Assessment of resistance induction to cytosine arabinoside following transfer and overexpression of the deoxycytidylate deaminase gene in vitro

Schröder, J; Seidelmann, M.; Kirch, Hans-Christoph; Seeber, S.; Schütte, J.

doi:10.1016/s0145-2126(98)00048-4

Cited by 16 publications

(14 citation statements)

References 14 publications

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“…Cytidine deaminase (CDA) and deoxycytidylate deaminase (dCMPD) convert Ara-C to Ara-U and Ara-CMP to Ara-UMP, respectively, by deaminating the cytosine base. Inactivation of Ara-C and Ara-CMP by these deaminating enzymes decreases the amount of Ara-CTP and thus the cytotoxic effects of Ara-C. 13,14 The mechanism underlying the remarkable Ara-C sensitivity in infants with ALL is unknown. Hypothetically, increased activation of the prodrug Ara-C to its active, cytotoxic form Ara-CTP caused by aberrant expression of the above-described enzymes may be involved.…”

Section: Introductionmentioning

confidence: 99%

Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia

Stam

Boer

Meijerink

et al. 2002

Blood

175

121

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Infant acute lymphoblastic leukemia (ALL) is characterized by a high incidence of mixed lineage leukemia (MLL) gene rearrangements, a poor outcome, and resistance to chemotherapeutic drugs. One exception is cytosine arabinoside (Ara-C), to which infant ALL cells are highly sensitive. To investigate the mechanism underlying Ara-C sensitivity in infants with ALL, mRNA levels of Ara-C-metabolizing enzymes were measured in infants (n ‫؍‬ 18) and older children (noninfants) with ALL (n ‫؍‬ 24). In the present study, infant ALL cells were 3.3-fold more sensitive to Ara-C (P ‫؍‬ .007) and accumulated 2.3-fold more Ara-CTP (P ‫؍‬ .011) upon exposure to Ara-C, compared with older children with ALL. Real-time quantitative reverse trancriptase-polymerase chain reaction (RT-PCR) (TaqMan) revealed that infants express 2-fold less of the Ara-C phosphorylating enzyme deoxycytidine kinase (dCK) mRNA (P ‫؍‬ .026) but 2.5-fold more mRNA of the equilibrative nucleoside transporter 1 (hENT1), responsible for Ara-C membrane transport (P ‫؍‬ .001). The mRNA expression of pyrimidine nucleotidase I (PN-I), cytidine deaminase (CDA), and deoxycytidylate deaminase (dCMPD) did not differ significantly between both groups. hENT1 mRNA expression inversely correlated with in vitro resistance to Ara-C (r s ‫؍‬ ؊0.58, P ‫؍‬ .006). The same differences concerning dCK and hENT1 mRNA expression were observed between MLL gene-rearranged (n ‫؍‬ 14) and germ line MLL cases (n ‫؍‬ 25). An oligonucleotide microarray screen (Affymetrix) comparing patients with MLL gene-rearranged ALL with those with nonrearranged ALL also showed a 1.9-fold lower dCK (P ‫؍‬ .001) and a 2.7-fold higher hENT1 (P ‫؍‬ .046) mRNA expression in patients with MLL generearranged ALL. We conclude that an elevated expression of hENT1, which transports Ara-C across the cell membrane, contributes to Ara-C sensitivity in MLL generearranged infant ALL.

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Section: Introductionmentioning

confidence: 99%

Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia

Stam

Boer

Meijerink

et al. 2002

Blood

175

121

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“…However, results obtained after transfection of this gene in murine fibroblasts were not promising enough to continue this approach. 86 Other genes involved in resistance and the cellular response to cytotoxic deoxynucleoside analogues could be used for the protection of hematopoietic cells. In particular, increased expression of the large subunit of the ribonucleotide reductase, RRM1, has been shown to be implicated in the resistance to gemcitabine and this gene could therefore represent another gene therapy candidate.…”

