Tamoxifen resistance alters sensitivity to 5-fluorouracil in a subset of estrogen receptor-positive breast cancer.

Sequential treatment with endocrine or chemotherapy is generally used in the treatment of estrogen receptor (ER)-positive recurrent breast cancer. To date, few studies have investigated the effect of long-term endocrine therapy on the response to subsequent chemotherapy in ER-positive breast cancer. We examined whether a preceding endocrine therapy affects the sensitivity to subsequent chemotherapy in ER-positive breast cancer cells. Three ER-positive breast cancer cell lines (T47D, MCF7, BT474) and tamoxifen-resistant sublines (T47D/T, MCF7/T, BT474/T) were analyzed for sensitivity to 5-fluorouracil, paclitaxel, and doxorubicin. The mRNA levels of factors related to drug sensitivity were analyzed by RT-PCR. MCF7/T cells became more sensitive to 5-fluorouracil than wild-type (wt)-MCF7 cells. In addition, the apoptosis induced by 5-fluorouracil was significantly increased in MCF7/T cells. However, no difference in sensitivity to chemotherapeutic agents was observed in T47D/T and BT474/T cells compared with their wt cells. Dihydropyrimidine dehydrogenase (DPYD) mRNA expression was significantly decreased in MCF7/T cells compared with wt-MCF7 cells. The expression of DPYD mRNA was restored with 5-azacytidine treatment in MCF7/T cells. In addition, DPYD 3'-UTR luciferase activity was significantly reduced in MCF7/T cells. These data indicated that the expression of DPYD mRNA was repressed by methylation of the DPYD promoter region and post-transcriptional regulation by miRNA in MCF7/T cells. In the mouse xenograft model, capecitabine significantly reduced the tumor volume in MCF7/T compared with MCF7. The results of this study indicate that endocrine therapy could alter the sensitivity to chemotherapeutic agents in a subset of breast cancers, and 5-fluorouracil may be effective in tamoxifen-resistant breast cancers

Beyond epidemiology: field studies and the physiology laboratory as the whole world

There is no exercise training regimen broadly available in the field to increase physical fitness and prevent lifestyle-related diseases in middle-aged and older people. We have developed interval walking training (IWT) repeating five or more sets of 3 min fast walking at ≥70% peak aerobic capacity for walking (w) per day with intervening 3 min slow walking at 40% w, for ≥4 days week−1, for ≥5 months. Moreover, to determine w in individuals and also to measure their energy expenditure even while incline walking, we have developed a portable calorimeter. Further, to instruct subjects on IWT even if they live remotely from the trainers, we have developed e-Health Promotion System. This transfers individual energy expenditure during IWT stored on the meter to a central server through the internet; it sends back the achievement to individuals along with advice generated automatically by the sever according to a database on ≥4000 subjects. Where we found that 5 months of IWT increased physical fitness and improved the indices of lifestyle-related diseases by 10–20% on average. Since our system is run at low cost with fewer staff for more subjects, it enables us to develop exercise prescriptions appropriate for individuals