Cytidine Deaminase Polymorphisms Research Articles

Association of Cytidine Deaminase Polymorphism with Capecitabine Effectiveness in Breast Cancer Patients.

Cancer is caused by abnormal growth and disruption of homeostatic mechanisms. Breast cancer is a major health problem and the second leading cause of death in women. Capecitabine is a prodrug of 5-fluorouracil, which is a non-cytotoxic agent and is used to treat advanced or metastatic breast cancer. Cytidine deaminase (CDA) plays an important role in the activation of capecitabine by acetylating 5-deoxycytidine in the liver, which ultimately leads to the formation of 5-fluorouracil. In this study, we aimed to investigate the relationship between cytidine deaminase polymorphism and capecitabine efficacy in breast cancer patients. One hundred breast cancer patients aged 45 to 75 years were included in this study, all of whom received capecitabine as monotherapy. The serum levels of CA15.3, calcium, and estradiol E2 in breast cancer patients were investigated. In addition, the relationship of these markers with cytidine deaminase polymorphism was investigated in order to show the association of cytidine deaminase polymorphism with capecitabine efficacy in breast cancer patients. The findings of this study showed that there is a statistically significant relationship between CDA enzyme polymorphisms (rs2072671 and rs532545) with estradiol and CA15.3 serum levels and a non-significant relationship with calcium level. Furthermore, patients who participated were highly polymorphic and heterozygotes genotypes had the highest frequency in both rs2072671 and rs532545 polymorphisms. The results obtained from the present study identified different genetic polymorphisms in the gene encoding the CDA enzyme. Overall, our results clearly showed direct evidence for the association of cytidine deaminase polymorphism with the efficacy of capecitabine in breast cancer patients, which could be useful in reducing side effects and improving drug response to capecitabine.

5'-nucleotidase, cytosolic II genotype, and clinical outcome in patients with acute myeloid leukemia with intermediate-risk cytogenetics.

Acute myeloid leukemia (AML) is a complex disease, and its treatment needs to be adjusted to the risk, which is conferred by cytogenetics and molecular markers. Cytarabine is the main drug to treat AML, and it has been suggested that the genotype of cytarabine metabolizing enzymes may have a prognostic relevance in AML. Here we report the association between the 5'-nucleotidase, cytosolic II (NT5C2) rs10883841, cytidine deaminase (CDA) rs2072671 and rs532545 genotypes and the clinical outcome of 477 intermediate-risk cytogenetic AML patients receiving cytarabine-based chemotherapy. Patients younger than 50 years old with the NT5C2 rs10883841 AA genotype had lower overall survival (OS) (p: .003; HR 2.16, 95% CI 1.29-3.61) and lower disease-free survival (DFS) (p: .002; HR 2.45, 95% CI 1.41-4.27), associated to a higher relapse incidence (p: .010; HR 2.23, 95% CI 1.21-4.12). Interestingly, subgroup analysis showed that the negative effect of the NT5C2 rs10883841 AA genotype was detected in all subgroups except in patients with nucleophosmin mutation without high ratio FLT-3 internal tandem duplication. CDA polymorphisms were associated with the complete remission rate after induction chemotherapy, without influencing OS. Further studies are warranted to determine whether this pharmacogenomic approach may be helpful to individualize AML treatment.

Correlation Between Cytidine Deaminase Polymorphism and Gemcitabine in Efficacy and Toxicity

Correlation Between Cytidine Deaminase Polymorphism and Gemcitabine in Efficacy and Toxicity

Severe acute toxicity following gemcitabine administration: A report of four cases with cytidine deaminase polymorphisms evaluation.

Gemcitabine (GCB) is a pyrimidine antimetabolite widely used in various solid tumors as a single agent or as a component of multidrug regimens. In the majority of patients, GCB is well tolerated, however life-threatening complications occasionally occur. The current report presents four cases of severe acute toxicity, which included two that were fatal, following administration of GCB alone or in combination with cisplatin. Of the four cases, in one, a Naranjo Adverse Drug Reaction Probability Score was definite, in two, probable and in one possible. To determine the potential causes of these toxicities, polymorphic variants of cytidine deaminase, the primary enzyme involved in the hepatic metabolism of GCB, were assessed. The homogeneous c.435TT variant was detected in one patient and a heterozygotic c.435CT variant in two, one of whom additionally harbored a heterozygotic c.79AC variant.

