Open AccessDeterminants of sensitivity and resistance to gemcitabine: The roles of human equilibrative nucleoside transporter 1 and deoxycytidine kinase in non‐small cell lung cancer
Author(s) -
Achiwa Hiroyuki,
Oguri Tetsuya,
Sato Shigeki,
Maeda Hiroyoshi,
Niimi Takashi,
Ueda Ryuzo
Publication year - 2004
Publication title -
cancer science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.035
H-Index - 141
eISSN - 1349-7006
pISSN - 1347-9032
DOI - 10.1111/j.1349-7006.2004.tb03257.x
Subject(s) - gemcitabine , deoxycytidine kinase , deoxycytidine , lung cancer , oncology , cancer research , medicine , nucleoside transporter , antimetabolite , nucleoside , nucleoside analogue , chemotherapy , biology , pharmacology , transporter , biochemistry , gene
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 IC 50 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.