[show abstract][hide abstract] ABSTRACT: Cyclooxygenase-2 (COX-2, PTGS2) is an enzyme involved in the synthesis of prostaglandins and thromboxanes, which are regulators of biologic processes such as inflammation, cell proliferation and angiogenesis. COX-2 over-expression was reported in many (pre) malignant tissues, but data strongly vary and seem to depend on the methodology used.
Normal colorectal mucosa and paired cancerous tissue from 60 patients with colorectal cancer was investigated for the levels of COX-2 mRNA by real-time quantitative Polymerase Chain Reaction (qPCR). COX-2 levels were expressed relative to either: tissue weight or levels of the housekeeping genes beta-2 microglobulin (B2M) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH).
COX-2 mRNA levels, normalized with respect to tissue weight or mRNA levels of the housekeeping genes B2M or GAPDH, were over-expressed in 80%, 70% and 40% of the colorectal tumor tissues, as compared to the paired adjacent normal colorectal mucosa samples, respectively. Highest mRNA COX-2 ratios tumor/normal were measured when expressed per mg tissue (mean ratio 21.6). When normalized with respect to the housekeeping genes B2M or GAPDH, mean tumor/normal ratios were 16.1 and 7.5, respectively.
Expression of COX-2 mRNA levels per mg tissue is most simple in comparison to normalization with respect to the housekeeping genes B2M or GAPDH. Levels of COX-2 mRNA are found over-expressed in almost 80% of the colorectal tumors, compared to paired adjacent normal colorectal mucosa, suggesting a role of COX-2 as a potential biomarker for cancer risk, whereas inhibitors of COX-2 could be of value in chemoprevention of colon cancer.
[show abstract][hide abstract] ABSTRACT: Numerous factors influence the development of gastrointestinal (GI) cancer. The insulin-like growth factor (IGF) axis plays a role in embryonic and postnatal growth and tissue repair. Elevated levels of IGFs, low levels of IGF binding proteins (IGFBPs) and over-expression of IGF receptor (IGFR-I) were associated with several stages of cancer. Here, the prevalence of the single nucleotide polymorphisms (SNPs) rs6214 in the IGF type I (IGF-I) gene and rs6898743 in the growth hormone receptor (GHR) gene in patients with GI cancer and controls was studied.
In this Dutch case-control study, DNA isolated from blood of 1,457 GI cancer patients; 438 patients with head and neck cancer (HNC), 475 with esophageal cancer (EC) and 544 with colorectal cancer (CRC) and 1,457 matched controls, was used to determine the rs6214 and rs6898743 genotypes by polymerase chain reaction. The association between these SNPs and GI cancer, HNC, esophageal adenocarcinoma (EAC), esophageal squamous-cell carcinoma (ESCC) and proximal or distal CRC was studied. Odds ratios (ORs) with 95% confidence interval (95% CI) were calculated via unconditional logistic regression.
Overall for GI cancer, the ORs for SNPs rs6214 and rs6898743 were approximately 1.0 (p-value>0.05), using the most common genotypes GG as reference. An OR of 1.54 (95% CI, 1.05-2.27) was found for EC for genotype AA of rs6214. The ORs for EAC were 1.45 (95% CI, 1.04-2.01) and 1.71 (95% CI, 1.10-2.68), for genotypes GA and AA, respectively. Genotype GC of rs6898743 showed an OR of 0.47 (95% CI, 0.26-0.86) for ESCC.
The A allele of SNP rs6214 in the IGF-I gene was associated with EAC, and with HNC in women. The GC genotype of rs6898743 in the GHR gene was negatively associated with ESCC.
PLoS ONE 01/2014; 9(3):e90916. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: Background & aims
It remains unclear whether impaired host defenses contribute to the increased risk for infectious complications seen in patients on home parenteral nutrition (HPN). The aim of this study was to compare the innate immune function of patients on olive oil-based HPN with that of healthy controls.
Innate immune functions and (anti-)oxidant balance were studied in 20 patients on olive oil-based HPN without an active underlying immune-mediated disease (Clinoleic®, ≥6 months; >3 times/week), and 21 age- and sex-matched healthy controls.
Neutrophils of patients and controls had a similar capacity to eliminate Streptococcus pneumoniae. Also, levels of activation markers (CD66b, CD11b, CD62L) in granulocytes and monocytes, phorbol ester- and zymosan-induced neutrophil oxygen radical production were not different between patients and controls. No differences in (anti-)oxidant status were found, except for higher concentrations of oxidized glutathione and lower plasma selenium and vitamin C in patients compared to controls.