Cytidine deaminase polymorphisms and worse treatment response in normal karyotype AML.

The cytidine deaminase (CDA) catalyzes the irreversible hydrolytic deamination of the cytarabine (AraC) into a 1-β-D-arabinofuranosyluracil (AraU), an inactive metabolite that plays a crucial role in lowering the amount of AraC, a key chemotherapeutic drug, in the treatment of patients with acute myeloid leukemia (AML). In this study, we hypothesized that CDA polymorphisms were associated with the AraC metabolism for AML treatment and/or related clinical phenotypes. We analyzed 16 polymorphisms of CDA among 50 normal karyotype AML (NK-AML) patients, 45 abnormal karyotype AML (AK-AML) patients and 241 normal controls (NC). Several polymorphisms and haplotypes, rs532545, rs2072671, rs471760, rs4655226, rs818194 and CDA-ht3, were found to have a strong correlation with NK-AML compared with NC and these polymorphisms also revealed strong linkage disequilibrium with each other. Among them, rs2072671 (79A>C), which is located in a coding region and the resultant amino acid change K27Q, showed significant associations with NK-AML compared with NC (P=0.009 and odds ratio=2.44 in the dominant model). The AC and CC genotypes of rs2072671 (79A>C) were significantly correlated with shorter overall survival rates (P=0.03, hazard ratio=1.84) and first complete remission duration (P=0.007, hazard ratio=3.24) compared with the AA genotype in the NK-AML patients. Our results indicate that rs2072671 in CDA may be an important prognostic marker in NK-AML patients.

Cytidine deaminase polymorphism predicts toxicity of gemcitabine-based chemotherapy

BackgroundThe aim of this study was to ascertain whether single nucleotide polymorphisms of cytidine deaminase (CDA), a key enzyme in the metabolism pathway of gemcitabine, could predict clinical outcomes of cancer patients with gemcitabine-based chemotherapy. MethodsWe searched MEDLINE and EMBASE up to January 2013 to identify eligible studies. A rigorous quality assessment of eligible studies was conducted according to the Newcastle–Ottawa Quality Assessment Scale. For each included study, the overall survival (OS), overall response rate (ORR) and toxicities were extracted and pooled using random-effects model. ResultsIn total, data from 13 studies were included. CDA 208A>G and CDA 435C>T were not included in quantified synthesis due to limited data. CDA 79A>C polymorphism was not significantly associated with OS; however, patients carrying the variant CDA 79C allele were likely to have a poor survival, hazard ratio (HR)=1.03, 95% CI 0.957–1.27 (AC+CC vs. AA). CDA 79A>C polymorphism did not correlated with ORR, odds ratio (OR)=0.719, 95% CI 0.363–1.425 (AC+CC vs. AA). However, patients with the variant CDA 79C allele would experience more grade≥3 leucopenia (OR=2.933, 95% CI 1.357–6.605) and tended to have more severe neutropenia (OR=1.313, 95% CI 0.157–10.981). ConclusionsThese results suggest that CDA 79A>C polymorphisms is a potential biomarker for toxicity of gemcitabine-based chemotherapy and a CDA testing before gemcitabine administration is preferred.

