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1.
Ann Oncol ; 30(3): 478-485, 2019 03 01.
Article in English | MEDLINE | ID: mdl-30698666

ABSTRACT

BACKGROUND: Increased vitamin B6 catabolism related to inflammation, as measured by the PAr index (the ratio of 4-pyridoxic acid over the sum of pyridoxal and pyridoxal-5'-phosphate), has been positively associated with lung cancer risk in two prospective European studies. However, the extent to which this association translates to more diverse populations is not known. MATERIALS AND METHODS: For this study, we included 5323 incident lung cancer cases and 5323 controls individually matched by age, sex, and smoking status within each of 20 prospective cohorts from the Lung Cancer Cohort Consortium. Cohort-specific odds ratios (ORs) and 95% confidence intervals (CIs) for the association between PAr and lung cancer risk were calculated using conditional logistic regression and pooled using random-effects models. RESULTS: PAr was positively associated with lung cancer risk in a dose-response fashion. Comparing the fourth versus first quartiles of PAr resulted in an OR of 1.38 (95% CI: 1.19-1.59) for overall lung cancer risk. The association between PAr and lung cancer risk was most prominent in former smokers (OR: 1.69, 95% CI: 1.36-2.10), men (OR: 1.60, 95% CI: 1.28-2.00), and for cancers diagnosed within 3 years of blood draw (OR: 1.73, 95% CI: 1.34-2.23). CONCLUSION: Based on pre-diagnostic data from 20 cohorts across 4 continents, this study confirms that increased vitamin B6 catabolism related to inflammation and immune activation is associated with a higher risk of developing lung cancer. Moreover, PAr may be a pre-diagnostic marker of lung cancer rather than a causal factor.


Subject(s)
Inflammation/blood , Lung Neoplasms/blood , Metabolism , Vitamin B 6/blood , Adult , Aged , Female , Humans , Inflammation/pathology , Lung Neoplasms/epidemiology , Lung Neoplasms/pathology , Male , Middle Aged , Pyridoxic Acid/metabolism , Risk Factors , Smokers
2.
Ann Oncol ; 29(6): 1468-1475, 2018 06 01.
Article in English | MEDLINE | ID: mdl-29617726

ABSTRACT

Background: There is observational evidence suggesting that high vitamin D concentrations may protect against lung cancer. To investigate this hypothesis in detail, we measured circulating vitamin D concentrations in prediagnostic blood from 20 cohorts participating in the Lung Cancer Cohort Consortium (LC3). Patients and methods: The study included 5313 lung cancer cases and 5313 controls. Blood samples for the cases were collected, on average, 5 years before lung cancer diagnosis. Controls were individually matched to the cases by cohort, sex, age, race/ethnicity, date of blood collection, and smoking status in five categories. Liquid chromatography coupled with tandem mass spectrometry was used to separately analyze 25-hydroxyvitamin D2 [25(OH)D2] and 25-hydroxyvitamin D3 [25(OH)D3] and their concentrations were combined to give an overall measure of 25(OH)D. We used conditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs) for 25(OH)D as both continuous and categorical variables. Results: Overall, no apparent association between 25(OH)D and risk of lung cancer was observed (multivariable adjusted OR for a doubling in concentration: 0.98, 95% CI: 0.91, 1.06). Similarly, we found no clear evidence of interaction by cohort, sex, age, smoking status, or histology. Conclusion: This study did not support an association between vitamin D concentrations and lung cancer risk.


Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Non-Small-Cell Lung/epidemiology , Lung Neoplasms/epidemiology , Small Cell Lung Carcinoma/epidemiology , Vitamin D Deficiency/physiopathology , Vitamin D/blood , Adenocarcinoma/blood , Adenocarcinoma/epidemiology , Adolescent , Adult , Aged , Aged, 80 and over , Carcinoma, Large Cell/blood , Carcinoma, Large Cell/epidemiology , Carcinoma, Non-Small-Cell Lung/blood , Carcinoma, Squamous Cell/blood , Carcinoma, Squamous Cell/epidemiology , Case-Control Studies , Female , Follow-Up Studies , Global Health , Humans , Lung Neoplasms/blood , Male , Middle Aged , Prognosis , Prospective Studies , Risk Factors , Small Cell Lung Carcinoma/blood , Vitamins/blood , Young Adult
3.
Cancer Causes Control ; 25(5): 583-9, 2014 May.
Article in English | MEDLINE | ID: mdl-24562905