Compromised innate immune function does not seem to explain the increased risk for infectious complications in HPN patients using olive oil-based lipid emulsions.
[show abstract][hide abstract] ABSTRACT: Susceptibility to esophageal carcinoma (EC) is influenced by the interaction between genetic and environmental factors. To clarify the etiology of EC, several genome-wide association studies have identified single nucleotide polymorphisms (SNPs) in PCLE1 and RFT2 genes as esophageal squamous cell carcinoma (ESCC) susceptibility loci in Asian populations. This study aimed to determine whether these SNPs also modify the risk of esophageal adenocarcinoma (EAC) and ESCC in western populations of Caucasian ethnicity. A European case-control study including 349 EC patients and 580 controls matched for age, sex, geographical location, and race was carried out. The SNPs rs2274223 in the PCLE1 gene at chromosome 10q23 and rs13042395 in the RFT2 gene at chromosome 20p13 were determined using PCR. Genotype distributions were compared between patients and controls, and odds ratios with 95% confidence intervals were calculated. The total EC group included 86 patients with ESCC and 258 patients with EAC. The distribution of PLCE1 and RFT2 genotypes did not differ between patients with EAC or ESSC, and the controls. In contrast to the modulation of the risk of ESCC in Asians, it is unlikely that the PLCE1 rs2274223 and RFT2 13042395 SNPs play a role in EAC or ESCC susceptibility in Dutch Caucasians.
European journal of cancer prevention: the official journal of the European Cancer Prevention Organisation (ECP) 12/2012; · 2.21 Impact Factor
[show abstract][hide abstract] ABSTRACT: Curcumin, quercetin, and eicosapentaenoic acid (EPA) are 3 natural compounds with the capacity to reduce adenoma burden in patients with familial adenomatous polyposis (FAP). The mechanistic basis of this anticarcinogenic capacity is largely unknown, but it was suggested that induction of detoxification enzymes is involved. Therefore, the effects of low-dose curcumin, quercetin, and EPA on phase II detoxification enzymes UDP-glucuronosyltransferase (UGT), glutathione S-transferase (GST), as well as on glutathione (GSH) content were analyzed in 4 cell line models of intestinal carcinogenesis. HT-29, HuTu 80, and Caco-2 intestinal cancer cells and LT97 colon adenoma cells from a patient with FAP were treated with low-dose noncytotoxic concentrations of curcumin, quercetin, and EPA. GST enzyme activity was measured by spectrophotometry, and expression of GSTA1, GSTM1, GSTP1, GSTT1, and UGT1 by Western blotting. Cytosolic GSH levels were determined by high performance liquid chromatography. An inducing effect of curcumin and quercetin on GST or UGT was seen in Caco-2, LT97, and HuTu 80 cells. GSH levels were reduced by quercetin and EPA in HT-29 cells and induced by curcumin in Caco-2 cells. In LT97 cells, GST activity and expression was reduced, but UGT1 expression was induced by curcumin and quercetin; whereas EPA only decreased GST or UGT levels. In summary, enhancement of the detoxification capacity by low dose of the potential anticarcinogens curcumin, quercetin, or EPA seems only a minor factor in explaining their anticarcinogenic properties.
Nutrition and Cancer 07/2012; 64(6):856-63. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: BACKGROUND: Combinations of genetic polymorphisms in biotransformation enzymes might modify the individual risk for head and neck cancer. METHODS: Blood from 432 patients with head and neck cancer and 437 controls was investigated for genetic polymorphisms in 9 different phase I and II biotransformation enzymes. Analysis of the risk-modifying effect was performed according to predicted enzyme activities, based on genetic polymorphisms in the corresponding genes. RESULTS: Combination of polymorphisms in COX-2 or EPHX1 with high activity polymorphisms in UGT1A1, UGT1A6, or UGT1A7 showed a risk-modulating effect in head and neck carcinogenesis, especially among heavy smokers and patients with laryngeal cancer. However, no additional effect for the combination of these polymorphisms was discovered when compared to the impact of polymorphism in UGT1A1, UGT1A6, and UGT1A7 individually. CONCLUSION: Predicted high activity polymorphisms in the phase II enzymes UGT1A1, UGT1A6, and UGT1A7 are associated with an increased risk of head and neck cancer. Head Neck, 2012.
