HEMOTOXICITY BY PROLONGED ETOPOSIDE ADMINISTRATION TO MICE CAN BE PREVENTED BY SIMULTANEOUS GROWTH-FACTOR THERAPY

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.