BACKGROUNDSingle nucleotide polymorphisms (SNPs) in the deoxycytidine kinase (dCK) gene are associated with chemosensitivity to nucleoside analogs. 2',2'-Difluoro 2'-deoxycytidine (gemcitabine) is a first-line nucleoside analog drug in the treatment of pancreatic cancer. However, the association between SNPs in the dCK gene and chemosensitivity to gemcitabine has not been fully established. Therefore, the present study aimed to investigate the relationship between SNPs in the dCK gene and chemosensitivity to gemcitabine in human pancreatic cancer cell lines.

METHODSSeven SNPs in the dCK gene were sequenced in six human pancreatic cancer cell lines. The chemosensitivity of these six cell lines to gemcitabine were evaluated in vitro with a Cell Counting Kit-8 (CCK-8) test. Inhibition rates were used to express the chemosensitivity of pancreatic cancer cell lines to gemcitabine.

RESULTSThe genotype of the A9846G SNP in the dCK gene was determined in six human pancreatic cancer cell lines. The cell lines BxPC-3 and T3M4 carried the A9846G SNP genotype AG, whereas cell lines AsPC-1, Mia PaCa2, SW1990 and SU86.86 carried the GG genotype. Cell lines with the AG genotype (BxPC-3 and T3M4) were more sensitive to gemcitabine compared with cell lines with the GG genotype (AsPC-1, Mia PaCa2, SW1990 and SU86.86) and significantly different inhibition rates were observed between cell lines carrying the AG and GG genotypes (P < 0.01).

CONCLUSIONSVariants in the A9846G SNP of the dCK gene were associated with sensitivity to gemcitabine in pancreatic cancer cell lines. The dCK A9846G SNP may act as a genetic marker to predict chemotherapy efficacy of gemcitabine in pancreatic cancer.

Antimetabolites, Antineoplastic ; pharmacology ; Cell Line, Tumor ; Cell Survival ; drug effects ; Deoxycytidine ; analogs & derivatives ; pharmacology ; Deoxycytidine Kinase ; genetics ; Genotype ; Humans ; Pancreatic Neoplasms ; enzymology ; genetics ; Polymorphism, Single Nucleotide ; genetics

Chemotherapy is expected to play an important role in the treatment of pancreatic cancer because most of pancreatic cancers are being discovered at locally advanced or metastatic stages and recurrence rate is high even after the curative resection. Gemcitabine is a key agent for the first-line therapy of advanced pancreatic cancer. It can enhance the quality of life and prolong the survival of patients. Combination of erlotinib or capecitabine with gemcitabine showed a marginal survival benefit over single-agent gemcitabine. If patient's performance state is good, gemcitabine-based platinum combination therapy showed overall survival benefit compared with gemcitabine monothrapy. If the first-line palliative chemotherapy fails, 5-FU, capcitabine, or tegafur with or without combination can be used as the second-line agents. Adjuvant chemotherapy using 5-FU or gemcitabine after curative resection has overall survival benefit. However, neoadjuvant chemotherapy has not been proven to be effective in the treatment of pancreatic cancer.
Antimetabolites/therapeutic use ; Antimetabolites, Antineoplastic/therapeutic use ; Chemotherapy, Adjuvant ; Deoxycytidine/analogs & derivatives/therapeutic use ; Fluorouracil/analogs & derivatives/therapeutic use ; Humans ; Pancreatic Neoplasms/*drug therapy ; Protein Kinase Inhibitors/therapeutic use ; Quinazolines/therapeutic use