[show abstract][hide abstract] ABSTRACT: Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Crucial risk factors are exposure to toxins or carcinogens. Microsomal epoxide hydrolase (mEH) is a biotransformation enzyme essential for the detoxification of xenobiotics. Polymorphisms in exon 3 and exon 4 of the microsomal epoxide hydrolase gene (EPHX1) modify catalytic activity of this enzyme and subsequently may play a role in EC etiology. This case-control study investigated whether these polymorphisms in the EPHX1 gene influence esophageal cancer susceptibility in a Dutch Caucasian population. A case-control study including 349 Caucasian EC patients and 581 Caucasian healthy controls was conducted and the polymorphisms Tyr113His (exon 3) and His139Arg (exon 4) in the EPHX1 gene were determined, using polymerase chain reaction. The distribution of exon 3 and exon 4 genotypes were compared between cases and controls. Analyses included a stratification according to tumor histology; esophageal adenocarcinoma (EAC) or squamous cell carcinoma (ESCC). Furthermore, on the basis of allelic in vitro enzyme activity assays, exon 3 and 4 genotypes were combined and categorized according to their predicted high, medium or low enzyme activity. Homozygosity and heterozygosity for both exon 3 and 4 polymorphisms were correlated with a decreased esophageal squamous cell carcinoma risk. Heterozygosity and homozygosity for both polymorphisms correlated with an increased and a decreased esophageal adenocarcinoma risk, respectively. Predicted intermediate and high activity genotypes were risk and protective factors for esophageal squamous cell carcinoma and esophageal adenocarcinoma, respectively. However, none of these associations were statistically significant. In conclusion, the polymorphisms in exon 3 and exon 4 of the EPHX1 gene do not seem to be modifiers of esophageal squamous cell carcinoma or esophageal adenocarcinoma risk in Dutch Caucasians.
[show abstract][hide abstract] ABSTRACT: Esophageal cancer (EC) has a globally increasing incidence with poor curative treatment options and survival rates. Environmental and dietary factors have crucial roles in esophageal carcinogenesis. Polymorphisms in the UGT genes, a superfamily of enzymes essential for the detoxification of carcinogens, may alter enzyme activity and subsequently may play a role in EC etiology. Rather than solely establishing differences in genotype distribution, we investigated whether functional polymorphisms in UGT genes that can predict enzyme activity in vivo, may influence EC risk. A case-control study including 351 Caucasian EC patients and 592 Caucasian controls was conducted and polymorphisms in seven UGT genes were determined, using the polymerase chain reaction. On the basis of allelic in vitro enzyme activity measurements, genotypes were categorized according to their predicted in vivo enzyme activity into high, medium and low categories. Predicted enzyme activity groups were combined and compared between patients and controls. The UGT1A1 and UGT1A8 predicted high enzyme activity genotypes were significantly more (OR=1.62; 95% CI, 1.02-2.56) and less frequent (OR=0.36; 95% CI, 0.15-0.84) among patients with esophageal squamous cell carcinoma (ESCC), respectively. High (OR=0.42; 95% CI, 0.22-0.84) and medium (OR=0.25; 95% CI, 0.12-0.52) activity UGT2B4 genotypes were significantly less often present in ESCC patients. No association was detected between UGT genotypes and esophageal adenocarcinoma (EAC) risk. Polymorphisms in UGT genes, resulting in altered enzyme activity genotypes, do not seem modifiers of EAC risk. However, the predicted high activity UGT1A1 genotype, associated with low serum levels of the antioxidant bilirubin, was associated with an increased ESCC risk. The UGT1A8 and UGT2B4 genotypes associated with decreased predicted enzyme activities, were significantly associated with an increased risk of ESCC, probably by a decreased detoxification of carcinogens.
International Journal of Oncology 02/2012; 40(6):1789-96. · 2.66 Impact Factor
[show abstract][hide abstract] ABSTRACT: Chemoprevention would be a desirable strategy to avoid duodenectomy in patients with familial adenomatous polyposis (FAP) suffering from duodenal adenomatosis. We investigated the in vitro effects on cell proliferation, apoptosis, and COX-2 expression of the potential chemopreventives celecoxib and tauro-ursodeoxycholic acid (UDCA). HT-29 colon cancer cells and LT97 colorectal micro-adenoma cells derived from a patient with FAP, were exposed to low dose celecoxib and UDCA alone or in combination with tauro-cholic acid (CA) and tauro-chenodeoxycholic acid (CDCA), mimicking bile of FAP patients treated with UDCA. In HT-29 cells, co-treatment with low dose celecoxib and UDCA resulted in a decreased cell growth (14-17%, p<0.01). A more pronounced decrease (23-27%, p<0.01) was observed in LT97 cells. Cell growth of HT-29 cells exposed to 'artificial bile' enriched with UDCA, was decreased (p<0.001), either in the absence or presence of celecoxib. In LT97 cells incubated with 'artificial bile' enriched with UDCA, cell growth was decreased only in the presence of celecoxib (p<0.05). No clear evidence was found for involvement of proliferating cell nuclear antigen, caspase-3, or COX-2 in the cellular processes leading to the observed changes in cell growth. In conclusion, co-treatment with low dose celecoxib and UDCA has growth inhibitory effects on colorectal adenoma cells derived from a patient with FAP, and further research on this combination as promising chemopreventive strategy is desired.
