Impact of cytidine deaminase activity on intrinsic resistance to cytarabine in carcinoma cells

Ohta, Takuya; Hori, Hiroki; Ogawa, Masahiro; Miyahara, Masazumi; Kawasaki, Hajime; Taniguchi, N; Komada, Yoshihiro

doi:10.3892/or.12.5.1115

Cited by 14 publications

(12 citation statements)

References 0 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…19,21 PM status has already been identified as the culprit in reports of cases of death resulting from toxicity with azacytidine. 22 Regarding Ara-C, so far the issue of CDA activity has been mainly addressed at the tumor level as a possible resistance factor 23 resulting from drug deactivation after cellular uptake. Case reports in children suggest PM CDA status is predictive of Ara-C toxicity, but to date, no such relationship has been investigated in adults.…”

Section: Introductionmentioning

confidence: 99%

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

View full text Add to dashboard Cite

Key Points• Ara-C is the mainstay of treatment for patients with AML, and life-threatening toxicities are common.• We demonstrated that cytidine deaminase downregulation predicts severe/lethal toxicities with cytarabine.Cytarabine (Ara-C) is the backbone of acute myeloid leukemia (AML) chemotherapy. Little is known about possible risk factors predictive for the frequent (ie, up to 16%) life-threatening or lethal toxicities caused by Ara-C. Ara-C is detoxified in the liver by a single enzyme, cytidine deaminase (CDA), coded by a gene known to be highly polymorphic. In this proof-of-concept study, we particularly investigated the role of the CDA poor metabolizer (PM) phenotype in Ara-C toxicities. CDA phenotyping (measurement of CDA residual activity in serum) and genotyping (search for the CDA*2 allelic variant) were performed in 58 adult patients with AML treated with the standard 713 (Ara-C 1 anthracyclines)protocol. Statistically significantly lower CDA activity was observed in patients experiencing severe/lethal toxicities as compared with patients who did not (1.5 6 0.7 U/mg vs 3.95 6 3.1 U/mg; Student t test P , .001). Subsequent receiver operating characteristic analysis identified a threshold in CDA activity (ie, 2 U/mg) associated with PM syndrome and increased risk of developing severe toxicities. Five percent of patients experienced lethal toxicities, all displaying CDA PM status (1.3 6 0.5 U/mg). In terms of efficacy, a trend toward higher response rates and longer progression-free survival and overall survival were observed in patients with low CDA activity. Taken together, the results of this study strongly suggest that CDA is a predictive marker of life-threatening toxicities in patients with AML receiving induction therapy with standard Ara-C.

show abstract

Section: Introductionmentioning

confidence: 99%

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

et al. 2018

View full text Add to dashboard Cite

show abstract

“…Initially, OCI-AML3 and U937 cells were shown to be more sensitive to cytarabine-treatment than Mylotarg using published IC 50 dosages 34,35 (Online Supplementary Figure S5). HOXA/TALE knockdown cells demonstrated significantly less growth in liquid culture and a measurable degree of sensitization compared to nonsilencing and non-drug-treated controls ( Figure 6A and Online Supplementary Figure S6A).…”

Section: Hoxa/tale Knockdown Sensitizes Acute Myeloid Leukemia Cells mentioning

confidence: 99%

“…AML cells, pre-treated with or without shRNA, were plated in liquid culture or methylcellulose with 1 μM cytarabine (cytosine arabinoside) 34 or 100 ng/mL Mylotarg (gemtuzumab ozogamicin).…”

Section: Drug Treatmentmentioning

confidence: 99%

HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy

et al. 2013

View full text Add to dashboard Cite

show abstract

“…[60][61][62] The relevance of this inactivation for the activity of these compounds has been shown both on cell models and in vivo using in particular the CDA inhibitor 3,4,5,6-tetrahydrouridine (THU). [63][64][65][66] Because of the high enzyme activity of CDA toward araC and gemcitabine in vitro and in vivo, this gene has been used to protect hematopoietic cells from the cytotoxic effect of these two drugs.…”

Section: Myeloprotection With Cytidine Deaminasementioning

confidence: 99%

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

2009

View full text Add to dashboard Cite

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.

show abstract

Impact of cytidine deaminase activity on intrinsic resistance to cytarabine in carcinoma cells

Cited by 14 publications

References 0 publications

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

CDA as a predictive marker for life-threatening toxicities in patients with AML treated with cytarabine

HOXA/PBX3 knockdown impairs growth and sensitizes cytogenetically normal acute myeloid leukemia cells to chemotherapy

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

Contact Info

Product

Resources

About