Hematotoxicity induced by paclitaxel: In vitro and in vivo assays during normal murine hematopoietic recovery

Paclitaxel is a drug widely used in several oncological trials. Like other antineoplastics, it causes severe neutropenia. However, it effects on eryth ropoiesis are not as well known. This study analyzes the recovery of normal murine hematopoiesis after single dose paclitaxel administration (29 mg/kg i.p.) over 20 days. Different assays were used to analyze the restorative kinetics from primitive early progenitors to mature functional erythroid ce lls. Proliferation of the erythroid compartment was assessed by DNA microcu lture assays in medullar and splenic cells stimulated with recombinant huma n erythropoietin (rh Epo 0-5000 mU/ml). Enhancement of early hematopoietic progenitors was determined using clonogenic assays and erythroid terminal m aturation by Fe-59 incorporation. Peripheral hematologic parameters and cel lularities in both tissues were also determined on each day of the experime ntal schedule. At 2 days post-paclitaxel treatment, medullar cellularity di minished drastically (>90%) AND Fe-59 incorporation decreased in all compar tments. DNA assay revealed maximum sensitivity to Epo (p>0.05 with 15 mU/ml ) while clonogenic cultures failed to show significant results. At 5 days b oth bone marrow and spleen semisolid cultures showed great expansion of ear ly hematopoietic progenitors (about 5- and 83-fold, respectively). Hormonal sensitivity decreased progressively along the experiment. Splenic cultures showed a linear dose-response to rh Epo at day 5 post-paclitaxel administr ation (p<0.05 with 125 mU/ml). Medullar and splenic total progenitor colony -forming units (CFU) scorings with and without rh Epo revealed a notable en hancement at 5 days post-paclitaxel treatment. Data from this study suggest that paclitaxel causes deep injury in the erythropoietic compartment, incl uding temporary variations of Epo sensitivity in late bone marrow erythroid progenitors, early multilineage hematopoietic explosion and terminal eryth roid precursors depletion as a result of a complex microenvironmental resti tutive regulation. (C) 2001 Prous Science. All rights reserved.