Szu-Hsien Wu

Side effects after docetaxel treatment in Taiwanese breast cancer patients with CYP3A4, CYP3A5, and ABCB1 gene polymorphisms

BACKGROUND Breast cancer patients initiating TEC (including docetaxel, epirubicin, and cyclophosphamide) treatment were genotyped for CYP3A4, CYP3A5, and ABCB1 to identify variability factors of side effects for docetaxel. METHODS The planned dose of docetaxel per course was formulated according to each patients height and weight. Each participant had received TEC treatment for 6 consecutive cycles. The single nucleotide polymorphisms (SNPs) of CYP3A4*4 (352A > G), CYP3A4*5 (653C > G), and CYP3A4*18A (20070T > C) for the CYP3A4 gene, CYP3A5*3A (6986A > G) for the CYP3A5 gene, and -41A > G, -145C > G, 1236C > T, 2677G > T(A), and 3435C > T SNPs for the ABCB1 gene were determined by using the restriction fragment length polymorphism of polymerase chain reaction products and the restriction enzymes. RESULTS Fifty-nine Taiwanese women (mean age, 46 y; range, 30-64 y) treated for breast cancer with TEC were recruited. We found that patients carrying the CYP3A5*1/*3 genotype demonstrated more side effects of fever, pleural effusion, and febrile neutropenia than those with the CYP3A5*3/*3 genotype (p = 0.075, 0.077, and 0.030, respectively); moreover, patients with the ABCB1 2677G/G genotype also showed more side effects of fever and febrile neutropenia than those with other genotypes (p = 0.024 and 0.027), In regard to ABCB1 3435C>T, patients with ABCB1 3435C/C tended to suffer leucopenia (p = 0.057). CONCLUSIONS There could be correlations between certain side effects of docetaxel treatment and polymorphisms of these metabolic enzymes. Unfortunately, there is not so much evidence due to the small sample size of this study which restricts the statistical power.

Evaluation of redox statuses in patients with hepatitis B virus-associated hepatocellular carcinoma.

Background Excess reactive oxygen species related to neoplasia of liver has been established. Essentially, the human body has developed different antioxidant systems for defence against these attacks. To evaluate the redox status in hepatocellular carcinoma (HCC) induced by hepatitis B virus (HBV), the most important aetiological factor in Taiwan, changes in O2 . generation, lipid peroxidation as well as antioxidant status in the blood of HCC patients with HBV carriers for more than 20 years were measured. Methods Superoxide anion radical (O2 .−) generation and the levels of malondialdehyde (MDA) served as an index of lipid peroxidation along with the analyses of activities of superoxide dismutase (SOD), glutathione peroxidase (GPx) and glutathione reductase (GRx); also, glutathione status, including reduced glutathione (GSH) and oxidized glutathione (GSSG), and the levels of vitamins A, C and E were determined. Results In 54 patients, the levels of O2 .−, MDA and GSSG, and the activities of SOD and GRx of blood were significantly higher than those of 57 controls. Conversely, the levels of GSH and total GSH, and GSH/GSSG ratio, and vitamins A and C were significantly decreased. Additionally, there were no significant changes in the activity of GPx and the levels of vitamin E. Conclusions Our data suggest that the redox statuses in patients with HBV-associated HCC were elevated or decreased in certain parameters. However, the increased activities of antioxidant enzymes may be a compensatory up-regulation and the decrease antioxidant statuses were responses to the enhanced oxidative stress in those patients.

Oxidative stress-related enzyme gene polymorphisms and susceptibility to breast cancer in non-smoking, non-alcohol-consuming Taiwanese women: a case-control study

Background Mitochondrial manganese superoxide dismutase (MnSOD) converts superoxide anion into H2O2, which is neutralized sequentially by either catalase (CAT) or glutathione peroxidase 1 (Gpx 1) into water or converted into highly reactive hypochlorous acid by myeloperoxidase (MPO). We hypothesize that gene variants for these enzymes might be associated with the risk of breast cancer in non-smoking, non-alcohol-consuming women. Methods Genotypes of oxidative stress-related enzymes (MnSOD1183T>C, MPO-463G>A, GPx1Pro198Leu and CAT-262C>T) were analysed in 260 non-smoking and non-alcohol-consuming female patients with breast cancer and 224 habit-matched controls. Results Subjects with the MnSOD1183T>C C carrier or those with the GPx1Pro198Leu CT genotype had significantly decreased age-adjusted risks (odds ratio [OR]: 0.56 and 0.16 with 95% confidence intervals [95% CI]: 0.38–0.83 and 0.08–0.29, respectively) for breast cancer. Certain combined genotypes of the polymorphisms also significantly modulated the age-adjusted risk. Conclusions We conclude that oxidative stress-related enzyme genetic variants, especially GPx1Pro198Leu CT, modify the risk of breast cancer development in non-smoking and non-alcohol-consuming women. The role of unidentified environmental factors predisposing to breast cancer development through an oxidative stress mechanism merits further investigation.