Section: New Systems and Perspectivesmentioning

confidence: 99%

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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“…Several factors such as lower AraC transport activity, reduced dCK activity and high hCDA activity are suggested to be associated with the development of AraC resistance, and accumulating evidence suggests that the latter factor may play a key role in this resistance (Cros et al, 2004;Fernandez-Calotti et al, 2005;Stam et al, 2006). For example, in vitro studies indicate a relationship between hCDA expression and resistance to AraC, and leukemic cells from patients in clinical studies have high hCDA expression levels, especially those of refractory AML patients (Steuart and Burke, 1971;Tattersall et al, 1974;Colly et al, 1987;Onetto et al, 1987;Momparler and Laliberte, 1990;Honma et al, 1991;Neff and Blau, 1996;Schroder et al, 1996Schroder et al, , 1998Jahns-Streubel et al, 1997;Ohta et al, 2004;Yoshida et al, 2010). Elevated hCDA levels in the liver and spleen may also contribute to drug resistance (Camiener and Smith, 1965;Ho, 1973).…”

Section: Introductionmentioning

confidence: 99%

“…Therefore, higher AraC doses may be necessary to improve clinical efficacy. However, because hematopoietic stem cells (HSCs)/bone marrow cells display low hCDA activity, this dose-intensified treatment may cause hematopoietic toxicity followed by severe and life-threatening myelosuppression of the patient (Nygaard and Sundström, 1987;Schroder et al, 1996). Two main approaches have been utilized to overcome these two hCDA-related side effects produced by AraC.…”

Section: Introductionmentioning

confidence: 99%

“…Compared with other drug resistance genes, hCDA is a highly promising candidate with several advantages including nonimmunogenicity, small size to facilitate genetic manipulation and delivery, and the ability to confer high levels of resistance to a class of cytidine nucleoside analogs with low toxic and mutagenic potential (Beauséjour et al, 2001;Eliopoulos et al, 2002). The protective potential of hCDA against AraC has been demonstrated in fibroblasts and hematopoietic cell lines, primary hematopoietic cells, and multiple in vivo mouse transplant models (Momparler et al, 1996;Neff and Blau, 1996;Schroder et al, 1996;Eliopoulos et al, 1998a,b;Flasshove et al, 1999;Budak-Alpdogan et al, 2004;Bardenheuer et al, 2005;Rattmann et al, 2006). The transfer of hCDA into hematopoietic cells would also allow for the enrichment of stably transduced cells (Beauséjour et al, 2001;Eliopoulos et al, 2002;Bardenheuer et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

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Creation of zebularine-resistant human cytidine deaminase mutants to enhance the chemoprotection of hematopoietic stem cells

Ruan

Qiu

Beard

et al. 2016

Protein Engineering, Design and Selection

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Human cytidine deaminase (hCDA) is a biomedically important enzyme able to inactivate cytidine nucleoside analogs such as the antileukemic agent cytosine arabinoside (AraC) and thereby limit antineoplastic efficacy. Potent inhibitors of hCDA have been developed, e.g. zebularine, that when administered in combination with AraC enhance antineoplastic activity. Tandem hematopoietic stem cell (HSC) transplantation and combination chemotherapy (zebularine and AraC) could exhibit robust antineoplastic potency, but AraC-based chemotherapy regimens lead to pronounced myelosuppression due to relatively low hCDA activity in HSCs, and this approach could exacerbate this effect. To circumvent the pronounced myelosuppression of zebularine and AraC combination therapy while maintaining antineoplastic potency, zebularine-resistant hCDA variants could be used to gene-modify HSCs prior to transplantation. To achieve this, our approach was to isolate hCDA variants through random mutagenesis in conjunction with selection for hCDA activity and resistance to zebularine in an Escherichia coli genetic complementation system. Here, we report the identification of nine novel variants from a pool of 1.6 × 10 6 transformants that conferred significant zebularine resistance relative to wild-type hCDA2. Several variants revealed significantly higher K i values toward zebularine when compared with wild-type hCDA values and, as such, are candidates for further exploration for gene-modified HSC transplantation approaches.

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Assessment of resistance induction to cytosine arabinoside following transfer and overexpression of the deoxycytidylate deaminase gene in vitro

Cited by 16 publications

References 14 publications

Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia

Differential mRNA expression of Ara-C-metabolizing enzymes explains Ara-C sensitivity in MLL gene-rearranged infant acute lymphoblastic leukemia

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

Creation of zebularine-resistant human cytidine deaminase mutants to enhance the chemoprotection of hematopoietic stem cells

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