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 Blood, 1 November 2006, Vol. 108, No. 9, pp. 2965-2971.
Prepublished online as a Blood First Edition Paper on July 11, 2006; DOI 10.1182/blood-2006-03-011734.

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GENE THERAPY

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

From the Department of Internal Medicine (Cancer Research), West German Cancer Center, University of Duisburg-Essen Medical School, Essen, Germany; and Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.

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 drugresistance genes such as MGMT (P140K) or MDR1.


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