Submitted March 21, 2006
Accepted May 31, 2006
Gene transfer of cytidine deaminase protects myelopoiesis from cytidine analogs in an in vivo murine transplant model
Ina Rattmann, Veronika Kleff, Ursula R Sorg, Walter Bardenheuer, Annette Brueckner, Ralf A Hilger, Bertram Opalka, Siegfried Seeber, Michael Flasshove, and Thomas Moritz*
Dept. of Internal Medicine, West German Cancer Center, University of Duisburg-Essen Medical School
* Corresponding author; email: thomas.moritz{at}uni-essen.de.
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; d 1-4; i.p.) significant myeloprotection was demonstrated with nadir counts of peripheral blood granulocytes and thrombocytes of 2.9 ± 0.6 /nl vs 0.7 ± 0.1 /nl (p = .0016) and 509 ± 147 /nl versus 80 ± 9 /nl (p = .008) respectively (CDD vs control). Protection also was observed from otherwise lethal gemcitabine treatment (250 mg/kg; d 1-3). Stable levels of gene-marked cells in primary and secondary recipients were demonstrated for up to 9 months, and while CDD overexpression clearly reduced B and T lymphocytes 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 MGMTP140K or MDR-1.
