hOGG1 Ser326Cys polymorphism and breast cancer risk among Asian women

To evaluate the potential association between breast cancer risk and Ser ³²⁶ Cys polymorphism of hOGG1 gene, encoding for an enzyme involved in the base excision repair of 8-hydroxyguanine, hospital based case-control studies were conducted in two Asian populations consisting of 475 breast cancer cases (271 Korean and 204 Japanese) and 500 controls (314 Korean and 186 Japanese). PCR-based methods were employed for the genotyping analyses and the statistical evaluations were performed by unconditional logistic regression model. The frequency of hOGG1 Ser/Ser, Ser/Cys, and Cys/Cys genotypes were 22.5, 48.7, and 28.8% in all cases, and 23.7, 52.1, and 24.1% in the controls. No statistically significant associations between the genotypes and breast cancer risk were observed, neither when the ethnic groups were examined separately nor when the total study population was included. Neither did stratification by menopausal status reveal any association between hOGG1 genotypes and breast cancer. Our novel findings therefore suggest that hOGG1 Ser ³²⁶ Cys polymorphism is unlikely to play a modifying role in individual susceptibility to breast cancer among Asian women.     

Immunohistochemical expression of integrins and extracellular matrix proteins in non-small cell lung cancer: correlation with lymph node metastasis

PURPOSE: For patients with non-small cell lung cancer (NSCLC), the biggest threat to survival is metastasis. During metastatic cascade, tumor cells interact with extracellular matrix (ECM) through certain adhesion molecules such as integrins. The aim of this study was to analyze the distribution of the main integrins and ECM in a series of patients with NSCLC to assess their distribution and correlate with lymph node (LN) metastasis of NSCLC. METHODS: Formalin-fixed and paraffin-embedded tissues of NSCLC with (n=45) or without (n=23) regional LN metastasis were obtained form 68 surgically treated patients. The expression of fibronectin, collagen type IV, tenascin and the integrin subunits (alpha2, alpha3, alpha4, alpha5 and beta1) was studied by immunohistochemistry. Chi-square and Fisher's exact tests were used to compare groups and parameters. RESULTS: Extensive (>50% of section area) fibronectin and collagen type IV staining were seen in 22 and 55% of tumors, respectively, with focal areas of immunoreactivity seen in another 75 and 38% of tumors, respectively. Tenascin staining showed just focal areas of immunoreactivity in 21% of tumors. Interstitial collagen matrices were more frequently lost in LN metastasis (P=0.007). Integrins alpha2, alpha5 and beta1 expressions were present in 9, 12 and 26% of tumors, respectively. The expression of integrins alpha5 and beta1 was significantly associated with LN metastasis (P=0.04 and 0.005, respectively). CONCLUSIONS: Increased expression of integrins alpha5 and beta1, and lost expression of collagen matrices significantly correlated with LN metastasis of NSCLC. These findings suggested that enhanced expression of integrins and disrupted collagen stroma in NSCLC might promote tumor cell survival and invasiveness.     

Estrogens in female thyroid cancer: alteration of urinary profiles in pre- and post-operative cases

To evaluate the potential effect of estrogens in premenopausal female thyroid cancer, the concentrations of 14 estrogens were quantitatively determined in the urine of pre- and post-operative patients with thyroid papillary cancer (18 patients case, 26 approximately 54 years) and normal female subjects (20 cases, 31 approximately 52 years). The highly sensitive gas chromatography-mass spectrometry-selected ion-monitoring method was used for estrogens analysis. And an estrogen-oxidative metabolism and 16alpha-hydroxyestrone to 2-hydroxyestrone (16alpha-OH E1/2-OH E1) which is the two primary and competing site of estrogen-oxidation, were determined. Catechol estrogens, including 2-OH E1, were also increased without significant changes of the other estrogen metabolites in pre-operative patients with thyroid papillary cancer compared with normal subjects. The lowest mean value of 16alpha-OH E1/2-OH E1 was remarked in pre-operative patients, and it was significantly different from the ratio of post-operative cases. As a result, it is suggested that the increase of 2-hydroxylation in estrogen metabolism may have a significant association with female thyroid cancer.     

Apoptosis and modulation of cell cycle control by synthetic derivatives of ursodeoxycholic acid and chenodeoxycholic acid in human prostate cancer cells

The effects of synthetic derivatives of ursodeoxycholic acid (UDCA), HS-1183, and chenodeoxycholic acid (CDCA), HS-1199 and HS-1200, on the proliferation of human prostate carcinoma PC-3 cells were investigated. Whereas CDCA and UDCA had no effects on the growth of cells in a concentration range we have tested, HS-1199 and HS-1200 completely inhibited the cell proliferation, and HS-1183 showed a weak inhibitory activity. This proliferation-inhibitory effect of the synthetic bile acid derivatives was due to the induction of apoptosis, which was confirmed by observing DNA fragmentation, chromatin condensation and cleavage of PARP. Flow cytometric analysis also revealed that the synthetic bile acid derivatives arrested the cell cycle progression at the G1 phase, which effects were associated with inhibition of phosphorylation of pRB and enhanced binding of pRB and E2F-1. They also suppressed Cdk2 and cyclin E-dependent kinase activities without changes of their expressions. Furthermore, the synthetic bile acids increased the levels of Cdk inhibitor, p21WAF1/CIP1, expression and activated the reporter construct of p21WAF1/CIP1 promoter in p53-independent manner, and p21WAF1/CIP1 proteins induced by the synthetic bile acid derivatives were associated with Cdk2 and proliferating cell nuclear antigen. These distinctive features suggest that it is possible to create the new drugs useful for cancer therapy from the synthetic bile acid derivatives as lead compounds.     