Association between the apolipoprotein E genotypes and breast cancer patients in Taiwanese.

SummaryTo display the association between the apolipoprotein E (APOE) genotypes and breast cancer patients, a cross sectional study including 291 patients and 148 controls was performed. The APOE genotypes were measured in all participants, and the pathological diagnosis, estrogen receptor, progesterone receptor and human epidermal growth factor receptor 2 (HER-2) among breast cancer patients were collected. The results showed the APOE allele frequency in breast cancer patients was 11.7% ɛ2 carriers, 74.6% ɛ3 carriers and 13.7% ɛ4 carriers, and there was no significant difference when they were compared with those of the control group (15.5% ɛ2 carriers, 74.3% ɛ3 carriers and 10.1% ɛ4 carriers; p=0.342). Among the patients in pre-menopause, showed a higher frequency of ɛ2 carriers had the cancer site on the left than that of the ɛ3 carriers (78.6% versus 40.3%; p=0.019). Among breast cancer patients, there was no significant association between the APOE genotypes and menopausal status, pathological diagnosis, estrogen receptor, progesterone receptor, and HER-2. Our findings demonstrated that the APOE genotypes were not associated with breast cancer patients, and ɛ2 allele tended to induce breast cancer on the left site among those patients in pre-menopause.

Epistasis of oxidative stress-related enzyme genes on modulating the risks in oral cavity cancer.

BACKGROUND The aim of this study was to evaluate the risks of the polymorphisms of oxidant stress-related enzymes on patients with oral cavity cancer by genotyping of manganese superoxide dismutase (MnSOD [1183T>C]), myeloperoxidase (MPO [-463G>A]), catalase (CAT [-15A>T]) and glutathione peroxidases 1 (GPx1 [Pro198Leu]). METHODS A case-control study was conducted on 122 biopsy-proven oral cavity cancer patients with, at least, one of the past habits of cigarette smoking, alcohol drinking or betel-quid chewing, and 122 approximately age- and habit-matched controls. RESULTS The independent risks of the polymorphisms for each enzyme on carcinogenicity were non-significant. The 2-order gene-gene interactions of the polymorphisms, assessed by using a logistic regression model, on risk did not show significant changes, neither. However, the epistasis, assessed by multifactor dimensionality reduction (MDR) for three-order (CAT, MnSOD, and MPO) and four-order was significant. Additionally, the fact that the levels of O(2)(-), GSSG and total GSH in the patients were significantly different according to certain genotypes which revealed that the polymorphisms of these enzymes could affect these parameters to some extent. CONCLUSIONS The results suggested that the genetic-effects of the polymorphisms of these enzymes could slightly modify the risk in oral cavity cancer development individually, but significantly when they functioned together.

Whey Protein Concentrate Renders MDA-MB-231 Cells Sensitive to Rapamycin by Altering Cellular Redox State and Activating GSK3β/mTOR Signaling

Whey protein concentrate (WPC) is an amino acid-rich supplement that has been shown to increase cellular antioxidant capacity. Mammalian target of rapamycin (mTOR) is a crucial regulator of signaling in mammalian cells, and serves as a therapeutic target for triple-negative breast cancer (TNBC). This study was designed to investigate the effect of combining WPC with rapamycin on MDA-MB-231 human breast cancer cells. These cells were found to be insensitive to rapamycin and exhibited higher glutathione (GSH) and reactive oxygen species levels than non-tumorigenic MCF-10A cells. However, for MDA-MB-231 cells, the half maximal inhibitory concentration of rapamycin was lower when this drug was administered in combination with WPC than when used alone. Furthermore, combining WPC with rapamycin depleted GSH levels and reduced Nrf2 nuclear accumulation. In addition, WPC activated GSK3β/mTOR signaling, and GSK3β appeared to be involved in the WPC-mediated Nrf2 reduction and mTOR activation. In conclusion, WPC induced rapamycin sensitivity in MDA-MB-231 cells by altering their redox state and activating GSK3β/mTOR signaling. These results not only suggest a novel therapeutic approach for breast cancer treatment, but also provide insight into the critical pathways affecting the resistance to mTOR inhibition observed in a subgroup of TNBC patients.

