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 gemcitabinesensitive 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. (Cancer Sci 2004; 95: 753-757) ung cancer is one of the most common malignancies worldwide 1) and remains the leading cause of cancer-related deaths in Western countries.2) Several randomized clinical trials and meta-analyses have demonstrated that survival in patients with advanced stage III or IV non-small cell lung cancer (NSCLC) can be slightly but significantly prolonged with chemotherapy.3, 4) Several new anticancer agents have recently been shown to have encouraging activity against NSCLC, and a recent randomized study provided data supportive of the efficacy and safety of a regimen including gemcitabine. 5)

We examined the expression levels of the multidrug resistance protein 5 (ABCC5) gene in non -small cell lung cancer (NSCLC) cell lines to clarify the relationship with the sensitivity to gemcitabine. The expression levels of ABCC5 were inversely correlated with gemcitabine sensitivity significantly (r = 0.628; P < 0.01) in 17 NSCLC cells, whereas the expression of ABCC5 in the gemcitabine-resistant NSCLC cell line H23/GEM-R was the same as that in parental NCI-H23 cells. Treatment with the ABCC5 inhibitor zaprinast altered the sensitivity to gemcitabine in ABCC5-expressing NSCLC cells. In addition, decreasing the expression of ABCC5 by small interfering RNA altered the cytotoxicity to gemcitabine. These results indicate that modulation of ABCC5 activity could be used to increase the gemcitabine sensitivity in NSCLC. Previously, we found a decreased expression of deoxycytidine kinase in H23/GEM-R cells, and further investigation in this study showed an increased expression of ribonucleotide reductase subunit 1 in H23/GEM-R cells. We therefore also examined the effect of modifying the expression of both genes on gemcitabine resistance. We found that using small interfering RNA to decrease the expression of ribonucleotide reductase subunit 1 resulted in a decreased resistance to gemcitabine in H23/GEM-R cells. Furthermore, pretreatment with pemetrexed resulted in an increased deoxycytidine kinase expression concomitant with the alteration of the resistance to gemcitabine in H23/GEM-R cells. The determinants for sensitivity and the acquired resistance in gemcitabine are quite different; nonetheless, modification of these factors may increase the efficacy of gemcitabine in the treatment of NSCLC.

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Serum lysozyme is used as a marker of sarcoidosis disease activity. In this study we examined the association between lysozyme levels and the clinical features of sarcoidosis and thus the clinical usability of this parameter in a large population. One hundred ten sarcoidosis patients from central Japan were examined for clinical features and serum lysozyme level at the first visit to our hospital and on a regular basis thereafter. The sensitivity of lysozyme for predicting sarcoidosis was 79.1%, whereas that of serum angiotensin-converting enzyme (ACE) was 59.0%. Even in the cases without an elevated serum ACE level, a value of 72.1% was obtained. The serum lysozyme level demonstrated a significant tendency to increase with the number of organs involved (p < 0.01). There were significant differences among the four radiographic stages (p < 0. 05). The maximum serum lysozyme levels of patients without a disappearance of abnormal shadows on chest radiography within 5 years were significantly greater than those of individuals with a disappearance (p < 0.05). A positive correlation between serum lysozyme and serum ACE levels was observed. Because serum lysozyme is much less specific for sarcoidosis than serum ACE, its diagnostic value may be limited. However, the sensitivity was high even when serum ACE levels were within normal limits and correlated well with clinical features in sarcoidosis. Therefore, this parameter seems suitable for disease monitoring in proven cases.