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, its effects on erythropoiesis 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 cells. Proliferation of the erythroid compartment was assessed by DNA microculture assays in medullar and splenic cells stimulated with recombinant human erythropoietin (rh Epo 0-500 mU/ml). Enhancement of early hematopoietic progenitors was determined using clonogenic assays and erythroid terminal maturation by 59Fe incorporation. Peripheral hematologic parameters and cellularities in both tissues were also determined on each day of the experimental schedule. At 2 days post-paclitaxel treatment, medullar cellularity diminished drastically (> 90%) and 59Fe incorporation decreased in all compartments. 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 both bone marrow and spleen semisolid cultures showed great expansion of early 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 administration (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 enhancement at 5 days post-paclitaxel treatment. Data from this study suggest that paclitaxel causes deep injury in the erythropoietic compartment, including temporary variations of Epo sensitivity in late bone marrow erythroid progenitors, early multilineage hematopoietic explosion and terminal erythroid precursors depletion as a result of a complex microenvironmental restitutive regulation.
Juaristi
J A
JA
Department of Basic Medical Sciences, Faculty of Medicine, National Northeast University, Corrientes, Argentina.
Aguirre
M V
MV
Carmuega
R J
RJ
Romero-Benítez
M
M
Alvarez
M A
MA
Brandan
N C
NC
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003114:Colony-Forming Units Assay; D004305:Dose-Response Relationship, Drug; D015672:Erythroid Precursor Cells / Q000187:drug effects*; D004920:Erythropoiesis / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology; D005260:Female; D007504:Iron Radioisotopes / Q000378:metabolism; D051379:Mice; D022423:Myeloid Cells / Q000187:drug effects; D017239:Paclitaxel / Q000008:administration & dosage / Q000097:blood / Q000494:pharmacology*; D011994:Recombinant Proteins; D013154:Spleen / Q000166:cytology / Q000187:drug effects
D000972:Antineoplastic Agents, Phytogenic; D007504:Iron Radioisotopes; D011994:Recombinant Proteins; D004921:Erythropoietin; D017239:Paclitaxel