Hemotoxicity by prolonged etoposide administration to mice can be prevented by simultaneous growth factor therapy.
In this study, we determined in vivo interactions between hemopoietic growth factors and etoposide (VP-16) to assess whether normal blood cell production could be maintained during chemotherapy if hemopoietic growth factors were simultaneously administered. Groups of mice were treated for 7 consecutive days with four different doses of VP-16 in combination with three different doses of erythropoietin (EPO) or granulocyte colony-stimulating factor (G-CSF). In total, 12 combinations of VP-16 plus EPO and 12 combinations of VP-16 plus G-CSF were thus evaluated. Intricate dose-response surfaces of the effects of the different treatments on colony-forming units-erythroid, reticulocytes, hematocrit, colony-forming units-granulocyte/macrophage, and absolute neutrophil count were obtained, which revealed that: (a) simultaneous EPO administration was able to maintain reticulocyte production and to protect mice from VP-16 induced anemia; (b) simultaneous G-CSF administration was able to maintain granulocyte production and to protect mice from VP-16 induced neutropenia; (c) VP-16 dose escalation was feasible when EPO or G-CSF were simultaneously administered; and (d) no increased myelotoxicity on erythroid or granuloid progenitors was observed when EPO or G-CSF was simultaneously administered with VP-16. These results suggest that in vivo either individual hemopoietic progenitors can become resistant against VP-16-induced cell death by appropriate simultaneous growth factor administration or that the loss of overall cell amplification, induced by VP-16, can be compensated by extra amplification of surviving progenitors. Furthermore, these data indicate that a strict separation in time of cytostatic drug and growth factor treatment is not necessarily the optimal schedule with respect to the reduction of hemotoxicity.
de Haan
G
G
Groningen Institute for Drug Studies, Department of Hematology, University of Groningen, The Netherlands.
Engel
C
C
Dontje
B
B
Loeffler
M
M
Nijhof
W
W
D000740:Anemia / Q000139:chemically induced / Q000517:prevention & control*; D000818:Animals; D001853:Bone Marrow / Q000187:drug effects; D001854:Bone Marrow Cells; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000187:drug effects; D004921:Erythropoietin / Q000008:administration & dosage*; D005047:Etoposide / Q000008:administration & dosage* / Q000009:adverse effects; D005260:Female; D016179:Granulocyte Colony-Stimulating Factor / Q000008:administration & dosage*; D006412:Hematopoietic Stem Cells / Q000187:drug effects*; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D009503:Neutropenia / Q000139:chemically induced / Q000517:prevention & control*; D012044:Regression Analysis; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D004921:Erythropoietin; D016179:Granulocyte Colony-Stimulating Factor; D005047:Etoposide