The Impact of CDA A79C Gene Polymorphisms on the Response and Hematologic Toxicity in Gemcitabine-Treated Patients: A Meta-Analysis

To investigate the impact of the cytidine deaminase (CDA) A79C polymorphism on both the response to gemcitabine in non-small cell lung cancer (NSCLC) patients and the risk of hematologic toxicities in patients bearing any kind of cancer taking gemcitabine. The PubMed and Embase databases were searched from the first available article to January 2013. Eligible studies included clinical trials that contained the keywords "gemcitabine" or "cytidine deaminase" and information about response rate of NSCLC patients or hematologic toxicities in patients with any kind of cancer. Relative risk (RR) of different genotypes and 95% confidence intervals (CI) were calculated. A total of 7 articles (623 patients from 6 studies) were included. The results showed that patients with wild type CDA (AA and AC) had a significantly lower rate of severe anemia than the homozygote mutant type CC (RR=0.308; 95%CI, 0.113-0.021, p=0.021). However, the rate of severe neutropenia, thrombocytopenia, and the response rate were identical between different CDA genotypes. The A79C CDA polymorphism did not show a significant impact on the response rate to gemcitabine in NSCLC patients, while the wild type CDA genotype was indeed correlated to a lower rate of incidence of severe anemia in patients taking gemcitabine.

Abstract 1170: Correlation between cytidine deaminase single nucleotide polymorphisms and in vitro drug sensitivity, DNA methylation and outcome in normal karyotype acute myelogenous leukemia.

Abstract Background: De novo AML with normal karyotype (NK-AML) comprise a large group of patients without common cytogenetic alterations but with a large variation in treatment response. New tools such as the analysis of nucleophosmine 1 (NPM1), FMS-like tyrosine kinase 3 (FLT3) and CCAAT/enhancer binding protein (CEBPA) mutations has emerged as clinical markers of prognosis, but there is still a need for additional tools to explain the variation in outcome. Cytarabine (Ara-C), a cornerstone in AML chemotherapy, is activated intracellularly by deoxycytidine kinase (dCK), and deactivated by cytidine deaminase (CDA) and poor treatment outcome or development of chemotherapy resistance can be due to altered activity of these enzymes. Single nucleotide polymorphisms (SNPs) of CDA genes have previously been reported to result in lower CDA allelic expression and to affect the outcome of treatment. In addition, pharmacological inhibition of CDA has been shown to reduce the degree of DNA methylation. DNA methylation may be an important regulatory mechanism for the expression of genes related to drug effect, and we therefore aimed to investigate the relationship between CDA polymorphisms and outcome in NK-AML, DNA methylation, and in vitro drug cytotoxicity. Method: 207 Swedish NK-AML patients were genotyped for the CDA SNPs 79A>C (rs2072671) and -451C>T (rs532545) and the results were correlated to treatment response and overall survival (OS) in the material as a whole as well as stratified based on FLT3 and NPM1 status. Cells from a subset of the patients were also investigated for genotype association with in vitro drug cytotoxicity (n=56) and global DNA methylation (n=82). Results: CDA 79C/C or -451T/T genotype was associated to a shorter OS compared to other genotypes (0.44 vs. 1.86 years, p=0.004; and 0.45 vs. 1.79 years, p=0.051) for FLT3-ITD+ patients, and this was even more pronounced in the FLT3-ITD+/NPM1+ cases. There was significantly less DNA methylation in cells heterozygous for both polymorphisms (A/C+C/T) compared to homozygous A/A+C/C cells (p=0.018). There was also a lower degree of methylation in homozygous C/C+T/T cells, but due to the small number of samples in this group significance was not reached. An altered in vitro sensitivity towards topoisomerase inhibitory drugs, but not towards nucleoside analogues was seen for both CDA SNPs with homozygous C/C or T/T cells being more sensitive. Conclusions: We found a significant correlation between CDA genotype and OS in NK-AML, the degree of DNA methylation in AML cells, and in vitro drug sensitivity. The change in methylation related to CDA genotype may be associated with differences in drug activation and subsequent sensitivity, making these polymorphisms potential markers of use for future individual chemotherapy decisions such as dose adjustments. Citation Format: Ingrid Jakobsen Falk, Anna Fyrberg, Monica Hermanson, Martin Höglund, Hareth Nahi, Lars Palmqvist, Christer Paul, Esbjörn Paul, Richard Rosenquist, Dick Stockelberg, Yuan Wei, Henrik Green, Kourosh Lotfi. Correlation between cytidine deaminase single nucleotide polymorphisms and in vitro drug sensitivity, DNA methylation and outcome in normal karyotype acute myelogenous leukemia. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1170. doi:10.1158/1538-7445.AM2013-1170

