Gene transfer of cytidine deaminase protects myelopoiesis from cytidine analogs in an in vivo murine transplant model.
Hematopoietic stem cell gene transfer of the drug-resistance gene cytidine deaminase (CDD) protecting cells from the cytotoxic cytidine analogs cytarabine and gemcitabine was investigated in a murine transplant model. Following transplantation of CDD-transduced cells and cytarabine application (500 mg/kg; days 1-4; intraperitoneally) significant myeloprotection was demonstrated with nadir counts of peripheral blood granulocytes and thrombocytes of 2.9 +/- 0.6/nL versus 0.7 +/- 0.1/nL (P < .001) and 509 +/- 147/nL versus 80 +/- 9/nL (P = .008), respectively (CDD versus control). Protection also was observed from otherwise lethal gemcitabine treatment (250 mg/kg; days 1-3). Stable levels of gene-marked cells in primary and secondary recipients were demonstrated for up to 9 months, and whereas CDD overexpression clearly reduced B- and T-lymphocyte numbers, no major toxicity was observed in the myeloid compartment. Despite the profound myeloprotective properties, however, CDD overexpression did not allow for pharmacologic enrichment of transduced hematopoiesis in our model. Thus, in summary, our data establish CDD as a drug-resistance gene highly suitable for myeloprotective purposes, which, given the lack of selection observed in our hands, might best be used in combination with selectable drug-resistance genes such as MGMT (P140K) or MDR1.
Rattmann
Ina
I
Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Hufelandstr 55, 45122 Essen, Germany.
Kleff
Veronika
V
Sorg
Ursula R
UR
Bardenheuer
Walter
W
Brueckner
Annette
A
Hilger
Ralf A
RA
Opalka
Bertram
B
Seeber
Siegfried
S
Flasshove
Michael
M
Moritz
Thomas
T
D016475:3T3 Cells; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology* / Q000401:mortality; D003114:Colony-Forming Units Assay; D003561:Cytarabine / Q000633:toxicity*; D003564:Cytidine Deaminase / Q000235:genetics* / Q000378:metabolism; D003841:Deoxycytidine / Q000031:analogs & derivatives* / Q000633:toxicity; D018014:Gene Transfer Techniques; D006085:Graft Survival / Q000502:physiology; D007958:Leukocyte Count; D051379:Mice; D023421:Models, Animal; D010976:Platelet Count; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D000093542:Gemcitabine
D011993:Recombinant Fusion Proteins; D003561:Cytarabine; D003841:Deoxycytidine; D003564:Cytidine Deaminase; D000093542:Gemcitabine