Pancreatic adenocarcinoma is one of the fatalist malignancies. A large proportion of patients are diagnosed with unresectable stage pancreatic cancer at the time of presentation. Gemcitabine is a standard chemotherapeutic agent since 1997, but survival benefit is not satisfactory. Recent clinical study proved that several new combination chemotherapy regimens are superior to gemcitabine single chemotherapy and extended overall survival. However, its prognosis still remains grim. Current research is taking a multidirectional approach in the hope of developing more effective treatments. This article reviews the major clinical trial data that is the basis for the current chemotherapy regimens used as first- and second-line treatments for advanced pancreatic adenocarcinoma. This article also reviews the current ongoing clinical trials, which include the use of molecular targeting agents and immune therapies.
Adenocarcinoma/*drug therapy/pathology ; Antimetabolites, Antineoplastic/therapeutic use ; Antineoplastic Agents/therapeutic use ; Antineoplastic Combined Chemotherapy Protocols/therapeutic use ; Deoxycytidine/analogs & derivatives/therapeutic use ; Humans ; Immunotherapy ; Pancreatic Neoplasms/*drug therapy/pathology ; Protein Kinase Inhibitors/therapeutic use

The study was purposed to explore the relationship between the expression of deoxycytidine kinase (dCK) gene and fludarabine (Flud) resistance in patients with chronic lymphocytic leukemia (CLL). The real time quantitative polymerase chain reaction (RQ-PCR) technique was used to detect the mRNA expression of dCK gene in the bone marrow or peripheral blood mononuclear cells from 30 CLL patients, the difference of dCK expression levels between CLL patients sensitive to Flud and patients resistant to Flud was analyzed. The results showed that dCK expression level in the Flud-sensitive patients was much higher than that in the Flud-resistant ones (p = 0.001); dCK expression level had no relationship with sex, age, Binet stage, IgVH mutations, CD38, ZAP-70 or p53 gene mutation (p > 0.05). It is concluded that low expression or deficiency of dCK in patients may contribute to resistance against Flud- and the prognostic significance of dCK expression remains to be further studied.
Aged ; Aged, 80 and over ; Case-Control Studies ; Deoxycytidine Kinase ; genetics ; Drug Resistance, Neoplasm ; genetics ; Female ; Gene Expression ; Humans ; Leukemia, Lymphocytic, Chronic, B-Cell ; drug therapy ; genetics ; Male ; Middle Aged ; Vidarabine ; analogs & derivatives ; pharmacology ; therapeutic use

OBJECTIVETo assay the expression of cytidine deaminase (CDA), ribonucleotide reductase subunit 1 (RRM1), phosphatase and tensin homologue deleted from chromosome 10 (PTEN), excision repair cross-complementation group 1 (ERCC1), deoxycytidine kinase (dCK) and RRM1(-)37A/C polymorphism, which have been shown relevant to gemcitabine resistance in two human gemcitabine-resistant non-small cell lung cancer cell lines A549/Gem and NCI-H460/Gem, so as to make clear how do they vary during the course of acquiring resistance to gemcitabine.

METHODSThe human gemcitabine-resistant non-small cell lung cancer cell lines A549/Gem and NCI-H460/Gem were established in our Department by repeated clinical serum peak concentration and gradually increasing doses. Real-time fluorescent quantitative PCR was used to examine the expression of CDA, RRM1, PTEN, ERCC1, dCK and RRM1(-)37A/C polymorphism in those cell lines at different time points during their induction process.

RESULTSThe resistance indexes of A549/Gem and NCI-H460/Gem cells reached 163.228 and 181.684, and then remained stable at 115.297 and 129.783, respectively. The expression of CDA, RRM1, PTEN and ERCC1 varied along with the changing gemcitabine resistance indexes, but expression of dCK did not change apparently. The wild type promoter was able to amplify the genomic DNA in different induction stages of A549/Gem and NCI-H460/Gem cells, but allelotype did not, indicating that the gene type of A549/Gem, NCI-H460/Gem and their parental cells remaining still wild type.

CONCLUSIONCompared with their parental cells, the expressions of CDA, RRM1, PTEN and ERCC1 in human gemcitabine-resistant non-small cell lung cancer cell lines A549/Gem and NCI-H460/Gem rise, the expression of dCK changes inapparently, therefore, their gene type are remaining wild type.

