Thymidylate synthase and dihydropyrimidine dehydrogenase expression levels are associated with response to S-1 plus carboplatin in advanced non-small cell lung cancer.

S-1 is an oral fluoropyrimidine derivative that is active against non-small cell lung cancer (NSCLC). Development of S-1 combination chemotherapy for advanced NSCLC is under way. Given the importance of designing therapeutic strategies based on specific tumor biology, we have evaluated the relation between immunohistochemical expression levels of thymidylate synthase (TS), orotate phosphoribosyltransferase (OPRT), or dihydropyrimidine dehydrogenase (DPD) and the response to treatment with S-1 plus carboplatin in patients with advanced NSCLC. Chemotherapy-naïve patients with advanced (stage IIIB or IV) NSCLC, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate organ function, and archival tumor tissue were assigned to receive S-1-carboplatin (n=22). The predictive or prognostic relevance of the molecular markers was also examined by their evaluation in patients treated with paclitaxel plus carboplatin (n=25). Expression levels of TS, OPRT, or DPD in tumor specimens did not differ significantly between patients treated with S-1-carboplatin and those treated with paclitaxel-carboplatin. A low expression level of TS or of DPD was associated with a better response and longer survival in patients treated with S-1-carboplatin but not in those treated with paclitaxel-carboplatin. Tumor expression levels of TS and DPD are predictive of response to S-1-carboplatin chemotherapy in patients with advanced NSCLC.

Identification of an estrogenic hormone receptor in Caenorhabditis elegans.

Changes in both behavior and gene expression occur in Caenorhabditis elegans following exposure to sex hormones such as estrogen and progesterone, and to bisphenol A (BPA), an estrogenic endocrine-disrupting compound. However, only one steroid hormone receptor has been identified. Of the 284 known nuclear hormone receptors (NHRs) in C. elegans, we selected nhr-14, nhr-69, and nhr-121 for analysis as potential estrogenic hormone receptors, because they share sequence similarity with the human estrogen receptor. First, the genes were cloned and expressed in Escherichia coli, and then the affinity of each protein for estrogen was determined using a surface plasmon resonance (SPR) biosensor. All three NHRs bound estrogen in a dose-dependent fashion. To evaluate the specificity of the binding, we performed a solution competition assay using an SPR biosensor. According to our results, only NHR-14 was able to interact with estrogen. Therefore, we next examined whether nhr-14 regulates estrogen signaling in vivo. To investigate whether these interactions actually control the response of C. elegans to hormones, we investigated the expression of vitellogenin, an estrogen responsive gene, in an nhr-14 mutant. Semi-quantitative RT-PCR showed that vitellogenin expression was significantly reduced in the mutant. This suggests that NHR-14 is a C. elegans estrogenic hormone receptor and that it controls gene expression in response to estrogen.