Interaction of the Effects of Alcohol Drinking and Polymorphisms in Alcohol-Metabolizing Enzymes on the Risk of Female Breast Cancer in Japan

Background

Epidemiological studies consistently indicate that alcoholic beverages are an independent risk factor for female breast cancer. Although the mechanism underlying this effect remains unknown, the predominant hypothesis implicates mutagenesis via the ethanol metabolite acetaldehyde, whose impact on the carcinogenesis of several types of cancer has been shown in both experimental models and molecular epidemiological studies. Many of the epidemiological studies have investigated genetic polymorphisms of alcohol dehydrogenase-1B (ADH1B) His48Arg and aldehyde dehydrogenase-2 (ALDH2) Glu504Lys, because of the strong impact these polymorphisms have on exposure to and accumulation of acetaldehyde. With regard to breast cancer, however, evidence is scarce.

Methods

To clarify the impact on female breast cancer risk of the interaction of the effects of alcohol consumption and polymorphisms in the alcohol-metabolizing enzymes ADH1B and ALDH2, we conducted a case–control study of 456 newly and histologically diagnosed breast cancer cases and 912 age- and menopausal status-matched noncancer controls. Gene–gene and gene–environment interactions between individual and combined ADH1B and ALDH2 gene polymorphisms and alcohol consumption were evaluated.

Results

Despite sufficient statistical power, there was no significant impact of ADH1B and ALDH2 on the risk of breast cancer. Neither was there any significant gene–environment interactions between alcohol drinking and polymorphisms in ADH1B and ALDH2.

Conclusions

Our findings do not support the hypothesis that acetaldehyde is the main contributor to the carcinogenesis of alcohol-induced breast cancer.Key words: breast cancer, alcohol drinking, acetaldehyde, polymorphisms in alcohol-metabolizing enzyme genes, case–control study     

The growth inhibition of liver cancer cells by paclitaxel and the involvement of extracellular signal-regulated kinase and apoptosis

Paclitaxel is a chemotherapeutic drug applied for the treatment of breast and non-small cell lung cancers. However, the biological effects of paclitaxel on hepatocellular carcinoma (HCC) are undefined. We examined these points by using the human HCC cell lines, and found that paclitaxel inhibited the growth of HCC cells and blocked the cell cycle at the G2/M phase. The cell death was partially mediated by apoptosis, because caspases were weakly activated and the cell death was partially rescued by a pan-caspase inhibitor. Paclitaxel activated extracellular signal-regulated kinase (ERK), and when ERK was inhibited by a mitogen-activated ERK-regulating kinase inhibitor, the cell death and cell cycle arrest induced by paclitaxel were rescued, demonstrating that paclitaxel inhibited the cellular growth via the ERK signaling pathway. Our data are promising for the application of paclitaxel in the treatment of patients with HCC.     

Mechanisms of anti-proliferative effect of JTE-522, a selective cyclooxygenase-2 inhibitor, on human liver cancer cells

Selective cyclooxygenase-2 (COX-2) inhibitors have been demonstrated to inhibit the proliferation of a variety of cancer cells including hepatocellular carcinoma (HCC). We sought to explore the mechanisms by which JTE-522, a selective COX-2 inhibitor, suppressed the growth of human HCC cells. HCC cells (HepG2, HLF, huH1, Huh7, and PLC/PRF/5 cells) did not express COX-2 at either the mRNA or protein level. Prostaglandin E2 (PGE2) levels in medium were not significantly modulated by the JTE-522 treatment. However, MTT assays disclosed that escalating doses (100 nM to 100 microM) of JTE-522 significantly inhibited the growth of all HCC cells in a dose- and time-dependent manner. JTE-522 induced cell cycle arrest at the G1 phase, which was in part mediated by downregulation of cyclin E. Hallmarks of apoptosis, including the sub-G1 fraction by flow cytometric analysis and nuclear fragmentation by nuclear staining, were not significantly induced after the JTE-522 treatment. In addition, JTE-522 enhanced the expression of peroxisome proliferator-activated receptor (PPAR)-gamma protein in HepG2 and PLC/PRF/5 cells. Our data demonstrate that JTE-522 inhibited the growth of HCC cells in a COX-2-independent manner, and that the growth inhibition was in part mediated by the cell cycle arrest and the upregulation of PPAR-gamma protein.     