Association of Polymorphisms of Cytosine Arabinoside- Metabolizing Enzyme Gene with Therapy Efficacy for Acute Myeloid Leukemia

AbstractAbstract 4328 BackgroundThe cytosine arabinoside (Ara-C)-based chemotherapy is the major remedial measure for acute myeloid leukemia (AML). Deoxycytidine kinase (DCK) and cytidine deaminase (CDA) are the key enzymes in the metabolism of Ara-C. Many single nucleotide polymorphisms (SNPs) and haplotypes of DCK and CDA, which contribute to susceptibility to Ara-C, have been identified in Africans and Europeans. However, there has been no report about the relation among three SNPs in DCK (rs115543896, rs72552079, and rs111454937) and two SNPs in CDA (rs2072671 and rs60369023), and their clinical response to Ara-C for a Chinese population. In this study, we aimed to investigate whether these five SNPs are associated with the therapeutic outcomes of Ara-C-based chemotherapy regimens in patients with AML. MethodsA total of 151 patients with AML in a Chinese population were enrolled in our study. SNPs genotyping were performed using the MassARRAY system (Sequenom) by means of the matrix-assisted laser desorption ionization-time of flight mass spectrometry (MALDI-TOF-MS) method. ResultsThe results illustrated that DCKrs111454937 AA genotype was more frequent in patients with higher platelet count, and A allele frequency was significantly higher in the group £40 years, lower white blood count (WBC) patients group and the group with platelet counts >60′109/L. Meanwhile, both DCKrs72552079 TC (OR=1.225, 95% CI=1.225–9.851, P=0.0192) and CDArs60369023 GA (OR=9.851, 95% CI=1.31–77.93, P=0.0263) significantly improved Ara-C-based chemotherapy response. While DCKrs11554389 AA (OR=0.147, 95% CI=0.027–0.801, P=0.0267) was associated with the decrease of Ara-C-based chemotherapy response. ConclusionIt is evident that the DCK and CDA polymorphisms might be the important markers for the AML patients' therapy outcomes in a Chinese population. Disclosures:No relevant conflicts of interest to declare.

Molecular Targets of Gemcitabine Action: Rationale for Development of Novel Drugs and Drug Combinations

Gemcitabine is one of the most widely used pyrimidine analogues, with a well-established role as a first- and second-line treatment of several types of tumors. Several preclinical and clinical studies have been done to obtain information on molecular determinants of gemcitabine activity and metabolism, in order to predict whether this drug will be effective and safe for the individual patient. Among these molecular determinants, the mRNA and protein expression of equilibrative transporter-1 (ENT1) and ribonucleotide reductase (RR) emerged as possible predictors of drug activity in studies on pancreatic and non-small cell lung cancer. However, cytidine deaminase polymorphisms and activity were correlated with clinical outcome and severe toxicities, whereas further studies should evaluate both P53 dependent and independent pathways involved in gemcitabine induced apoptosis. Improved knowledge on these determinants is critical for the optimal development of combination of gemcitabine with other conventional or biological therapies, as well as to exploit the radiosensitizing potential of gemcitabine. Emerging technologies such as massive parallel sequencing, gene expression arrays and proteomics may identify novel biomarkers in tumor material, while polymorphisms and phenotyping analysis should unravel factors involved in drug toxicity. Validation of these markers in preclinical models should be used for the appropriate patient enrolment into subsequent prospective studies. Hopefully, novel pharmacogenetic biomarkers will be validated in these prospective studies and used to select cancer patients to be treated with gemcitabine-based regimens in the near future or to enroll them in studies with prodrugs in order to bypass resistance mechanisms.