ABSTRACT

PURPOSE: Epithelial ovarian cancers either arise directly from Mullerian-type epithelium or acquire Mullerian characteristics in the course of neoplastic transformation. The anti-Mullerian hormone (AMH) causes regression of Mullerian structures during fetal development in males and has been shown to inhibit the growth of epithelial ovarian cancer. Therefore, we hypothesized that pre-diagnostic serum concentrations of AMH are inversely associated with risk of invasive serous ovarian cancer. METHODS: A case-control study (107 cases, 208 controls) was nested within the population-based Finnish Maternity Cohort (1986-2007). The sample donated during the first trimester of the last pregnancy preceding cancer diagnosis of the case subjects was selected for the study. For each case, two controls, matched on age and date at sampling, as well as parity at sampling and at cancer diagnosis were selected. AMH was measured by a second-generation AMH ELISA. Conditional logistic regression was used to compute odds ratios (OR) and 95 % confidence intervals (CI) for invasive serous ovarian cancer associated with AMH concentrations. RESULTS: Overall AMH concentrations were not associated with risk of invasive serous ovarian cancer (OR 0.93; 95 % CI 0.49-1.77 for top vs. bottom tertile, P trend=0.83). In women older than the median age at sampling (32.7 years), a doubling of AMH was associated with decreased risk (OR 0.69; 95 % CI 0.49-0.96), whereas an increased risk (OR 1.64; 95 % CI 1.06-2.54) was observed in younger women, P homogeneity = 0.002. CONCLUSIONS: In this first prospective investigation, risk of invasive serous ovarian cancer was not associated with pre-diagnostic AMH concentrations overall; however, the association may depend on age at AMH measurement.


Subject(s)
Anti-Mullerian Hormone/blood , Cystadenocarcinoma, Serous/blood , Neoplasms, Glandular and Epithelial/blood , Ovarian Neoplasms/blood , Adult , Carcinoma, Ovarian Epithelial , Case-Control Studies , Female , Humans , Pregnancy , Prospective Studies , Young Adult
4.
Clin Chim Acta ; 432: 33-7, 2014 May 15.
Article in English | MEDLINE | ID: mdl-24269503

ABSTRACT

Standardized protocols for patient preparation for laboratory testing are currently lacking. Moreover, a great heterogeneity exists in the definitions of "fasting" currently being used among healthcare workers and in the literature. Marked metabolic and hormonal changes occur after food ingestion, mainly due to the absorption of fluids, lipids, proteins, carbohydrates and other food constituents. This postprandial response varies markedly in response to numerous factors, such as eating behavior, food composition, fasting duration, time of the day, chronic and acute smoking, coffee and alcohol consumption. It is therefore crucial to minimize the total variability by controlling as many of these modifying factors as possible. Control of the abovementioned effects on postprandial response can only be achieved by standardizing the way patients are prepared for laboratory testing, i.e. by defining the fasting duration, as well as what is and what is not allowed (e.g., coffee, tea, smoking, water) during the period of fasting prior to sample collection. The aim of this article is to describe the range of effects of different approaches to fasting on laboratory tests, and to provide a framework for the harmonization of definitions for fasting requirements for laboratory tests.


Subject(s)
Blood Chemical Analysis/standards , Blood Specimen Collection/standards , Fasting , Humans , Patient Compliance , Postprandial Period , Reference Standards
5.
Ann Oncol ; 22(8): 1916-21, 2011 Aug.
Article in English | MEDLINE | ID: mdl-21292643

ABSTRACT

BACKGROUND: Evidence suggests that inflammation may be associated with increased risk of ovarian cancer but there is paucity of studies investigating this association, especially using over-time changes in inflammatory biomarkers. MATERIALS AND METHODS: We conducted a prospective population-based case-control study nested within the Finnish Maternity Cohort (FMC). Within the FMC, 170 women with ovarian cancer who had donated serum samples to the cohort twice, ≥1 year apart, before cancer diagnoses were identified. One control per case was matched for age, parity and sampling date. RESULTS: Comparing the highest with lowest tertiles, the odds ratio (OR) of ovarian cancer using the first set of serum samples (mean lag time to cancer diagnosis 9.0 years) was 1.62 [95% confidence interval (CI) 0.93-2.83]. However, analysis conducted using the second set of serum samples donated closer to cancer diagnosis (mean lag time 6.4 years) revealed a significantly increased risk of ovarian cancer comparing extreme tertiles of C-reactive protein (CRP) concentrations; OR 1.96 (95% CI 1.11-3.4). Over time, increases in individuals' CRP concentrations were also associated with increased risk; OR 1.90 (95% CI 1.12-3.23). CONCLUSION: The results suggest that inflammation may precede ovarian cancer since increasing CRP concentrations, both across tertiles and longitudinally at the individual level, were associated with increased risk.


