Xenobiotic/drug metabolizing enzyme and TP53 polymorphisms and clinical outcome in advanced nonsmall cell lung cancer patients.

BACKGROUND/AIM: The association between polymorphisms of xenobiotic/drug metabolizing enzymes and TP53 and response to chemotherapy and survival of patients with nonsmall cell lung cancer (NSCLC) are limited and inconclusive. In this study, CYP2E1*5B, CYP2E1*6, CYP2E1*7B, GSTO1 (A140D), and TP53 (Arg72Pro) polymorphisms and response to platinum-based chemotherapy and survival in 137 advanced stage NSCLC patients were investigated. MATERIALS AND METHODS: Genetic polymorphism analyses were determined by polymerase chain reaction (PCR) coupled with restriction fragment length polymorphism (RFLP). RESULTS: The patients with TP53 Pro/Pro variant were more likely to be resistant to chemotherapy than those with Arg/Arg variants with marginal significance (P = 0.066). We also analyzed these gene variants in combination with CYP1A1 (Ile462Val), CYP1B1 (Asn453Ser), GSTM1, GSTP1 exon 5 (Ile105Val), and GSTP1 exon 6 (Ala114Val) and GSTT1 polymorphic genes that we have previously genotyped in the same patients (Ada et al., Neoplasma, 57, 512-527, 2010). The multivariate analysis revealed that adjusted hazard ratio (HR) of death of the combined variant genotypes of TP53 (Arg72Pro, Pro72Pro) and CYP1A1 (Ile462Val, Val462Val) increased significantly as compared to wild-type genotypes (HR, 6.03; 95% CI, 1.39-26.04, P = 0.016). CONCLUSION: These results show that combined variant genotypes of TP53 (Arg72Pro, Pro72Pro) and CYP1A1 (Ile/Val, Val/Val) are associated with worsening of survival in NSCLC patients.

Association between the TP53 and CYP2E1*5B gene polymorphisms and non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is the most common form of lung cancer. Genetic polymorphisms in tumour suppressor genes and genes encoding xenobiotic metabolising enzymes alter the activity of their corresponding enzymes and are important individual susceptibility factors for NSCLC. Because of the lack of information in literature, the aim of our study was to investigate the role of the tumour suppressor gene TP53 (Arg72Pro) and the xenobiotic metabolising CYP2E1*5B gene polymorphisms on the risk of NSCLC development. The study population consisted of 172 patients and 172 controls (156 men and 16 women in each group). Genetic polymorphisms were determined with real-time polymerase chain reaction (PCR) and PCR restriction fragment length polymorphism (PCR-RFLP). Multivariate analysis showed a significant association with NSCLC for the combination between the TP53 codon72 Arg/Pro and the Pro/Pro genotypes (OR 2.21, 95 % CI 1.390-3.51; p=0.001). We also analysed whether combinations of these gene variants with GSTM1, GSTT1, GSTP1 exon 5 (Ile105Val), and GSTP1 exon 6 (Ala114Val) gene polymorphisms were associated with the NSCLC risk. A significant increase in the risk was observed for the following combinations: TP53 codon72 variant with GSTM1 null (OR 2.22, 95 % CI 1.23-4.04; p=0.009), GSTT1 null (OR 2.98, 95 % CI 1.49-5.94; p=0.002), and GSTP1 (Ala114Val) variant genotypes (OR 3.38, 95 % CI 1.54-7.41; p=0.002). Further studies with larger samples are needed to verify these findings.

The Effect of Etoricoxib on Hepatic Ischemia-Reperfusion Injury in Rats.

UNLABELLED: Ischemia-reperfusion (I/R) damage is known to be a pathological process which continues with the increase of oxidants and expands with the inflammatory response. There is not any study about protective effect of etoricoxib on the liver I/R damage in literature. OBJECTIVE: This study investigates the effect of etoricoxib on oxidative stress induced by I/R of the rat liver. MATERIAL AND METHODS: Experimental animals were divided into four groups as liver I/R control (LIRC), 50 mg/kg etoricoxib + liver I/R (ETO-50), 100 mg/kg etoricoxib + liver I/R (ETO-100), and healthy group (HG). ETO-50 and ETO-100 groups were administered etoricoxib, while LIRC and HG groups were orally given distilled water by gavage. Hepatic artery was clamped for one hour to provide ischemia, and then reperfusion was provided for 6 hours. Oxidant, antioxidant, and COX-2 gene expressions were studied in the liver tissues. ALT and AST were measured. RESULTS: Etoricoxib in 50 and 100 mg/kg doses changed the levels of oxidant/antioxidant parameters such as MDA, MPO, tGSH, GSHRd, GST, SOD, NO, and 8-OH/Gua in favour of antioxidants. Furthermore, etoricoxib prevented increase of COX-2 gene expression and ALT and AST levels. This important protective effect of etoricoxib on the rat liver I/R can be tested in the clinical setting.

Does bosentan protect diabetic brain alterations in rats? The role of endothelin-1 in the diabetic brain.

Diabetes mellitus (DM) is a major problem all over the world, affecting more people in recent years. Individuals with diabetes are more prone to disease than non-diabetics, especially vascular complications. The aim of this study was to examine the roles of the endothelin (ET)-1 in brain damage formed in a streptozocin (STZ)-induced diabetes model, and the effect of bosentan, which is the non-specific ET1 receptor blocker in the prevention of the diabetes-induced brain damage. To examine the effects of bosentan (50 mg/kg and 100 mg/kg) in this study, the rats were given the drug for 3 months. The rats were divided into four groups: the sham group (n = 10), the diabetic control group (n = 10), the group of diabetic rats given bosentan 50 mg/kg (n = 10) and the group of diabetic rats given bosentan 100 mg/kg (n = 10). Diabetes was induced in the rats by STZ (60 mg/kg i.p.). On day 91, all rats were killed. Brain tissues of the rats were measured by molecular, biochemical and histopathological methods. Antioxidant levels in the therapy groups were observed as quite near to the values in the healthy group. In this study, while the brain eNOS levels in the diabetic groups decreased, the ET1 and iNOS levels were found to be increased. However, in the diabetes group, hippocampus and cerebellum, pericellular oedema and a number of neuronal cytoretraction were increased in neuropiles, whereas these results were decreased in the therapy group. Based on all of these results, ET1 will not be ignored in diabetes-induced cerebral complications.

High serum HTATIP2/TIP30 level in serous ovarian cancer as prognostic or diagnostic marker.

BACKGROUND: Human HIV-1 TAT interactive protein 2 (HTATIP2/TIP30) is an evolutionarily conserved gene that is expressed ubiquitously in human tissues and some tumor tissues. This protein has been found to be associated with some gynecological cancers; as such, this study aimed to investigate blood HTATIP2/TIP30 levels in patients with ovarian cancer. METHODS: Twenty-three women with ovarian cancer and 18 patients with various non-cancerous gynecological complaints (for example, dysfunctional uterine bleeding, fibroids, and urinary incontinence) were included in the study. The pathological diagnosis of ovarian cancer was adenocarcinoma. HTATIP2/TIP30 concentration in the patients' blood samples was determined using ELISA kits. RESULTS: The HTATIP2/TIP30 level was significantly higher in the cancer group than in the control group (1.84 ± 0.82 versus 0.57 ± 0.13 ng/ml, mean ± SD). CONCLUSIONS: We demonstrated the potential role of HTATIP2/TIP30 in ovarian cancer for the first time, thereby enlightening future studies targeting HTATIP2/TIP30 in ovarian cancer treatment, diagnosis, and prevention.