Increased Igf-I/Igfbp-3 Ratios in Postmenopausal Taiwanese with Breast Cancer, Irrespective of Er and Pr Statuses and Her2 Expression in a Case–Control Study

In most research, there were positive associations between the insulin‐like growth factor I (IGF‐I) status, including IGF‐I, insulin‐like growth factor binding protein‐3 (IGFBP‐3), and ratio of IGF‐I/IGFBP‐3, and risks of breast cancer (BC), which was influenced by many factors, including hormone statuses and ethnicity. Therefore, the alterations of the IGF‐I status in Taiwanese women with BC by menopausal statuses and hormone receptors were investigated.

The Immune Regulator VTCN1 Gene Polymorphisms and Its Impact on Susceptibility to Breast Cancer.

VTCN1, a T‐cell regulator, belongs to the immunoglobulin superfamily. It is more highly expressed in tumor tissues than in normal tissues, which suggests that it could serve as a tumor‐related agent. We hypothesize the gene variants for this coinhibitory molecule may be associated with the risk of breast cancer, given such gene polymorphisms could affect its related gene expression.

Multiple Extraocular Sebaceous Carcinomas of the Foot-A Case Report

Background: Sebaceous carcinoma (SC) is a rare neoplasm. The majority of SCs arise within the sebaceous glands of the eyelid. Extraocular SC is an uncommon neoplasm usually localized on the head and neck. Aim and Objectives: The purpose of this study is to report our experience in the management of patient with extra-ocular sebaceous carcinomas that were treated by surgery with combination of radiation and review the literatures in an effort to identify the outcome of treatment. Materials and Methods: From 1995 to 2005, twenty nine cases of sebaceous carcinoma treated in our hospital were collected. There was only one (3.4%) patient whose tumors arose beyond the sebaceous glands of the eyelid. Results: We report the case of multiple extraocular SCs located at the right foot dorsum and right 1st toe accompany with rectal tubular adenoma with focal intramucosal adenocarcinoma. Multiple extraocular SCs were treated by surgery with combination of radiation. He was followed up for four year without locoregional recurrence or distant metastasis. Conclusion: This report describes multiple extraoccular sebaceous carcinoma of foot. The patient did not develop lymph node and distant metastases after wide excision of the primary neoplasms with adjuvant radiotherapy. To our knowledge, this is the first report of multiple SCs arising in the foot.

Coexistence of the Increasing Oxidative Stress and the Clinical Severity of Patients with Oral Cavity Cancer

Background: Even though oxidative stress has been reported to be associated with the development of oral cavity cancer, there is little evidence to show whether patients with more clinical severity suffer from more oxidative stress. Aim and Objectives: We would like to find out the coexistence of the increasing oxidative stress and the clinical severity of patients with oral cavity cancer. Materials and Methods: We launched this study to assess changes of the oxidant statuses, including malondialdehyde (MDA), the activities of superoxide dismutase (SOD), glutathione peroxidase (GPx), and glutathione reductase (GRx) and glutathione status, including reduced glutathione (GSH) and oxidized glutathione (GSSG), in patients with oral cavity cancer at various clinical stages. Blood samples of 116 male biospy-proven and untreated patients with oral cavity cancer at various clinical stages (from stage Ⅰ to stage Ⅳ) and 122 male healthy controls were obtained. Results: The levels of GSH, GSSG, and total GSH were significantly decreased in the patients in comparison with those of the controls. Conversely, MDA levels and GSH/GSSG were significantly increased. Additionally, MDA, the activities of SOD, and GRx were significantly elevated in the patients, while the activity of GPx was reversed. There were significant changes in the aforementioned parameters in the linear contract test from stage Ⅰ to stage Ⅳ. Conclusions: This study reveals that patients with oral cavity cancer suffered from excessive oxidative stress, which was consistent with other previous studies; moreover, oxidative stress will aggravate as the disease progresses.