Subject(s)
Biomarkers, Tumor/blood , C-Reactive Protein/analysis , Ovarian Neoplasms/blood , Ovarian Neoplasms/epidemiology , Adolescent , Adult , Biological Specimen Banks , Case-Control Studies , Female , Finland , Humans , Inflammation/blood , Inflammation/epidemiology , Longitudinal Studies , Odds Ratio , Risk Factors , Young Adult
6.
Cell Death Dis ; 1: e78, 2010 Sep 23.
Article in English | MEDLINE | ID: mdl-21364680

ABSTRACT

Apoptotic cysteine-aspartate proteases (caspases) are essential for the progression and execution of apoptosis, and detection of caspase fragmentation or activity is often used as markers of apoptosis. Cisplatin (cis-diamminedichloroplatinum (II)) is a chemotherapeutic drug that is clinically used for the treatment of solid tumours. We compared a cisplatin-resistant pleural malignant mesothelioma cell line (P31res1.2) with its parental cell line (P31) regarding the consequences of in vitro acquired cisplatin-resistance on basal and cisplatin-induced (equitoxic and equiapoptotic cisplatin concentrations) caspase-3, -8 and -9 fragmentation and proteolytic activity. Acquisition of cisplatin-resistance resulted in basal fragmentation of caspase-8 and -9 without a concomitant increase in proteolytic activity, and there was an increased basal caspase-3/7 activity. Similarly, cisplatin-resistant non-small-cell lung cancer cells, H1299res, had increased caspase-3 and -9 content compared with the parental H1299 cells. In P31 cells, cisplatin exposure resulted in caspase-9-mediated caspase-3/7 activation, but in P31res1.2 cells the cisplatin-induced caspase-3/7 activation occurred before caspase-8 or -9 activation. We therefore concluded that in vitro acquisition of cisplatin-resistance rendered P31res1.2 cells resistant to caspase-8 and caspase-9 fragments and that cisplatin-induced, initiator-caspase independent caspase-3/7 activation was necessary to overcome this resistance. Finally, the results demonstrated that detection of cleaved caspase fragments alone might be insufficient as a marker of caspase activity and ensuing apoptosis induction.


Subject(s)
Antineoplastic Agents/pharmacology , Caspase 8/metabolism , Caspase 9/metabolism , Cisplatin/pharmacology , Mesothelioma/enzymology , Pleural Neoplasms/enzymology , Apoptosis , Caspase 3/metabolism , Caspase 7/metabolism , Cell Line, Tumor , Drug Resistance, Neoplasm , Humans , X-Linked Inhibitor of Apoptosis Protein/metabolism
7.
Scand J Clin Lab Invest ; 67(8): 836-47, 2007.
Article in English | MEDLINE | ID: mdl-17852838

ABSTRACT

OBJECTIVE: Most mistakes in laboratory medicine are the result of human error occurring before the blood sample reaches the laboratory. This survey of preanalytical procedures was designed to identify sources of error and potential targets for quality improvement strategies. MATERIAL AND METHODS: The staff in a highly specialized surgical ward at a university hospital completed a questionnaire addressing the collection and handling of venous blood samples in plastic vacuum test-tubes for general clinical chemistry testing. RESULTS: The results suggest that venous blood sampling instructions are not always followed. When uncertain about how a sample should be collected, the majority of respondents rely on potentially poor sources of information, such as out-of-date printed instructions or the advice of a colleague, rather than consult up-to-date electronic instructions. Furthermore, they do not always report errors and the referrals are not always handled according to sampling instructions. The respondents were highly motivated, however, and had a strong interest in receiving further education in, and assuming increased responsibility for, venous blood sampling procedures in the ward. CONCLUSIONS: We believe that the introduction of standardized routines and regular staff training, combined with an exchange of the existing paper-based referral management system with an electronic system for managing referrals, could increase safety in the preanalytical process, with positive effects on patient safety. Given the importance of venous blood samples in patient care, a more extensive study covering other hospital wards and primary health-care centres is needed.


Subject(s)
Attention , Blood Specimen Collection/methods , Patient-Centered Care , Surveys and Questionnaires , Female , Humans , Male , Medical Errors , Middle Aged , Transportation
8.
J Pediatr Endocrinol Metab ; 19(6): 787-94, 2006 Jun.
Article in English | MEDLINE | ID: mdl-16886586

ABSTRACT

INTRODUCTION: We investigated whether thyroid receptor antibodies (TRAb) could result in transient neonatal thyroid disease by transfer through milk from mothers treated for thyrotoxicosis. AIM: To analyse whether breast milk content of TRAb in euthyroid mothers with treated thyrotoxicosis resulted in neonatal thyroid disease and whether extended breastfeeding prolonged the neonatal disease. PATIENTS: We tested three TRAb-positive mothers and the course, treatment and outcome for their offspring with neonatal thyrotoxicosis, and six healthy and two TRAb-negative euthyroid mothers with treated thyrotoxicosis during breastfeeding. METHOD: TRAb was analysed in serum and breast milk by a radioreceptor assay. RESULTS: TRAb in serum was detectable in all treated mothers, in one mother during her four pregnancies, resulting in all neonates requiring treatment for thyrotoxicosis. Serum TRAb concentration in neonates decreased continuously with time after birth. Breast milk TRAb was detectable in all cases but not in the controls or in TRAb-negative mothers treated for thyrotoxicosis. The calculated half-life for offspring serum and breast milk TRAb was calculated as approx. 3 weeks and 2 months, respectively. CONCLUSION: Euthyroid TRAb-positive mothers may cause transient neonatal thyroid disease which seems to be worse and more prolonged during breastfeeding as a consequence of TRAb in breast milk.


