Gene transfer of cytidine deaminase protects myelopoiesis from cytidine analogs in an in vivo murine transplant model
| Autor: | Siegfried Seeber, Walter Bardenheuer, Veronika Kleff, Michael Flasshove, Ursula R. Sorg, Ralf A. Hilger, Ina Rattmann, T. Moritz, Annette Brueckner, Bertram Opalka |
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| Rok vydání: | 2006 |
| Předmět: |
Myeloid
Recombinant Fusion Proteins Immunology Biology Deoxycytidine Biochemistry Colony-Forming Units Assay Leukocyte Count Mice chemistry.chemical_compound Cytidine Deaminase medicine Animals Bone Marrow Transplantation Platelet Count Graft Survival Cytarabine Gene Transfer Techniques Hematopoietic stem cell Cytidine 3T3 Cells Cell Biology Hematology Cytidine deaminase Gemcitabine Molecular biology Transplantation Haematopoiesis medicine.anatomical_structure chemistry Models Animal Myelopoiesis medicine.drug |
| Zdroj: | Blood. 108:2965-2971 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2006-03-011734 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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