Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice

Eliopoulos, Nicoletta; Bovenzi, Veronica; Le, Ngoc Loan Oanh; Momparler, Louise F.; Greenbaum, Mona; Létourneau, Sylvain; Cournoyer, Denis; Momparler, Richard L.

doi:10.1038/sj.gt.3300767

Cited by 26 publications

(14 citation statements)

References 18 publications

(25 reference statements)

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“…However, also this group later described resistance in the aforementioned dose range only. 25 These similarities between murine and human data were expected, as for both human and murine CD34 þ cells low CDD enzyme activity has been shown 8 and in both species the hematopoietic system represents a critical target organ for cytarabine-as well as gemcitabineinduced toxicity. 25,26 From a clinical perspective, these data appear highly relevant.…”

Section: Discussionmentioning

confidence: 66%

“…25 These similarities between murine and human data were expected, as for both human and murine CD34 þ cells low CDD enzyme activity has been shown 8 and in both species the hematopoietic system represents a critical target organ for cytarabine-as well as gemcitabineinduced toxicity. 25,26 From a clinical perspective, these data appear highly relevant. Cytarabine is the most effective single agent in the treatment of acute myeloid leukemia, and additionally shows considerable activity in acute lymphocytic leukemia and non-Hodgkin's lymphoma.…”

Section: Discussionmentioning

confidence: 66%

“…The degree of resistance to cytarabine or gemcitabine which we observed in human hematopoietic cells was comparable to that already described in hematopoetic cell lines or primary murine hematopoietic cells. Here, in general, resistance to cytarabine doses ranging from 10 to 500 nM 11,25 and gemcitabine doses ranging from 1 to 10 nM 9 has been reported, with the only exception of early work from Momparler et al 12 reporting resistance of CFU-C to cytarabine doses of up to 50 mM. However, also this group later described resistance in the aforementioned dose range only.…”

Section: Discussionmentioning

confidence: 82%

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Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells

et al. 2005

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Overexpression of the detoxifying enzyme cytidine deaminase (CDD) renders normal and leukemic hematopoietic cells resistant to cytarabine (1-b-D-arabinofuranosylcytosine), and studies on murine cells have suggested transgenic CDD overexpression as a way to reduce the substantial myelotoxicity induced by the deoxycytidine analogs cytarabine and gemcitabine (2 0 ,2 0 -difluorodeoxycytidine). We now have investigated CDD (over-)expression in the human hematopoietic system. Retroviral gene transfer significantly increased the resistance of CDD-transduced cord blood and peripheral bloodderived progenitor cells for doses ranging from 20 to 100 nM cytarabine and 8-10 nM gemcitabine. Protection was observed for progenitors of erythroid as well as myeloid differentiation, though the degree of protection varied for individual drugs. In addition, significant selection of CDD-transduced cells was obtained after a 4-day culture in 30-100 nM cytarabine. Thus, our data demonstrate that overexpression of CDD cDNA results in significant protection of human progenitors from cytarabineas well as gemcitabine-induced toxicity, and allows in vitro selection of transduced cells. This strongly argues for a potential therapeutic role of CDD gene transfer in conjunction with dose-intensive cytarabine-or gemcitabine-containing chemotherapy regimen.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 82%

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Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells

et al. 2005

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“…These data are consistent with those of other investigators who have shown long-term and high-level expression of transgenes in mice or rats transplanted with MFG-transduced hematopoietic cells. [22][23][24] Concordant with the high level enzymatic expression, an almost complete correction of the reticuloendothelial system pathology, which was observed only when high-level engraftment (ie Ͼ90%) was achieved by BMT, 18 was seen in gene therapy-treated animals engrafted 30% or less.…”

Section: Discussionmentioning

confidence: 82%

Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann–Pick disease

et al. 2000

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Types A and B Niemann-Pick disease (NPD) result from the deficient activity of acid sphingomyelinase (ASM). Currently, no treatment is available for either form of NPD. Using the ASM knockout (ASMKO) mouse model, we evaluated the effects of ex vivo hematopoietic stem cell gene therapy on the NPD phenotype. Thirty-two newborn ASMKO mice were preconditioned with low dose radiation (200 cGy) and transplanted with ASMKO bone marrow cells which had been transduced with an ecotropic retroviral vector encoding human ASM. Engraftment of donor-derived cells ranged from 15 to 60% based on Y-chromosome in situ hybridization analysis of peripheral white blood cells, and was achieved in 92% of the transplanted animals. High levels of ASM activity (up to five-fold above normal) were found in the engrafted animals for up to 10 months after transplantation, and their life-span was extended from a mean of 5 to 9 months by the gene therapy procedure. Biochemical and histological analysis of tissues obtained 4-5 months after

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“…70 In the next step, transduced hematopoietic cells were transplanted into the bone marrow of mice to show the production of CDA in blood and different tissues. 73 Human CDA activity was observed in these mice 11-13 months after transplantation, and cells from bone marrow and spleen were resistant to araC in an ex vivo experiment. In vitro selection of transduced cells to select cells with high CDA expression before transplantation was easily obtained with murine leukemic L1210 cells and, although less easily, in murine bone marrow cells.…”

Section: Myeloprotection With Cytidine Deaminasementioning

confidence: 88%

Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues

2009

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The clinical use of cytotoxic deoxynucleoside analogues is often limited by resistance mechanisms due to enzymatic deficiency, or high toxicity in nontumor tissues. To improve the use of these drugs, gene therapy approaches have been proposed and studied, associating clinically used deoxynucleoside analogues such as araC and gemcitabine and suicide genes or myeloprotective genes. In this review, we provide an update of recent results in this area, with particular emphasis on human deoxycytidine kinase, the deoxyribonucleoside kinase from Drosophila melanogaster, purine nucleoside phosphorylase from Escherichia coli, and human cytidine deaminase. Data from literature clearly show the feasibility of these systems, and clinical trials are warranted to conclude on their use in the treatment of cancer patients.

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Retroviral transfer and long-term expression of human cytidine deaminase cDNA in hematopoietic cells following transplantation in mice

Cited by 26 publications

References 18 publications

Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells

Resistance to cytarabine and gemcitabine and in vitro selection of transduced cells after retroviral expression of cytidine deaminase in human hematopoietic progenitor cells

Hematopoietic stem cell gene therapy leads to marked visceral organ improvements and a delayed onset of neurological abnormalities in the acid sphingomyelinase deficient mouse model of Niemann–Pick disease

Development of gene therapy in association with clinically used cytotoxic deoxynucleoside analogues

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