Subject(s)
Autoantibodies/adverse effects , Milk, Human/immunology , Thyroid Diseases/etiology , Adult , Control Groups , Female , Humans , Immunoglobulins, Thyroid-Stimulating , Infant, Newborn , Male , Maternal-Fetal Exchange , Methimazole/therapeutic use , Pregnancy , Receptors, Thyrotropin , Reproducibility of Results , Risk , Thyrotoxicosis/blood , Thyrotoxicosis/drug therapy
9.
Toxicol In Vitro ; 20(6): 986-94, 2006 Sep.
Article in English | MEDLINE | ID: mdl-16483738

ABSTRACT

Depletion of intracellular potassium ions (K+) is necessary for cells to shrink, activate caspases and induce DNA fragmentation, events which are features of apoptosis. Here we describe a 96-well plate method using the cell permeable form of K+ binding benzofuran isophtalate (PBFI-AM) to measure intracellular K+ content in relation to untreated control. Cultured human pulmonary mesothelioma cells (P31) and small-cell lung cancer cells (U1690) were treated with K+ flux modulators in order to deprive the cells of intracellular K+. The combination of K+ influx inhibition with 10 micromol/L bumetanide plus 10 micromol/L ouabain and K+ efflux stimulation with 3 mg/L amphotericin B or 5 micromol/L nigericin efficiently reduced the intracellular K+ content after 3 h. Manipulation of K+ fluxes with subsequent intracellular K+ depletion induced apoptosis of lung cancer cells, as detected by caspase-3 activity after 3 h K+ depletion followed by 24 h proliferation and TUNEL positive staining after 48 h proliferation. We concluded that the PBFI-AM assay was a useful tool to determine intracellular K+ content in relation to untreated control, and that intracellular K+ depletion of lung cancer cells by clinically used drugs of relevant concentrations induced apoptosis. These findings may lead to novel therapeutic strategies in the treatment of lung cancer.


Subject(s)
Apoptosis/drug effects , Benzofurans/pharmacology , Ethers, Cyclic/pharmacology , Potassium/analysis , Caspase 3 , Caspases/metabolism , Cell Line, Tumor , Humans , In Situ Nick-End Labeling , Lung Neoplasms/pathology , Potassium/metabolism
10.
BJU Int ; 93(3): 297-302, 2004 Feb.
Article in English | MEDLINE | ID: mdl-14764126

ABSTRACT

OBJECTIVE: To evaluate the effect of vascular endothelial growth factor (VEGF, one of the most important angiogenetic factors) in renal cell carcinoma (RCC) by analysing many RCCs for the expression of immunohistochemical (IHC) VEGF-staining related to clinicopathological findings and survival. PATIENTS AND METHODS: VEGF immunostaining was examined with the tissue microarray (TMA) method on tumour samples from 229 patients and validated in 71 by ordinary tissue sections (TS). IHC VEGF expression was quantified by estimating the volume density and staining intensity on a three-grade scale. RESULTS: In most RCCs there was VEGF staining in the cell cytoplasm and membrane. In cell membranes the VEGF expression declined with storage time. IHC VEGF expression analysed by TMA and TS gave corresponding results. There was no difference in VEGF expression among conventional, papillary and chromophobe RCCs. There were significant correlations between VEGF expression and tumour size and stage. In univariate analysis VEGF expression correlated with survival, especially in conventional RCCs; this prognostic information was lost in multivariate analysis. The VEGF staining intensity correlated only with VEGF expression but not with any clinicopathological factors. CONCLUSIONS: VEGF protein was present in most RCC cells. There was no difference in VEGF expression among the different RCC types. The correlation between VEGF expression and tumour stage and with prognosis indicates the significance of VEGF within tumour growth and progression in RCC.


