The contribution of keratinocytes in capecitabine-stimulated hand-foot-syndrome.

Capecitabine, as the first-line treatment for multiple tumor types, has a serious drawback of hand-foot-syndrome (HFS) that limits its clinical use. However, the pathophysiology and mechanism of capecitabine-induced HFS is rarely known. Here we built the experimental mouse model of HFS induced by capecitabine at first and it was shown that 3 of 6 mice appeared HFS in the 5th day and 5 mice occurred HFS in the 30th day. The corneous layer was reduced in capecitabine-induced HFS in vivo. Moreover, we found that capecitabine could significantly induce keratinocytes cells death in vitro through activated apoptosis pathway and decreased mitochondrial membrane potential. In conclusion, these results suggested that HFS of capecitabine may be developed from reduction of corneous layer through stimulation of intracellular mitochondrial dysfunction following activation of caspase-dependent apoptosis pathway.

Gefitinib Synergizes with Irinotecan to Suppress Hepatocellular Carcinoma via Antagonizing Rad51-Mediated DNA-Repair.

Chemotherapy is the only choice for most of the advanced hepatocellular carcinoma (HCC) patients, while few agents were available, making it an urgent need to develop new chemotherapy strategies. A phase II clinical trial suggested that the efficacy of irinotecan in HCC was limited due to dose-dependent toxicities. Here, we found that gefitinib exhibited synergistic activity in combination with SN-38, an active metabolite of irinotecan, in HCC cell lines. And the enhanced apoptosis induced by gefitinib plus SN-38 was a result from caspase pathway activation. Mechanistically, gefitinib dramatically promoted the ubiquitin-proteasome-dependent degradation of Rad51 protein, suppressed the DNA repair, gave rise to more DNA damages, and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of gefitinib combined with irinotecan was further validated in a HepG2 xenograft mice model. Taken together, our data demonstrated for the first time that the combination of irinotecan and gefitinib showed potential benefit in HCC, which suggests that Rad51 is a promising target and provides a rationale for clinical trials investigating the efficacy of the combination of topoisomerase I inhibitors and gefitinib in HCC.

All-trans retinoic acid synergizes with topotecan to suppress AML cells via promoting RARα-mediated DNA damage.

BACKGROUND: Chemotherapy is the only therapy option for the majority of AML patients, however, there are several limitations for this treatment. Our aim was to find a new chemotherapy strategy that is more effective and less toxic. METHODS: MTT assays and a xenograft mouse model were employed to evaluate the synergistic activity of all-trans retinoic acid (ATRA) combined with topotecan (TPT). Drug-induced DNA damage and apoptosis were determined by flow cytometry analysis with PI and DAPI staining, the comet assay and Western blots. Short hairpin RNA (shRNA) and a RARα plasmid were used to determine whether RARα expression influenced DNA damage and apoptosis. RESULTS: We found that ATRA exhibited synergistic activity in combination with Topotecan in AML cells, and the enhanced apoptosis induced by Topotecan plus ATRA resulted from caspase pathway activation. Mechanistically, ATRA dramatically down regulated RARα protein levels and led to more DNA damage and ultimately resulted in the synergism of these two agents. In addition, the increased antitumor efficacy of Topotecan combined with ATRA was further validated in the HL60 xenograft mouse model. CONCLUSIONS: Our data demonstrated, for the first time, that the combination of TPT and ATRA showed potential benefits in AML, providing a novel insight into clinical treatment strategies.

Menopausal symptoms in mid-life women in southern China.

OBJECTIVES: To explore the prevalence of menopausal symptoms in Chinese women aged 40-65 years living in Guangdong province in southern China, and to investigate their care-seeking behavior. DESIGN: A cross-sectional population-based study performed in Guangdong province, PR China. METHODS: A total of 9939 women were selected by multistage cluster sampling. From November 2003 to July 2004, women were interviewed in person with a prepared questionnaire about symptoms experienced in the 2 months preceding the survey. The main outcome measurements were self-reported menopausal symptoms and related factors. RESULTS: The mean age of natural menopause was 48.9 years. The prevalence and severity of menopausal symptoms were low. The three most prevalent symptoms were insomnia, joint and muscle pain, and dizziness (in 37.2%, 35.7%, and 31.5% of the sample, respectively). Hot flushes were experienced by 17.5% of women. The factors associated with the frequency of menopausal symptoms included profession, education, type of menopause and the presence of physical or emotional problems. Ever and current hormone replacement therapy usage was reported in 0.8% and 1.3% of women, respectively. Of the total study population, 28.9% had sought health care because of menopausal symptoms. CONCLUSIONS: The prevalence of menopausal symptoms in southern Chinese women is low, and this is accompanied by low usage of hormone replacement therapy.