Correlation of cytidine deaminase polymorphisms and activity with clinical outcome in gemcitabine-/platinum-treated advanced non-small-cell lung cancer patients

The aim of this study was to evaluate whether cytidine deaminase (CDA) polymorphisms 79A>C and 435C>T and/or CDA enzymatic activity influenced clinical outcome in 126 advanced non-small-cell lung cancer patients treated with gemcitabine-platinum-regimens. CDA polymorphisms and activity were analysed by PCR and high-performance liquid chromatography, respectively. Univariate and multivariate analyses compared biological/clinical parameters with response, clinical benefit, time to progression (TtP) and overall survival (OS) using Pearson's χ(2) test, log-rank test and Cox proportional hazards model. Patients with CDA A79A/A79C genotypes had significantly longer TtP (6.0 versus 3.0 months; P = 0.001) and OS (11.0 versus 5.0 months; P = 0.001) than patients with C79C genotype. Patients harbouring CDA C435C/C435T genotypes also had a longer OS (P = 0.025), but no correlations were observed with TtP. Conversely, patients with low-CDA activity had a significantly higher response rate (37.7% versus 13.8%; P = 0.006), clinical benefit (91.8% versus 51.7%; P < 0.001), as well as longer TtP (8.0 versus 3.0 months; P < 0.001) and OS (19.0 versus 6.0 months; P < 0.001). Furthermore, enzymatic activity emerged as an independent predictor for death/progression risk at multivariate analysis. CDA enzymatic activity appears to be the strongest candidate biomarker of activity and efficacy of platinum-gemcitabine-based chemotherapy and should be validated in a prospective study.

The influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma

Identification of biomarkers that could predict gemcitabine efficacy and toxicity is a key issue in the development of individualized therapy. The aim of our study was to evaluate the influence of gemcitabine pathway polymorphisms on treatment outcome in patients with malignant mesothelioma (MM). In total, 107 patients with MM, treated with gemcitabine-platinum chemotherapy, were genotyped for 11 polymorphisms in deoxycytidine kinase, ribonucleotide reductase M1 (RRM1), and cytidine deaminase genes using KASPar assays. Binary logistic regression was used to evaluate the influence of selected polymorphisms on tumor response and occurrence of treatment-related toxicity, while their influence on survival was estimated by Cox proportional hazards model. A haplotype analysis was carried out to assess the combined effect of RRM1 polymorphisms. Deoxycytidine kinase and cytidine deaminase polymorphisms did not influence treatment outcome in patients with MM. In multivariable analysis, RRM1 2927A>C polymorphism significantly decreased overall survival probability [hazard ratio (HR)=2.02; 95% confidence interval (CI)=1.11-3.65; P=0.021]. Two promoter polymorphisms, RRM1 -524T>C and -37C>A, decreased the odds of nausea/vomiting grade≥2 occurrence [odds ratio (OR)=0.25; 95% CI=0.10-0.60; P=0.002 and OR=0.26; 95% CI=0.11-0.63; P=0.003, respectively]. RRM1 TTCCA haplotype was associated with worse tumor response (OR=16.67; 95% CI=2.38-100.00; P=0.004) and worse overall survival (HR=2.97; 95% CI=1.46-6.06; P=0.003) compared with the most frequent TTCAA haplotype, while TCACA haplotype influenced nausea/vomiting grade≥2 occurrence (OR=0.27; 95% CI=0.12-0.60; P=0.001). RRM1 polymorphisms as well as haplotypes showed an association with gemcitabine treatment efficacy and toxicity; therefore, they should be validated as potential markers for the prediction of clinical outcome in patients with MM.