Experimental Cell Research 02/2012; 318(7):819-27. · 3.56 Impact Factor
[show abstract][hide abstract] ABSTRACT: Oxidative stress is presumed to play an important role in inflammatory bowel disease (IBD). Accordingly, antioxidant supplementation might be protective. Dietary calcium inhibited colitis development in HLA-B27 transgenic rats, an animal model mimicking IBD. As antioxidants might act at mucosa level and calcium predominantly in the gut lumen, we hypothesize that the combination has additive protective effects on colitis development.
HLA-B27 rats were fed a control diet or the same diet supplemented with the antioxidants glutathione, vitamin C, and vitamin E, or supplemented with both antioxidants and calcium. Oxidative stress in colonic mucosa, colonic inflammation, intestinal permeability, and diarrhea were quantified.
Intestinal permeability, diarrhea, myeloperoxidase, and interleukin-1β levels were significantly lower in rats fed both antioxidants and calcium compared to rats supplemented with antioxidants only. No beneficial effects were observed in rats fed the diet supplemented with antioxidants only. Strikingly, despite extremely low colonic mucosal glutathione levels in HLA-B27 rats, there was no oxidative stress-related damage. Subsequent analyses showed no defect in expression of glutathione synthesis genes. Additional experiments, comparing young and older HLA-B27 rats, showed that glutathione levels and also reactive oxygen species production decreased with progression of intestinal inflammation.
Antioxidant supplementation was ineffective in HLA-B27 rats despite low mucosal glutathione levels, because colitis development did not coincide with oxidative stress in this model. This indicates that the neutrophilic respiratory burst, and thus innate immune defense, is compromised in HLA-B27 rats. As supplementation with both calcium and antioxidants attenuated colitis development, we speculate that this protective effect is attributed to calcium only.
[show abstract][hide abstract] ABSTRACT: Studies suggest clinical benefits of parenteral fish oil (FO), rich in n-3 polyunsaturated fatty acids (PUFAs), over soyabean oil (SO), rich in n-6 PUFAs, in patients with pro-inflammatory conditions such as sepsis and trauma. Because the mechanisms behind these observations remain unclear, the present study explored the effects of intravenous infusion of FO and SO on fatty acid incorporation, immune functions and (anti)oxidant balance in healthy human volunteers.
Saline, a SO emulsion and a FO emulsion were administered for one hour on three consecutive days at a rate of 0·2 g/kg BW/h to eight subjects in a randomized cross-over design with a 3-week interval between treatments. Plasma phospholipid and peripheral blood mononuclear cell (PBMC) fatty acid compositions, and leucocyte counts and functions were assessed prior to the first infusion (T = 0, baseline) and 1 day (T = 4, early effects) and 8 days (T = 11, late effects) after the third infusion.
Fish oil infusion significantly increased n-3 PUFA proportions and decreased n-6 PUFA proportions in plasma phospholipids and PBMCs. There were no differences in immune functions or (anti)oxidant balance between treatments at any time.
The present lipid infusion protocol appears to be safe and well tolerated and provides significant incorporation of n-3 PUFAs into plasma phospholipids and PBMCs. In the absence of overt inflammation, no direct effects of FO were observed on immune function or (anti)oxidant balance. This model may be useful to evaluate effects of parenteral lipids in other settings, for example in individuals displaying an inflammatory state.
European Journal of Clinical Investigation 07/2011; 42(3):290-302. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: There is a growing body of evidence showing that dietary constituents and lipids in particular, influence the function of the human immune system. However, although the beneficial effects of oleic acid (OA) are clear, its mechanism of action at the molecular level is poorly understood.
To evaluate neutrophil activation under the influence of OA and compare this with several n-6 PUFAs.