Antimetabolites, Antineoplastic ; pharmacology ; Carcinoma, Large Cell ; genetics ; metabolism ; pathology ; Carcinoma, Non-Small-Cell Lung ; genetics ; metabolism ; pathology ; Cell Line, Tumor ; Cytidine Deaminase ; genetics ; metabolism ; DNA-Binding Proteins ; genetics ; metabolism ; Deoxycytidine ; analogs & derivatives ; pharmacology ; Deoxycytidine Kinase ; genetics ; metabolism ; Drug Resistance, Neoplasm ; Endonucleases ; genetics ; metabolism ; Humans ; Lung Neoplasms ; genetics ; metabolism ; pathology ; PTEN Phosphohydrolase ; genetics ; metabolism ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; RNA, Messenger ; metabolism ; Tumor Suppressor Proteins ; genetics ; metabolism

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 Chinese patients with AML were enrolled in our study. SNPs genotyping were performed using the MassARRAY system 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 cell (WBC) count patients group and the group with platelet counts > 60'10(9)/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.

Adolescent ; Adult ; Aged ; Aged, 80 and over ; Cytarabine ; therapeutic use ; Cytidine Deaminase ; genetics ; Deoxycytidine Kinase ; genetics ; Female ; Gene Frequency ; genetics ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; genetics ; Male ; Middle Aged ; Polymorphism, Single Nucleotide ; genetics ; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization ; Treatment Outcome ; Young Adult

OBJECTIVEIt has been reported that high-dose cytarabine (HD-AraC) was very effective for childhood hematological malignancies, especially for improving the long-term survival of high-risk acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), and T-cell lymphoid malignancies (T-ALL, T-cell non-Hodgkin's lymphoma). This study aimed to evaluate the pharmacokinetics of HD-AraC for childhood hematological malignancies, and the relationship between the expression of the genes coding the key enzymes for Ara-C metabolism with the outcome of the patients.

METHODSThe drug levels of Ara-C in plasma and cerebrospinal fluid were detected with HPLC while HD-AraC was used, the expression of deoxycytidine kinase (dCK) and cytidine deaminase (CDA) mRNA in human leukemia cell lines and the bone marrow cells were investigated in 48 cases of childhood hematological malignancies with RT-PCR methods, and the relationship between the expression of these enzymes mRNA and the outcome of the patients was analyzed.

RESULTS(1) When HD-AraC was used, the plasma levels of Ara-C and Ara-U could be respectively about 50 times and 25 times higher than those obtained when the patients were treated with regular dose of Ara-C treatment, and the level of Ara-C in cerebrospinal fluid could reach about 10% of plasma level of Ara-C. (2) There were significantly different expressions of dCK mRNA in different childhood acute leukemia (AL) patients, which were markedly related to the chemotherapy results. The expression of dCK in ALL was much higher than that in AML and relapsed AL cases. There were no significant differences in expressions of dCK in T-ALL and B lineage ALL. (3) In vitro study found that the expressions of dCK and CDA mRNA did not change in leukemia cell lines incubated at different doses and times of Ara-C.

CONCLUSIONSHD-AraC was a very effective protocol for childhood hematological malignancies for it could significantly elevate the plasma and cerebrospinal fluid drug levels. The expression of dCK may be an important factor in predicting the long-term outcomes of children with hematological malignancies. Good long-term outcomes of the childhood T-ALL could be achieved as the B lineage ALL had been treated with HD-AraC regimen. As the expression levels of dCK were much lower, it may be necessary for the treatment of AML with HD-AraC for consecutive three days.

Antimetabolites, Antineoplastic ; pharmacokinetics ; Child ; Cytarabine ; administration & dosage ; pharmacokinetics ; therapeutic use ; Cytidine Deaminase ; genetics ; Deoxycytidine Kinase ; genetics ; Gene Expression ; Humans ; Leukemia ; drug therapy ; genetics ; metabolism ; Leukemia, Myeloid, Acute ; drug therapy ; genetics ; metabolism ; Lymphoma, Non-Hodgkin ; drug therapy ; genetics ; metabolism ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; drug therapy ; genetics ; metabolism