Chemotherapy prior to autologous bone marrow transplantation impairs long-term engraftment in mice.
OBJECTIVE
Autologous bone marrow transplantation in cancer patients is often preceded by multiple cycles of chemotherapy. In this study, we assessed in a mouse model whether stem cells were affected by prior chemotherapy.


METHODS
Donor mice were treated with three consecutive injections of 150 mg/kg 5-fluorouracil (5-FU). Peripheral blood counts were allowed to recover before the subsequent dose of 5-FU was given. Mice recovered from three doses of 5-FU and showed normal steady-state hematopoiesis. Bone marrow cells from these mice were mixed with congenic competitor cells and transplanted into lethally irradiated recipients.


RESULTS
Although in vivo homing of cells from these mice was not impaired, donor leukocyte contribution steadily decreased posttransplantation. In contrast to in vivo homing, both in vitro migration toward stromal-derived factor (SDF)-1 and the average CXC chemokine receptor-4 (CXCR4) expression were lower in 5-FU-treated cells. Moderate reductions in L-selectin and CD11a expression were observed on stem cells of 5-FU-treated mice. CD43, CD44, CD49d, and CD49e were normally expressed and could thus not explain the reduced engraftment of these cells.


CONCLUSIONS
We therefore conclude that 5-FU either directly damages stem cells or that the replicative stress induced by 5-FU causes a decline in stem cell reconstitution potential resulting in lower chimerism levels posttransplantation, that declines in time.
Noach
Estelle J K
EJ
Department of Stem Cell Biology, University of Groningen, University Hospital Groningen, A. Deusinglaan 1, NL-9713 AV Groningen, The Netherlands.
Ausema
Albertina
A
van Os
Ronald
R
Akkerman
Imre
I
Koopal
Sonja
S
Weersing
Ellen
E
Dontje
Bert
B
Vellenga
Edo
E
de Haan
Gerald
G
D000818:Animals; D015703:Antigens, CD / Q000032:analysis; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D016026:Bone Marrow Transplantation / Q000379:methods*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D002633:Chemotaxis / Q000187:drug effects; D005472:Fluorouracil / Q000008:administration & dosage; D006085:Graft Survival / Q000187:drug effects*; D006412:Hematopoietic Stem Cells / Q000187:drug effects; D051379:Mice; D023421:Models, Animal; D019718:Receptors, CXCR4; D018183:Transplantation Chimera; D014182:Transplantation, Autologous
D015703:Antigens, CD; D000970:Antineoplastic Agents; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; C515256:Cxcl12 protein, mouse; D019718:Receptors, CXCR4; D005472:Fluorouracil