka K, Shikita M, Nara N. Effects of recombinant human granulocyte colony-stimulating factor on the hematologic recovery and survival of irradiated mice. Blood. 1990;76:445–449. 3. Kim SK, Demetri GD. Chemotherapy and neutropenia. Hematol Oncol Clin North Am. 1996;10:377–395.
4. Stroncek DF, Clay ME, Petzoldt ML, et al. Treatment of normal individuals with granulocyte colony-stimulating factor: donor experiences and the effects on peripheral blood CD34þ cell counts and on the collection of peripheral blood stem cells. Transfusion. 1996;36: 601–610. 5. Tassi C, Tazzari PL, Bonifazi F, et al. Short- and long-term hematological surveillance of healthy donors of allogeneic peripheral hematopoietic progenitors mobilized with G-CSF: a single institution prospective study. Bone Marrow Transplant. 2005;36:289–294.