Subject(s)
Carcinoma, Renal Cell/metabolism , Kidney Neoplasms/metabolism , Neoplasm Proteins/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adult , Aged , Aged, 80 and over , Female , Follow-Up Studies , Humans , Immunohistochemistry , Male , Middle Aged , Neoplasm Staging/methods , Prognosis , Survival Analysis
11.
Eur J Cancer ; 40(1): 33-42, 2004 Jan.
Article in English | MEDLINE | ID: mdl-14687787

ABSTRACT

The aim of this study was to investigate possible associations between the expression of c-erbB-2 and the angiogenic factors vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), p53 status, routine breast cancer prognostic factors and survival. Expression of c-erbB-2, VEGF, bFGF, and p53 protein was determined with an enzyme-linked immunosorbent assay (ELISA) in 656 patients with primary breast cancer (median follow-up time of 83 months). In 60 cases, we also used immunohistochemistry (IHC) for c-erbB-2 evaluation, to be used as a reference for the ELISA. Overexpression of c-erbB-2 was significantly related to a higher expression of VEGF, lower bFGF content, negative steroid receptor status, and a high S-phase fraction. In multivariate analysis, c-erbB-2 was an independent prognostic factor for relapse-free survival (RFS) and overall survival (OS) in all patients, and in node-positive patients, irrespective of the adjuvant systemic therapy. Combined survival analyses regarding c-erbB-2 and VEGF yielded additional prognostic information.


Subject(s)
Breast Neoplasms/metabolism , Carcinoma, Ductal, Breast/metabolism , Carcinoma, Lobular/metabolism , Receptor, ErbB-2/metabolism , Vascular Endothelial Growth Factor A/metabolism , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Breast Neoplasms/drug therapy , Carcinoma, Ductal, Breast/mortality , Carcinoma, Ductal, Breast/therapy , Carcinoma, Lobular/mortality , Carcinoma, Lobular/therapy , Chemotherapy, Adjuvant , Disease-Free Survival , Female , Fibroblast Growth Factor 2/metabolism , Follow-Up Studies , Humans , Lymphatic Metastasis , Neoplasm Recurrence, Local , Prognosis , Regression Analysis , Sweden/epidemiology , Tumor Suppressor Protein p53/metabolism
13.
Eur J Cancer Prev ; 11(3): 245-52, 2002 Jun.
Article in English | MEDLINE | ID: mdl-12131658

ABSTRACT

It has been shown that both serum vascular endothelial growth factor (VEGF) and also platelet counts are associated with survival in renal cell carcinoma (RCC). It is not known, however, whether VEGF in serum relates to the angiogenic activity of the tumour or is derived from circulating blood components. Therefore, the interrelation between serum VEGF, platelet and leukocyte counts compared with health history, clinicopathological findings and outcome was evaluated in patients with RCC. Blood samples were collected before nephrectomy in 161 patients. Serum VEGF165 was assessed by a quantitative ELISA method. Platelet and leukocyte counts were analysed routinely and obtained from medical records. The variables were compared using univariate and multivariate analysis. There were significant correlations between VEGF levels, and platelet (P < 0.001) and leukocyte counts (P < 0.001). Serum VEGF levels, platelet counts, as well as leukocyte counts correlated significantly to stage and grade. Platelet counts were significantly lower in men with medication (P = 0.042), and decreased with age particularly in women (P = 0.001). Age or medication did not affect VEGF levels or leukocyte counts. Both VEGF and platelets gave significant prognostic information in univariate analysis. Using Cox multivariate analysis, VEGF was the last variable to be excluded. Only stage and grade remained as independent prognostic factors. Both VEGF levels and platelet counts gave prognostic information but VEGF was more reliable as predictor of survival in patients with RCC.


Subject(s)
Carcinoma, Renal Cell/blood , Endothelial Growth Factors/blood , Intercellular Signaling Peptides and Proteins/blood , Kidney Neoplasms/blood , Leukocyte Count , Lymphokines/blood , Platelet Count , Adult , Age Factors , Aged , Aged, 80 and over , Carcinoma, Renal Cell/mortality , Female , Humans , Kidney Neoplasms/mortality , Male , Middle Aged , Prognosis , Sex Factors , Survival Rate , Vascular Endothelial Growth Factor A , Vascular Endothelial Growth Factors
14.
Med Oncol ; 19(1): 1-9, 2002.
Article in English | MEDLINE | ID: mdl-12025885

ABSTRACT

The influence of radiotherapy on malignant glioma multidrug resistance to chemotherapy was evaluated because patients with glioma often are treated with a combination of radiotherapy and chemotherapy. Multidrug resistance gene (MDR1, mdr1a, and mdr1b) transcripts were found in human and rat glioma cell lines. P-Glycoprotein (Pgp) was immunohistochemically detected in glioma cell lines and in the rat brain vascular endothelial cell line (RBE4). A multidrug resistance pump efflux activity assay demonstrated increased calcein efflux of RBE4 endothelial cells, but not glioma cells, 2 h after irradiation and still increased 14 d after irradiation. The increased efflux was equally inhibited by verapamil with or without irradiation. In the rat intracranial glioma model (BT4C), Pgp was demonstrated in capillary endothelial cells of the tumor tissue and surrounding normal brain, but not in tumor cells. The expression of gene transcripts or Pgp was not affected by irradiation. The results indicate that long-lasting verapamil-resistant drug efflux mechanisms are activated in brain endothelial cells after irradiation. The results might explain the poor efficacy of chemotherapy following radiotherapy and contribute to consideration of new treatment strategies in the management of malignant glioma.


