ABSTRACT
Cytidine deaminase (CDA) is the major enzyme of gemcitabine inactivation. The aim of this study was to determine whether the CDA Lys27Gln polymorphism influenced gemcitabine deamination in blood samples from 90 lung cancer patients. The polymorphism was studied with Taqman probes-based assay; CDA activity was evaluated by HPLC in cytoplasmic extracts from red blood cells. Mean enzymatic activity was significantly lower in patients carrying the CDA Lys27Lys than in patients with the Lys27Gln or Gln27Gln protein (P < 0.05). CDA genotyping may be useful in screening patients before gemcitabine treatment, in order to identify subjects with lower CDA activity and potentially better clinical outcomes after gemcitabine-based chemotherapy.
Subject(s)
Antineoplastic Agents/blood , Antineoplastic Agents/metabolism , Cytidine Deaminase/genetics , Cytidine Deaminase/metabolism , Deoxycytidine/analogs & derivatives , Deamination , Deoxycytidine/blood , Deoxycytidine/metabolism , Genotype , Humans , Polymorphism, Genetic , GemcitabineABSTRACT
The present study was performed to investigate the capability of gemcitabine and pemetrexed to synergistically interact with respect to cytotoxicity and apoptosis in T24 and J82 bladder cancer cells, and to establish a correlation between drug activity and gene expression of selected genes in tumour samples. The interaction between gemcitabine and pemetrexed was synergistic; indeed, pemetrexed favoured gemcitabine cytotoxicity by increasing cellular population in S-phase, reducing Akt phosphorylation as well as by inducing the expression of a major gemcitabine uptake system, the human equilibrative nucleoside transporter-1 (hENT1), and the key activating enzyme deoxycytidine kinase (dCK) in both cell lines. Bladder tumour specimens showed an heterogeneous gene expression pattern and patients with higher levels of dCK and hENT1 had better response. Moreover, human nucleoside concentrative transporter-1 was detectable only in 3/12 patients, two of whom presented a complete response to gemcitabine. These data provide evidence that the chemotherapeutic activity of the combination of gemcitabine and pemetrexed is synergistic against bladder cancer cells in vitro and that the assessment of the expression of genes involved in gemcitabine uptake and activation might be a possible determinant of bladder cancer response and may represent a new tool for treatment optimization.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Deoxycytidine/analogs & derivatives , Glutamates/administration & dosage , Guanine/analogs & derivatives , Urinary Bladder Neoplasms/drug therapy , Urinary Bladder Neoplasms/metabolism , Administration, Intravesical , Adult , Aged , Apoptosis/drug effects , Cell Cycle/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Deoxycytidine/administration & dosage , Deoxycytidine/antagonists & inhibitors , Deoxycytidine/pharmacology , Deoxycytidine Kinase/antagonists & inhibitors , Deoxycytidine Kinase/genetics , Dipyridamole/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Equilibrative Nucleoside Transporter 1/drug effects , Equilibrative Nucleoside Transporter 1/genetics , Excitatory Amino Acid Antagonists , Female , Gene Expression Regulation, Neoplastic/drug effects , Glutamates/pharmacology , Guanine/administration & dosage , Guanine/antagonists & inhibitors , Guanine/pharmacology , Humans , Male , Middle Aged , Neoplasm Staging , Pemetrexed , Phosphoribosylglycinamide Formyltransferase/antagonists & inhibitors , Phosphoribosylglycinamide Formyltransferase/genetics , Phosphorylation , Proto-Oncogene Proteins c-akt/antagonists & inhibitors , Proto-Oncogene Proteins c-akt/metabolism , S Phase/drug effects , Thioinosine/analogs & derivatives , Thioinosine/pharmacology , Thymidylate Synthase/antagonists & inhibitors , Thymidylate Synthase/genetics , Treatment Outcome , GemcitabineABSTRACT
The use of gemcitabine in combination with chemotherapeutic agents, including cisplatin, pemetrexed and taxanes, is characterized by the enhancement of their anticancer activity. The analysis of the underlying pharmacodynamics has revealed that modulation of nucleotide pools, drug metabolism, and cellular DNA repair capability are the most common factors to explain the additive to synergistic interaction between gemcitabine and anticancer agents in several human cancers in vitro and in vivo.