Two key aspects of neutrophil activation were investigated: oxygen radical (ROS) production and intracellular Ca(2+) signaling.
OA and the n-6 PUFA arachidonic acid (AA) both induced ROS production in a dose-dependent manner, although AA was the more potent stimulus. When looking for the mechanisms behind these effects, we found that both FA induce increases in cytosolic calcium concentration [Ca(2+)](i)), but whereas OA-induced ROS production is totally mediated through Ca2+ signaling, this is not the case for AA since ROS generation by AA is only partly inhibited in BAPTA-treated cells. We also found evidence for the involvement of protein kinase C (PKC) in the OA-induced ROS generation; by contrast, other enzymes apart from PKC seem to be implicated in n-6 PUFA-induced ROS production. In addition, our results argue against the involvement of a pertussis toxin-sensitive receptor activated by OA.
OA differs from the n-6 PUFA AA in the activation of human neutrophils and these differences may be related to their distinct inmunomodulatory properties.
Cellular Physiology and Biochemistry 01/2011; 28(2):329-38. · 3.42 Impact Factor
[show abstract][hide abstract] ABSTRACT: In order to define future chemoprevention strategies for adenomas or carcinomas in the pouch of patients with familial adenomatous polyposis (FAP), a 4-weeks intervention with (1) sulindac, (2) inulin/VSL#3, and (3) sulindac/inulin/VSL#3 was performed on 17 patients with FAP in a single center intervention study. Primary endpoints were the risk parameters cell proliferation and glutathione S-transferase (GST) detoxification capacity in the pouch mucosa; secondary endpoints were the short chain fatty acid (SCFA) contents, pH, and cytotoxicity of fecal water.
Before the start and at the end of each 4-week intervention period, six biopsies of the pouch were taken and feces was collected during 24 h. Cell proliferation and GST enzyme activity was assessed in the biopsies and pH, SCFA contents, and cytotoxicity were assessed in the fecal water fraction. The three interventions (sulindac, inulin/VSL#3, sulindac/inulin/VSL#3) were compared with the Mann-Whitney U test.
Cell proliferation was lower after sulindac or VSL#3/inulin, the combination treatment with sulindac/inulin/VSL#3 showed the opposite. GST enzyme activity was increased after sulindac or VSL#3/inulin, the combination treatment showed the opposite effect. However, no significance was reached in all these measures. Cytotoxicity, pH, and SCFA content of fecal water showed no differences at all among the three treatment groups.
Our study revealed non-significant decreased cell proliferation and increased detoxification capacity after treatment with sulindac or VSL#3/inulin; however, combining both regimens did not show an additional effect.
International Journal of Colorectal Disease 01/2011; 26(5):575-82. · 2.24 Impact Factor
[show abstract][hide abstract] ABSTRACT: UDP-glucuronosyltransferase 1A1 (UGT1A1) is an enzyme which catalyses not only the glucuronidation of tobacco smoke carcinogens like benzopyrene, but also of the endogenous substrate bilirubin. Bilirubin for a long time was considered to be only a toxic waste product of hemoglobin degradation, but recent findings have shown that bilirubin is a potent antioxidant, which may play a protective role against cancer. We investigated whether a genetic polymorphism in UGT1A1 (UGT1A1*28), associated with a reduced UGT1A1 enzyme activity, may have a risk-modifying effect on head and neck carcinogenesis. Blood samples from 421 patients with oral, pharyngeal or laryngeal carcinoma, and 417 healthy controls were investigated for the UGT1A1*28 polymorphism. On the basis of the occurrence of this polymorphism, patients and controls were divided according to predicted UGT1A1 enzyme activity (low, intermediate, high). Logistic regression analysis showed a significant increased distribution of predicted high activity UGT1A1*1 polymorphisms among the patients (OR: 1.37; 95% CI: 1.02-1.83). Stratified analyses demonstrated that predicted high activity UGT1A1 polymorphisms were present even more significantly in patients with laryngeal cancer, older patients, heavy smokers and heavy drinkers. In conclusion, the predicted high activity UGT1A1*1 polymorphism, which results in lower serum levels of the endogenous antioxidant bilirubin, was associated with an increased risk of head and neck cancer.
International Journal of Cancer 12/2010; 127(12):2815-21. · 6.20 Impact Factor
[show abstract][hide abstract] ABSTRACT: Lipid-induced modulation of phagocyte function seems to contribute to increased susceptibility to infections in patients on parenteral nutrition, and an increased risk for development of pneumonia has been observed in this group. The role of various structurally different lipid emulsions, however, remains unclear. In this study, we therefore assessed phagocyte function, as the capacity of neutrophils to eliminate Streptococcus pneumoniae (i.e. combined result of phagocytosis and killing), in the presence of these lipids.
