Drastic effect of cell density on the cytotoxicity of daunorubicin and cytosine arabinoside

Abstract

White blood cell count (WBC) is generally accepted as a prognostic risk factor in acute myeloid leukemia (AML) outcome and displays a marked interindividual variation. The dose regimen currently used ignores the size of the tumor burden and the standardization of the dose is generally based on body surface area. In this study we have investigated the effect of cell density on the cytotoxic activity of daunorubicin (DNR) and cytosine arabinoside (AraC) towards HL60 cells and leukemic cells isolated from patients with AML. We demonstrate that drug cytotoxicity decreased with cell density and that apoptosis induction by DNR in isolated leukemic cells was greatly reduced at higher cell density. A marked reduction of the uptake of DNR and AraC in HL60 parental and mitoxantrone resistant cells was observed with increasing cell density. Such a drug depleting effect by cells at high density has been previously described for vincristine, doxorubicin and paclitaxel. By extrapolating the in vitro results to the in vivo situation, one could hypothesize that a high WBC can lower the plasma concentration through high uptake in the tumor burden, leading to a shortage of drug in leukemic blasts. Patients with high WBC might therefore benefit from a dose increase of DNR and/or AraC.