Subject(s)
Brain Neoplasms/radiotherapy , Drug Resistance, Neoplasm/physiology , Endothelium, Vascular/radiation effects , Glioma/radiotherapy , ATP Binding Cassette Transporter, Subfamily B/genetics , ATP Binding Cassette Transporter, Subfamily B/metabolism , ATP Binding Cassette Transporter, Subfamily B, Member 1/genetics , ATP Binding Cassette Transporter, Subfamily B, Member 1/metabolism , ATP-Binding Cassette Transporters/genetics , ATP-Binding Cassette Transporters/metabolism , Animals , Brain Neoplasms/metabolism , Calcium Channel Blockers/pharmacology , DNA Primers/chemistry , Endothelium, Vascular/drug effects , Endothelium, Vascular/metabolism , Fluoresceins/metabolism , Glioma/metabolism , Humans , Immunoenzyme Techniques , RNA, Messenger/metabolism , Rats , Reverse Transcriptase Polymerase Chain Reaction , Tumor Cells, Cultured/drug effects , Tumor Cells, Cultured/metabolism , Tumor Cells, Cultured/radiation effects , Verapamil/pharmacology , ATP-Binding Cassette Sub-Family B Member 4
15.
J Antimicrob Chemother ; 48(6): 781-6, 2001 Dec.
Article in English | MEDLINE | ID: mdl-11733461

ABSTRACT

The antifungal antibiotic amphotericin B causes considerable toxic effects during clinical therapy. We have shown previously that amphotericin B-induced cytotoxicity and apoptosis were eradicated by the Na+, K+, 2Cl- cotransport inhibitor bumetanide. To elucidate the role of K+ flux and the activity of Na+, K+ ATPase and Na+, K+, 2Cl- cotransport in apoptosis and cytotoxicity induced by amphotericin B alone and combined with bumetanide, we quantified the influx and efflux of K+ of mesothelioma cells (P31) using the K+ analogue 86Rb+ with ouabain (100 micromol/L) as the K+ influx probe. To determine the susceptibility of Candida albicans to amphotericin B when combined with bumetanide we used a plate diffusion method. Amphotericin B or bumetanide alone significantly stimulated 86Rb+ efflux during the first 15 min. However, when added simultaneously, the cellular 86Rb+ efflux was markedly decreased. Amphotericin B (3 mg/L) had no effect on immediate (15 min) total 86Rb+ influx. When bumetanide (100 micromol/L) was added, the total 86Rb+ influx was markedly reduced due to inhibition of augmented Na+, K+, 2Cl- cotransport and low Na+, K+ ATPase activity. Bumetanide did not affect the susceptibility of C. albicans to amphotericin B, which suggests that bumetanide or related drugs could be used in antifungal therapy to increase amphotericin B effectiveness without increasing its adverse effects. We suggest that bumetanide hampering of amphotericin B-induced cytotoxicity and apoptosis could be due to an immediate reduction of cellular K+ efflux as well as disordered K+ influx.


Subject(s)
Amphotericin B/pharmacology , Antifungal Agents/pharmacology , Apoptosis/drug effects , Bumetanide/pharmacology , Potassium Channel Blockers , Antibiotics, Antineoplastic/pharmacology , Candida albicans/drug effects , Diuretics/pharmacology , Enzyme Inhibitors/pharmacology , Humans , Ouabain/pharmacology , Potassium Channels/metabolism , Rubidium Radioisotopes/pharmacokinetics , Sodium Potassium Chloride Symporter Inhibitors , Sodium-Potassium-Chloride Symporters/metabolism , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Sodium-Potassium-Exchanging ATPase/metabolism , Tumor Cells, Cultured
16.
Eur J Cancer ; 37(17): 2199-203, 2001 Nov.
Article in English | MEDLINE | ID: mdl-11677107

ABSTRACT

Renal cell carcinoma is often characterised by extensive vascularity and angiogenic factors may be of importance for disease progression. Using a sandwich enzyme immunoassay, basic fibroblast growth factor (bFGF) was analysed in the sera from 206 patients with renal cell carcinoma before the initiation of therapy. The median bFGF level was 3.0 pg/ml (range <1.0-70.9 pg/ml). The serum levels were significantly correlated to tumour stage and nuclear grade. Patients with tumour thrombus to the renal or the inferior caval vein had significantly higher serum bFGF levels compared with those with non-invading tumours (P=0.007). Patients with serum bFGF levels above 3.0 pg/ml had a worse prognosis, compared with those with lower levels (P=0.001). Furthermore, patients with tumours with vein invasion had a worse prognosis compared with those without invasion. After multivariate analysis, only tumour stage and grade remained as independent prognostic factors.


Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Renal Cell/blood , Fibroblast Growth Factor 2/blood , Kidney Neoplasms/blood , Adult , Aged , Aged, 80 and over , Analysis of Variance , Carcinoma, Renal Cell/blood supply , Carcinoma, Renal Cell/pathology , Female , Humans , Kidney Neoplasms/blood supply , Kidney Neoplasms/pathology , Male , Middle Aged , Multivariate Analysis , Neoplasm Invasiveness , Neoplasm Staging , Neovascularization, Pathologic/blood , Prognosis , Renal Veins/pathology , Survival Rate , Vena Cava, Inferior/pathology
17.
Int J Cancer ; 93(4): 577-83, 2001 Aug 15.
Article in English | MEDLINE | ID: mdl-11477563

ABSTRACT

Chemotherapeutic anti-cancer drugs induce cell death by the process of apoptosis. Efflux of potassium ions (K(+)) is necessary for cell volume reduction during apoptosis and increased inward pumping of K(+) thus counteracts apoptosis. Potassium flux modulation could therefore interact with apoptosis and affect the efficiency of cancer chemotherapeutics. We explored if the K(+) efflux stimulator amphotericin B, with or without the Na(+), K(+), 2Cl(-)-cotransport (K(+) influx) blocker bumetanide, could affect cisplatin- and carboplatin-induced apoptosis and cytotoxicity in the pulmonary mesothelioma cell line (P31). Apoptosis was determined by quantifying free nucleosomes and caspase-3 activity, and cytotoxicity was determined by clone formation and a fluorometric assay. The pan-caspase enzyme inhibitor Boc-D-FMK was used to further determine the role of caspase activity in K(+)-flux-modulated cisplatin-/carboplatin-induced apoptosis and cytotoxicity. Amphotericin B (3.2 micromol/L) combined with bumetanide (100 micromol/L) potentiated cisplatin-induced free nucleosome and caspase-3 activity. The combination of the K(+) modulators did not, however, increase cisplatin cytotoxicity. The caspase inhibitor Boc-D-FMK, but unexpectedly also bumetanide, markedly reduced cisplatin cytotoxicity and annihilated the augmented cytotoxicity of cisplatin in the presence of amphotericin B. Carboplatin cytotoxicity was reduced by bumetanide, but not affected by amphotericin B. Carboplatin and carboplatin/bumetanide cytotoxicity was further reduced by Boc-D-FMK. We conclude that the ability of cisplatin, and to a lesser extent carboplatin, to induce apoptosis is indeed influenced by cellular potassium flux modulators. We suggest that K(+) ionophores such as amphotericin B, and K(+) influx blockers such as bumetanide, alone or in combination, should be further evaluated for their potential clinical usefulness in influencing tumor cell apoptosis induced by cisplatin and other cancer chemotherapeutics.


Subject(s)
Amphotericin B/pharmacology , Antineoplastic Agents/pharmacology , Antineoplastic Combined Chemotherapy Protocols/pharmacology , Apoptosis/drug effects , Bumetanide/pharmacology , Cisplatin/pharmacology , Lung Neoplasms/drug therapy , Mesothelioma/drug therapy , Potassium/metabolism , Amphotericin B/administration & dosage , Antineoplastic Agents/toxicity , Apoptosis/physiology , Bumetanide/administration & dosage , Carboplatin/pharmacology , Carboplatin/toxicity , Carrier Proteins/antagonists & inhibitors , Carrier Proteins/metabolism , Caspase 3 , Caspases/metabolism , Cisplatin/administration & dosage , Cisplatin/toxicity , Diuretics/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Humans , Lung Neoplasms/metabolism , Lung Neoplasms/pathology , Mesothelioma/metabolism , Mesothelioma/pathology , Potassium/antagonists & inhibitors , Potassium Channel Blockers , Potassium Channels/metabolism , Sodium-Potassium-Chloride Symporters , Tumor Cells, Cultured
18.
Pharmacol Toxicol ; 88(5): 244-9, 2001 May.
Article in English | MEDLINE | ID: mdl-11393584

