Determinants of sensitivity and resistance to gemcitabine: The roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non‐small cell lung cancer

• Published in: Cancer science Vol. 95; no. 9; pp. 753 - 757
• Main Authors: Achiwa, Hiroyuki, Oguri, Tetsuya, Sato, Shigeki, Maeda, Hiroyoshi, Niimi, Takashi, Ueda, Ryuzo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.09.2004; Blackwell; John Wiley & Sons, Inc
• Subjects: Affinity Labels - pharmacology; Antimetabolites, Antineoplastic - therapeutic use; Apoptosis - drug effects; Biological and medical sciences; Carcinoma, Non-Small-Cell Lung - drug therapy; Carcinoma, Non-Small-Cell Lung - metabolism; Carcinoma, Non-Small-Cell Lung - pathology; Cell Division - drug effects; Chemotherapy; Deoxycytidine - analogs & derivatives; Deoxycytidine - therapeutic use; Deoxycytidine kinase; Deoxycytidine Kinase - genetics; Deoxycytidine Kinase - metabolism; Drug Resistance, Neoplasm; Equilibrative Nucleoside Transporter 1 - antagonists & inhibitors; Equilibrative Nucleoside Transporter 1 - genetics; Equilibrative Nucleoside Transporter 1 - metabolism; Gemcitabine; Humans; Lung cancer; Lung Neoplasms - drug therapy; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Medical sciences; Non-small cell lung carcinoma; Nucleoside transporter; Pneumology; Reverse Transcriptase Polymerase Chain Reaction; Small cell lung carcinoma; Thioinosine - analogs & derivatives; Thioinosine - pharmacology; Tumor cell lines; Tumor Cells, Cultured; Tumors; Tumors of the respiratory system and mediastinum; Antineoplastic agent; Human; Lung disease; Gemcitabine; Respiratory disease; Enzyme; Transferases; Lung cancer; Malignant tumor; non-small cell lung carcinoma; Deoxycytidine kinase; Cancerology; Sensitivity resistance; Antimetabolic; Bronchus disease; Nucleoside; Fluorine Organic compounds; Pyrimidine nucleoside
• ISSN: 1347-9032; 1349-7006
• DOI: 10.1111/j.1349-7006.2004.tb03257.x

Gemcitabine is one of the most commonly used agents for lung cancer chemotherapy, but the determinants of sensitivity and/or resistance to this agent are not yet fully understood. In this study we used quantitative RT‐PCR to examine the expression levels of human equilibrative nucleoside transporter 1 (hENT1) and deoxycytidine kinase (dCK) genes in non‐small cell lung cancer (NSCLC) cell lines in relation to sensitivity and resistance to gemcitabine. The basal expression levels of hENT1 were significantly correlated with the IC50 values for gemcitabine (r=‐0.6769, P=0.0005), whereas dCK expression levels were not. In a highly gemcitabine‐sensitive cell line, NCI‐H23, the sensitivity to gemcitabine was inhibited by nitrobenzylmercaptopurine ribonucleoside (NBMPR), an inhibitor of hENT1, without significant modulation of hENT1 expression. These data suggest that hENT1 is associated with gemcitabine sensitivity in lung cancer. We also continuously exposed NCI‐H23 cells to gemcitabine and subsequently established the drug‐resistant clone H23/GEM‐R, which showed a significant decrease of dCK expression; however, hENT1 expression was not altered in the continuously exposed sublines or in the resistant clone. We conclude that increased hENT1 expression is a determinant of gemcitabine sensitivity, while decreased dCK expression is associated with acquired resistance to gemcitabine in NSCLC cells. Thus, hENT1 and dCK might be useful as predictive markers for efficacy of gemcitabine therapy in NSCLC.