Oral Administration of Low-Dose Decitabine and Tetrahydrouridine In Combination Increases Fetal Hemoglobin to Therapeutic Levels In the Absence of Cytotoxicity and Reduces Inter-Individual Drug Bioavailability In Baboons

Abstract 2147Increased fetal hemoglobin (HbF) levels alleviate the symptoms and improve survival of patients with sickle cell disease and β-thalassemia. Because therapeutic options remain limited for a large group of patients refractory to hydroxyurea (HU) therapy, alternative therapeutic agents to increase HbF are urgently needed. Decitabine (DAC) increases HbF to therapeutic levels in sickle cell disease patients refractory to HU. Oral administration of DAC would ease administration, increase compliance, and lower costs. Previous studies showed that oral administration of high doses of DAC increased HbF levels in baboons (Lavelle et al Am J Hematol 82:981, 2007). The oral bioavailability of DAC is limited by the degradative action of cytidine deaminase (CDA), and patients with CDA polymorphisms associated with reduced CDA activity may exhibit increased risk of cytotocity. We hypothesized that oral administration of low-dose DAC in combination with the CDA inhibitor THU would improve the DAC concentration-time profile while avoiding high peak drug levels likely to cause DNA damage and cytotoxicity and reduce risks of cytotoxicity in patients with CDA polymorphisms. Pharmacokinetics (PK) analysis in six baboons following oral administration of high-dose DAC alone showed that a dose (10mg/kg) previously shown sufficient to induce maximal (62.3–72%) HbF levels in 3 of 5 baboons when administered daily for ten days was associated with a mean AUC value of 355min*ng/ml. PK analysis following administration of varying doses of DAC in combination with THU showed that this AUC of 355min*ng/ml was attained with a 0.5 mg/kg DAC dose administered orally in combination with THU. The effect of oral low-dose DAC in combination with THU on HbF was then evaluated in four baboons. Initially, a single baboon (7482) was treated at 0.5mg/kg/d 3X/week for 3 weeks followed by 2X/week for an additional 5 weeks. Three additional baboons (7484, 7472, and 7470) were treated with either 0.25 or 0.5mg/kg/d 2X/week for eight weeks. Results (Table 1) showed significant increases in HbF associated with modest decreases in ANC and increases in platelets in all animals.AnimalDecitabine dose (mg/kg/d)SchedulePre-treatment HbF (%)Maximal HbF (%)ΔHbFANC nadirPlt max(x103)74820.53Xwk/3wks 2Xwk/5wks3.523.820.32580100474840.52Xwk/8wks4.223.118.91680102974720.252Xwk/8wks12.830.117.3146060074700.252Xwk/8wks9.929.319.42130895Decreased DNA methylation in the 5’ γ-globin gene region was observed in post-treatment BM samples by quantitative MassARRAY DNA methylation analysis. PK analysis showed that DAC bioavailability following oral administration of high-dose DAC alone differed 33 fold between 7470 and 7484 but only 1.3 fold following oral administration of low-dose DAC in combination with THU. Thus co-administration of low-dose DAC with THU reduced inter-individual variability of drug bioavailability and this was consistent with the similar HbF responses observed in these animals. Importantly, the ability of oral low dose DAC-THU to increase HbF to similar levels in the absence of cytotoxicity in two baboons differing in DAC bioavailability following oral administration of high-dose DAC alone predicts that oral low-dose DAC-THU in combination will reduce risks of cytotoxicity in patients with differences in DAC bioavailability due to CDA polymorphisms. These experiments have determined a dose and schedule of oral low-dose DAC in combination with THU that effectively increases HbF to therapeutic levels in the absence of cytotoxic effects in baboons and thus provide critical information important for the design of a future clinical trial of this drug combination in patients with sickle cell disease refractory to hydroxyurea therapy. Disclosures:No relevant conflicts of interest to declare.