ABSTRACT

We used 86Rb+ (K+ analogue) to study potassium influx during the interaction of highly specific 5-HT3-receptor antagonists, ondansetron and granisetron, with the effects of the anticancer drug, estramustine phosphate, on P31 mesothelioma cells. Estramustine phosphate (80 mg/l, 142 micromol/l) for 120 min. reduced 86Rb+ influx by 18.7%. The reduction was inhibited by ondansetron (0.1 micromol/l), but augmented by granisetron (0.1 micromol/l). Serotonin (1.0 micromol/l) antagonized ondansetron inhibition and restored granisetron-augmented reduction of estramustine phosphate-induced 86Rb+ influx to the level of the drug itself. Estramustine phosphate inhibited cellular Na+, K+, 2Cl- -cotransport activity whereas Na+, K+, ATPase activity was unaffected. Ondansetron blockade of estramustine phosphate-induced reduction of 86Rb+ influx was due to increased Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport whereas augmentation of estramustine phosphate-induced reduction of 86Rb+ influx by granisetron, or combination of 5-HT3 receptor antagonists with serotonin was due mainly to inhibition of cellular Na+, K+, ATPase activity Thus, ondansetron possesses a distinct ability to reverse K+ influx of tumour cells exposed to estramustine phosphate whereas granisetron does not, due to different effect on cellular Na+, K+, ATPase and Na+, K+, 2Cl- -cotransport activity. Highly 5-HT3 receptor-specific antiemetic agents may have different effects on ion transport of tumour cells during treatment with cytotoxic drugs.


Subject(s)
Estramustine/pharmacology , Granisetron/pharmacology , Ondansetron/pharmacology , Potassium/metabolism , Receptors, Serotonin/physiology , Serotonin Antagonists/pharmacology , Antiemetics/pharmacokinetics , Antiemetics/pharmacology , Antineoplastic Agents/pharmacology , Biological Transport/drug effects , Bumetanide/pharmacology , Chlorides/metabolism , Drug Interactions , Humans , Lung Neoplasms , Mesothelioma , Ouabain/pharmacology , Serotonin/pharmacology , Sodium/metabolism , Sodium-Potassium-Exchanging ATPase/antagonists & inhibitors , Symporters , Time Factors , Tumor Cells, Cultured , K Cl- Cotransporters
19.
Acta Oncol ; 40(1): 83-7, 2001.
Article in English | MEDLINE | ID: mdl-11321667

ABSTRACT

Cortisol and dehydroepiandrosterone (DHEA) and its sulphate (DHEAS) are the major steroid hormones produced by the human adrenal cortex. The serum levels of cortisol and DHEAS were analysed in 211 consecutive patients with renal cell carcinoma before initiation of therapy. Serum cortisol was significantly higher in patients with renal cell carcinoma compared with that in patients with benign cysts (p < 0.0001). Serum cortisol was independent of disease stage, but positively correlated to tumour diameter and grade. The serum levels of DHEAS were higher in men than in women, and decreased with age, but did not correlate with disease stage, tumour diameter or grade. The prognosis of patients with elevated serum cortisol tended to be poorer (p = 0.06) than the prognosis of those with lower levels. In a multivariate analysis, disease stage and tumour grade were independent predictors of prognosis. Age, gender and serum levels of cortisol and DHEAS were of limited value for prognosis.


Subject(s)
Carcinoma, Renal Cell/diagnosis , Dehydroepiandrosterone/blood , Hydrocortisone/blood , Kidney Neoplasms/diagnosis , Adult , Age Factors , Aged , Carcinoma, Renal Cell/blood , Carcinoma, Renal Cell/mortality , Female , Humans , Kidney Neoplasms/blood , Kidney Neoplasms/mortality , Male , Middle Aged , Prognosis , Sex Factors , Survival Rate
20.
Gynecol Endocrinol ; 14(3): 173-81, 2000 Jun.
Article in English | MEDLINE | ID: mdl-10923278

ABSTRACT

Somatic symptoms in the premenstrual syndrome (PMS) may have an etiology separate from that of the mental symptoms. A disturbance in mineralocorticoid action has been discussed, as mineralocorticoids regulate water balance. Desoxycorticosterone (DOC) is interesting, as it has mineralocorticoid effects and is a precursor to the neurosteroid 5 alpha-pregnan-3 alpha,21-diol-20-one (THDOC). THDOC is a steroid with direct benzodiazepine-like effects on the GABA-A receptor in the brain that is metabolized from DOC within the brain and in the periphery. Ten women with PMS having swelling as a major symptom and eight controls were recruited. They marked, on a validated visual-analog scale, three physical symptoms every evening during one menstrual cycle in conjunction with giving blood samples for progesterone and DOC measurements. DOC showed menstrual cycle-linked variation correlating with progesterone. There was no difference in plasma DOC concentrations between patients and controls. The symptoms reached a maximum 1-3 days before the onset of menstruation, with a delay of 3-6 days after the hormone peak. DOC was less strongly correlated with the symptoms than progesterone. These results do not support the hypothesis that DOC is involved in the etiology of physical symptoms in PMS or that physical and mental symptoms have separate etiologies.


Subject(s)
Desoxycorticosterone/blood , Premenstrual Syndrome/blood , Progesterone/blood , Adult , Edema/blood , Female , Humans , Menstrual Cycle/blood , Premenstrual Syndrome/etiology , Premenstrual Syndrome/psychology
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