G. Dehaan et al., HEMOTOXICITY BY PROLONGED ETOPOSIDE ADMINISTRATION TO MICE CAN BE PREVENTED BY SIMULTANEOUS GROWTH-FACTOR THERAPY, Cancer research, 55(2), 1995, pp. 324-329
In this study, eve determined in vivo interactions between hemopoietic
growth factors and etoposide (VP-16) to assess whether normal blood c
ell production could be maintained during chemotherapy if hemopoietic
growth factors were simultaneously administered. Groups of mice were t
reated for 7 consecutive days with four different doses of VP-16 in co
mbination with three different doses of erythropoietin (EPO) or granul
ocyte 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 evalu
ated. Intricate dose-response surfaces of the effects of the different
treatments on colony-forming units-erythroid, reticulocytes, hematocr
it, colony-forming units-granulocyte/macrophage, and absolute neutroph
il count were obtained, which revealed that: (a) simultaneous EPO admi
nistration 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 m
yelotoxicity on erythroid or granuloid progenitors was observed when E
PO or G-CSF was simultaneously administered with VP-16. These results
suggest that in vivo either individual hemopoietic progenitors can bec
ome resistant against VP-16-induced cell death by appropriate simultan
eous growth factor administration or that the loss of overall cell amp
lification, induced by VP-16, can be compensated by extra amplificatio
n of surviving progenitors. Furthermore, these data indicate that a st
rict separation in time of cytostatic drug and growth factor treatment
is not necessarily the optimal schedule with respect to the reduction
of hemotoxicity.