Pharmacogenomic Research for Avoiding Adverse Reactions by Anti-cancer Drugs

Anti-cancer drugs have relatively low effective rates and high frequencies of adverse reactions, occasionally leading to cessation of their treatments. Use of pharmacogenomic (PGx) information could be able to select the patients with high-response and less-adverse reactions, resulting in increase of patients' QOL and proper use of drugs. We have been collaborating with National Cancer Center for PGx analysis of anti-cancer drugs including irinotecan and gemcitabine in Japanese cancer patients. Irinotecan, now used for treatments of many cancers, is metabolically activated to SN-38 and then inactivated to SN-38 glucuronide by a UDP-glucuronosyltransferase UGT1A1. In the UGT1A1 gene, two representative genetic polymorphisms, *28 and *6, were detected at 0.138 and 0.167, respectively in 177 Japanese cancer patients. When the patients were homozygotes of *28 or *6, or compound heterozygotes of them, statistically significant decreases were observed in the SN-38 glucuronidation activity and increases in the rate of severe neutropenia, compared to those in the patients without *28 or *6. Our results and papers were cited in the Japanese package inserts of irinotecan. Gemcitabine was inactivated by cytidine deaminase (CDA) into 2'-2'-difluorodeoxyuridine. A CDA polymorphism 208G>A (Ala70Thr) was detected at 0.037 frequency in 256 Japanese cancer patients and associated with reduced gemcitabine clearance as well as increased frequency of severe neutropenia. In the 4 patients suffered from very severe bone marrow toxicities, 3 patients were homozygous CDA*3, suggesting that this polymorphism is exquisite for predicting severe adverse reactions by gemcitabine in Japanese.

Effect of genetic alterations of cytarabine-metabolizing enzymes in childhood acute lymphoblastic leukemia

Single nucleotide polymorphisms (SNPs) of deoxycytidine kinase (dCK) and cytidine deaminase (CDA) are known to alter their enzymatic activities, which affect the metabolism of cytarabine. Currently, treatment of childhood acute lymphoblastic leukemia (ALL) includes cytarabine, especially in high-risk patients. Therefore, we hypothesized that a genetic variation of dCK and CDA genes may influence the risk of cytarabine-related toxicities and early response to treatment. We included children diagnosed with ALL and lymphoblastic lymphoma (LL) stage III and IV. The patients received a modified St Jude Total Therapy Study XV protocol. Cytarabine was used during induction remission (low-dose cytarabine) and reinduction II (high-dose cytarabine) phases. Genotyping of dCK-360C>G and -201C>t and CDA 79A>C and 208G>A was performed. Minimal residual disease (MRD) at the end of the induction phase was measured using flow cytometry. Ninety-four children with ALL (n=90) and LL (n=4) were analyzed. The median age at diagnosis was 5.8 years (range, 0.4-15 years). All four SNPs showed predominant wild type alleles. There was no CDA-208A allele in our population. Children with dCK-360G allele were at risk of mucositis after receiving low-dose cytarabine (OR=3.7; 95%CI, 1.2--11.3). neither dCK nor CDA polymorphisms affected the MRD status at the end of the induction phase. The dCK-360G allele was found to increase the risk of mucositis after exposure to low-dose cytarabine in childhood ALL therapy.

Letter to the editor: pharmacokinetics of gemcitabine in non-small-cell lung cancer patients: impact of the 79A&gt;C cytidine deaminase polymorphism

Complete List of Authors: Mercier, Cedric; La Timone University Hosiptal, Medical Oncology Dahan, Laetitia; La Timone University Hospital, Digestive Oncology Ouafik, L'Houcine; North University Hospital, Transfer Oncology Laboratory Andre, Nicolas; La Timone university Hospital, Paediatric Oncology Ciccolini, joseph; North University Hospital of Marseille, Transfer Oncology Laboratory European Journal of Clinical Pharmacology

Impact of Cytidine Deaminase Polymorphisms on Toxicity After Gemcitabine: The Question Is Still Ongoing

Impact of Cytidine Deaminase Polymorphisms on Toxicity After Gemcitabine: The Question Is Still Ongoing

Phase II Studies of Gemcitabine and Cisplatin in Heavily and Minimally Pretreated Metastatic Breast Cancer