Report of two cases of advanced renal cell carcinoma and our experience at Mito Saiseikai General Hospital

A tumor thrombus in the vena cava (infrahepatic) was identified in a 70-year-old male with chronic obstructive lung disease, and right nephrectomy and thrombectomy were performed successfully. Therefore, he enjoyed good health for 6 months until he developed bone metastasis in the vertebrae and upper gastrointestinal bleeding. In another case of a 51-year-old male who presented with a mass in the posterior part of the chest; the biopsy specimen of the mass was reported to at least resemble renal-cell carcinoma. Subsequently, he underwent right nephrectomy and thoracotomy to remove the mass. He has since led an uneventful life without tumor recurrence. In our hospital from 1971 to 1980, 9 cases of renal-cell carcinoma have been experienced, including the above 2 cases. Their average age was 49.4 years, with ages ranging from 34 to 70 years. Seven patients presented with gross hematuria, and 2 patients, with flank pain. All 9 cases, all of whom underwent radical nephrectomy, were diagnosed pathologically as having renal cell carcinoma. The right side was involved in 3 cases, and the left, in 6 cases. The upper pole of the kidney was involved in 2 cases the middle in 1 case, and the lower in 5 cases. The mean 5-year survival rate was 69.2% and was closely associated with the tumor stage.     

Efficacy of methylcobalamin on lowering total homocysteine plasma concentrations in haemodialysis patients receiving high-dose folic acid supplementation.

BACKGROUND: Hyperhomocysteinaemia, which is considered to be induced by impairment of the remethylation pathway in patients with chronic renal failure (CRF), cannot be cured solely by folic acid therapy. In the present study, we investigated the additional benefit of administration of methylcobalamin, which is a co-enzyme in the remethylation pathway, on lowering total homocysteine (tHcy) plasma concentrations in haemodialysis (HD) patients receiving high-dose folic acid supplementation. METHODS: In order to assess the efficacy on lowering plasma tHcy levels (fasting concentration), 21 HD patients, were randomly assigned and provided folic acid supplementation: 15 mg/day orally (group I, n=7); methylcobalamin 500 mg intravenously after each HD, in addition to folic acid (group II, n=7); or vitamin B(6) (B(6)), 60 mg/day orally, in addition to folic acid and methylcobalamin (group III, n=7). All patients were treated for 3 weeks. A methionine-loading test was conducted before and after supplementation. The following measurements were also made before and after supplementation for each group: serum folic acid, B(6), and vitamin B(12) (B(12)) concentrations (including measurement of proportion of methylcobalamin fraction). Twelve HD patients receiving methylcobalamin alone served as the HD control group and seven healthy volunteers served as the normal control group for this study. RESULTS: In our randomized HD patients the proportions of methylcobalamin fraction (48.3+/-7.5%) and plasma vitamin B(6) concentration (2.9+/-1.1 ng/ml) were significantly lower than in the normal controls (methylcobalamin 58.7+/-2.2%, P<0.01; B(6) 20.1+/-10.8 ng/ml, P<0.01), while folic acid and vitamin B(12) were not significantly different from the normal controls. Mean percentage reduction in fasting tHcy was 17.3+/-8.4% in group I, 57.4+/-13.3% in group II, 59.9+/-5.6% in group III, and 18.7+/-7.5% in HD controls. The power of the test to detect a reduction of tHcy level was 99.6% in group II and 99.9% in group III when type I error level was set at 0.05. Groups II and III had normal results for the methionine-loading test after treatment. Treatment resulted in normalization of fasting tHcy levels (<12 ng/ml) in all 14 patients treated by the combined administration of methylcobalamin and supplementation of folic acid regardless of whether there was supplementation of vitamin B(6). CONCLUSION: The benefit of methylcobalamin administration on lowering plasma tHcy levels in HD patients was remarkable. Our study suggested that both supplementations of high-dose folic acid and methylcobalamin are required for the remethylation pathway to regain its normal activity. This method could be a therapeutic strategy to combat the risk associated with atherosclerosis and cardiovascular disease in patients with chronic renal failure.     

Double ventricular response caused by longitudinal dissociation in the his bundle.

Electrocardiograms were taken from a 36-year-old woman with normal sinus rhythm in which 4 types of QRS complexes and 2 types of fusion QRS complexes were found in configuration. To interpret this arrhythmia, we proposed 3 unique mechanisms: a) double ventricular response through the fast pathway mainly directing to the right bundle branch and the slow pathway mainly directing to the left bundle branch, b) longitudinal dissociation in the His bundle, and c) transverse conduction in the lower edge of the dissociation. Although functional longitudinal dissociation in the atrioventricular node has been reported, longitudinal dissociation in the His bundle is a rare arrhythmia.     

Precise detection of the germinomatous component of intracranial germ cell tumors of the basal ganglia and thalamus using placental alkaline phosphatase in cerebrospinal fluid

Journal of Neuro-Oncology - The disadvantages of biopsy for lesions in the basal ganglia and thalamus include a risk of various complications, difficulty in selecting the target tissue in some...