Immunohistochemical localization of cyclooxygenase-2 in pregnant rat uterus by Sp-6 acupuncture

As pregnancy advances, prostaglandins (PG) increase in the uterus, leading to elevated uterine contractility. Therefore, regulating the concentration of PG in the uterus can be a key factor for controlling the duration of labor. Since the synthesis of PGs in the uterus is catalyzed by cyclooxygenase-2 (COX-2), devising a tool to regulate the expression of COX-2 could provide a method for treating complicated labor. In this study, Sp-6 acupuncture treatment was evaluated for its potential in controlling uterine motility. Immunohistochemical methods showed the COX-2 enzyme was primarily found in the endometrium and myometrium of rat uterus. COX-2 expression in these two locations were intensified by pregnancy, but reduced by acupuncture at the Sp-6 acupoint. Uterine motility monitored during Sp-6 acupuncture was reduced by 28.15% (p < 0.05) and 19.88% (p < 0.05) in pregnant rats and non-pregnant rats, respectively. The significant reduction of uterine motility in pregnant rat suggests a role for Sp-6 acupuncture in regulating the expression of COX-2 during pregnancy. These results suggest that Sp-6 acupuncture could be used as a complementary method for controlling labor in human pregnancy.     

Involvement of DNA-dependent protein kinase in regulation of the mitochondrial heat shock proteins

Since DNA-dependent protein kinase (DNA-PK) has been known to play a protective role against drug-induced apoptosis, the role of DNA-PK in the regulation of mitochondrial heat shock proteins by anticancer drugs was examined. The levels of basal and drug-induced mitochondrial heat shock proteins of drug-sensitive parental cells were higher than those of multidrug-resistant (MDR) cells. We also demonstrated that the development of MDR might be correlated with the increased expression of Ku-subunit of DNA-PK and concurrent down-regulation of mitochondrial heat shock proteins. The basal mtHsp70 and Hsp60 levels of Ku70(-/-) cells, which were known to be sensitive to anticancer drugs, were higher than those of parental MEF cells, but conversely these mitochondrial heat shock proteins of R7080-6 cells over-expressing both Ku70 and Ku80 were lower than those of parental Rat-1 cells. Also, the mtHsp70 and Hsp60 levels of DNA-PKcs-deficient SCID cells were higher than those of parental CB-17 cells. Our results suggest the possibility that mitochondrial heat shock protein may be one of determinants of drug sensitivity and could be regulated by DNA-PK activity.     

Doxorubicin-based chemotherapy for diffuse large B-cell lymphoma in elderly patients: comparison of treatment outcomes between young and elderly patients and the significance of doxorubicin dosage

BACKGROUND: Although many studies of elderly patients with non-Hodgkin lymphoma have focused on the dose intensity of chemotherapy, few studies have restricted the histologic inclusion criteria such that only patients with diffuse large B-cell lymphoma (DLCL) are considered. In the current study, treatment outcomes for elderly patients (age > or = 60 years) were analyzed, with emphasis on the dose intensity of doxorubicin. METHODS: Between 1994 and 2000, 195 patients with DLCL were treated initially with doxorubicin-based chemotherapy (cyclophosphamide, doxorubicin, vincristine, and prednisone; or cyclophosphamide, vincristine, bleomycin, doxorubicin, procarbazine, and prednisone). Of these patients, 70 were aged 60 years or older. RESULTS: Elderly patients had poorer treatment outcomes than did young patients (5-year survival, 30% vs. 57%; P < 0.001); however, elderly patients who received doxorubicin at dose intensities > or = 10 mg/m2 per week (n = 25) had outcomes (5-year survival, 52%) that were comparable to those of young patients. Among prognostic factors, only International Prognostic Index score (P = 0.022) and dose intensity of doxorubicin (P = 0.039) were found to have significant effects on the overall survival of elderly patients. When the reasons for doxorubicin dose reduction in 45 elderly patients who ultimately received doxorubicin at dose intensities < 10 mg/m2 per week were analyzed, it was found that 20 patients received reduced doses from the start of treatment because of their old age alone; these dose reductions in the 20 cases resulted in poorer treatment outcomes. CONCLUSIONS: Elderly patients with DLCL who received doxorubicin at dose intensities > or = 10 mg/m2 per week had treatment outcomes that were comparable to those of young patients; however, physician bias associated with patient age was found to be related to unnecessary dose reductions. Efforts to maintain doxorubicin dose intensities > or = 10 mg/m2 per week and more objective standards for the selection of elderly patients capable of tolerating doxorubicin-based regimens are required.     

BRAF and KRAS mutations in stomach cancer

Ras proteins control signaling pathways that are key regulators of several aspects of normal cell growth and malignant transformation. BRAF, which encodes a RAF family member in the downstream pathway of RAS, is somatically mutated in a number of human cancers. The activating mutation of BRAF is known to play a role in tumor development. As there have been no data on the BRAF mutation in stomach cancer, we analysed the genomic DNAs from 319 stomach carcinomas for the detection of somatic mutations of BRAF. Overall, we detected BRAF mutations in seven stomach carcinomas (2.2%). Five of the seven BRAF mutations involved Val 599, the previously identified hotspot, but the substituted amino acid (V599 M) was different from the most common BRAF mutation (V599E). The remaining two mutations involved a conserved amino acid (D593G). One tumor had both BRAF and KRAS mutations. This is the first report on BRAF mutation in stomach cancer, and the data indicate that BRAF is occasionally mutated in stomach cancer, and suggest that alterations of RAS pathway both by RAS and BRAF mutations contribute to the pathogenesis of stomach cancer.