Cisplatin and gemcitabine have single-agent activity in metastatic breast cancer, and preclinical data support synergy of the combination. Two parallel, phase II trials were conducted to evaluate the response rate, response duration, and toxicities of the combination. Genetic polymorphisms were analyzed for correlation with outcomes. Eligible women had measurable disease and heavily or minimally pretreated metastatic breast cancer. The heavily pretreated protocol required prior anthracycline and taxane therapy; cisplatin as part of high-dose therapy was allowed. All patients received cisplatin 25 mg/m(2) on days 1 through 4 and gemcitabine 1,000 mg/m(2) on days 2 and 8 of a 21-day cycle with prophylactic granulocyte colony-stimulating factor in the heavily pretreated group. Sera from a subset of patients were evaluated by polymerase chain reaction restriction fragment length polymorphism for polymorphisms in 10 genes of interest. Of 136 women enrolled, 74 were heavily pretreated. Both protocols accrued to their two-stage design. The response rate for both the heavily and minimally pretreated cohorts was 26%, and the median durations of response were 5.3 and 5.9 months, respectively. In a multivariate analysis, hormone receptor-negative disease was associated with a higher response rate. The most common grades 3 or 4 toxicities were thrombocytopenia (71%), neutropenia (66%), and anemia (38%). In a subset of 55 patients, the xeroderma pigmentosum group D (XPD)-751, x-ray cross-complementing group 3 (XRCC3) and cytidine deaminase polymorphisms were significantly associated with clinical outcomes. Combination cisplatin and gemcitabine is active in metastatic breast cancer regardless of prior therapy. Genetic polymorphisms may tailor which patients benefit from this regimen.

Pharmacogenomics of gemcitabine in non-small-cell lung cancer and other solid tumors

The validation of predictive biomarkers to tailor chemotherapy is a key issue in the development of effective treatment modalities against cancer. Examples of how genetics might affect drug response are offered by gemcitabine. A substantial number of potential biomarkers for sensitivity or resistance to gemcitabine have been proposed, including ribonucleotide reductase and cytidine deaminase polymorphisms, human equilibrative transporter-1 and ribonucleotide reductase gene-expression and AKT phosphorylation status. These markers displayed a significant relationship with disease response to the drug; however, their robustness needs to be evaluated within prospective studies. Moreover, recent trials of customized chemotherapy based on genetic markers have been carried out in non-small-cell lung cancer and promising pharmacogenetic determinants are gaining momentum, including BRCA1 and ERCC1. Hopefully, biomarkers to select patients most likely to respond to gemcitabine will be validated in the near future.

Pharmacokinetics of Gemcitabine in Japanese Cancer Patients: The Impact of a Cytidine Deaminase Polymorphism

Gemcitabine is rapidly metabolized to its inactive metabolite, 2',2'-difluorodeoxyuridine (dFdU), by cytidine deaminase (CDA). We previously reported that a patient with homozygous 208A alleles of CDA showed severe adverse reactions with an increase in gemcitabine plasma level. This study extended the investigation of the effects of CDA genetic polymorphisms on gemcitabine pharmacokinetics and toxicities. Genotyping of CDA was performed by a direct sequencing of DNA obtained from the peripheral blood of Japanese gemcitabine-naïve cancer patients (n = 256). The patients recruited to the association study received a 30-minute intravenous infusion of gemcitabine at a dose of either 800 or 1,000 mg/m2, and eight blood samples were periodically collected (n = 250). Plasma levels of gemcitabine and dFdU were measured by high-performance liquid chromatography. Plasma CDA activities toward cytidine and gemcitabine were also measured (n = 121). Twenty-six genetic variations, including 14 novel ones and two known nonsynonymous single nucleotide polymorphisms (SNPs), were detected. Haplotypes harboring the nonsynonymous SNPs 79A>C (Lys27Gln) and 208G>A (Ala70Thr) were designated *2 and *3, respectively. The allelic frequencies of the two SNPs were 0.207 and 0.037, respectively. Pharmacokinetic parameters of gemcitabine and plasma CDA activities significantly depended on the number of haplotype *3. Haplotype *3 was also associated with increased incidences of grade 3 or higher neutropenia in the patients who were coadministered fluorouracil, cisplatin, or carboplatin. Haplotype *2 showed no significant effect on gemcitabine pharmacokinetics. Haplotype *3 harboring a nonsynonymous SNP, 208G>A (Ala70Thr), decreased clearance of gemcitabine, and increased incidences of neutropenia when patients were coadministered platinum-containing drugs or fluorouracil.