Neutrophils from six healthy volunteers were incubated for 1 h in emulsions (5 mmol L(-1)) derived from soybean- (LCT), fish- (VLCT), olive- (LCT-MUFA), mixed soybean/coconut oils (LCT/MCTs) or structured lipids (SL). After opsonization of the pneumococci (strain OREP-4) by human immunoglobulins, bacteria and neutrophils were incubated in the presence of complement. Next, pneumococcal elimination was evaluated and expressed as the percentage of bacteria eliminated relative to the initial bacterial numbers in neutrophil-free samples.
Neutrophils that were not exposed to lipids showed a pneumococcal elimination capacity of 75 +/- 3% (mean +/- SD). This significantly decreased after exposure to LCT-MUFA (70 +/- 6%), VLCT (67 +/- 2%), SL (63 +/- 9%), LCT (66 +/- 10%) and LCT/MCT (47 +/- 15%).
These data demonstrate that parenteral lipids impair the microbial elimination capacity of neutrophils in a structure-dependent manner. In accordance with our previously reported in vitro effect on a range of phagocyte functions, LCT/MCT is by far the most potent in this respect.
European Journal of Clinical Investigation 08/2010; 40(8):729-34. · 3.37 Impact Factor
[show abstract][hide abstract] ABSTRACT: To determine the possible modulating effect of the COX-2 polymorphisms, -765G-->C and -1195A-->G, on the risk of colorectal cancer (CRC) in a Dutch population.
This case-control study includes 326 patients with CRC and 369 age- and gender-matched controls. Genotypes of the COX-2 polymorphisms -765G-->C and -1195A-->G were determined by polymerase chain reaction-based restriction fragment length polymorphism. COX-2 genotypes and haplotypes were analyzed and odds ratios with 95% confidence intervals were estimated by logistic regression.
The -765GG genotype was associated with an increased risk of developing CRC (OR, 1.45; 95% CI, 1.03-2.04). No significant difference was observed in the genotype distribution of the -1195A-->G polymorphism between patients and controls. The GG/AC haplotype was present significantly less often in patients than in controls (OR 0.44; 95% CI, 0.22-0.85). When the AC, AG and GG haplotypes were investigated separately, the AC haplotype showed a tendency to be less frequent in patients than in controls (OR((AG/AC)) 0.78; 95% CI, 0.57-1.06).
The -765GG genotype is associated with an increased risk of developing CRC and the GG/AC haplotype seems to protect against CRC. These findings suggest a modulating role for the COX-2 polymorphisms -765G-->C and -1195A-->G in the development of CRC in a Dutch population.
World Journal of Gastroenterology 09/2009; 15(36):4561-5. · 2.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Detoxification enzymes, especially glutathione S-transferase P1-1 (GSTP1-1), have been implicated in resistance to platinum-based chemotherapy. We studied GSTP1-1 levels in ovarian cyst fluid (oCF), obtained during surgery before chemotherapy, of patients with epithelial ovarian cancer and clinical outcomes were correlated. GSTP1-1 was determined by ELISA in oCF of 56 patients with epithelial ovarian cancer and 109 noncancer controls (21 borderline and 88 benign ovarian tumors). Differences in median GSTP1-1 between clinicopathologic subgroups were studied using Mann-Whitney U and Kruskal Wallis tests. Differences in disease-free (DFS) and overall survival (OS) between groups were analyzed by applying Kaplan-Meyer estimates and log-rank tests. Univariate and multivariate analysis were done using Cox proportional hazard model. Significantly higher levels of GSTP1-1 were found in the oCF of malignant (median, 383; range, 10-32,695 ng/mL) compared with benign (median, 20; range, 0-1,128 ng/mL) ovarian tumors (P < 0.01). Significantly higher GSTP1-1 levels were found in patients with advanced International Federation of Gynaecologists and Obstetricians stage (P = 0.01), high-grade tumors (P = 0.44), and/or high levels of preoperative CA 125 (P = 0.01). Of patients who received chemotherapy (stage, >or=Ic; n = 30), high GSTP1-1 levels were significantly associated with a poor DFS and OS (log-rank P = 0.047 and P = 0.033, respectively). International Federation of Gynaecologists and Obstetricians stage was the only independent predictor for DFS. GSTP1-1 was the only independent predictor for OS.