ascorbic-acid and Ovarian-Neoplasms

Changes in dietary vitamin C intake have been related to the risks of various cancers. However, the association between dietary vitamin C intake and the risk of ovarian cancer has not been fully determined. A meta-analysis was performed to evaluate the relationship between vitamin C intake and ovarian cancer risk. Observational studies that evaluated the association between vitamin C intake and ovarian cancer risk were identified via systematic search of PubMed and Embase databases. A random-effect model was used to combine relative risk (RR) with corresponding 95% confidence intervals (CIs). As a result, 16 studies (5 cohort studies and 11 case-control studies) with 4553 cases and 439,741 participants were included. Pooled results showed that dietary vitamin C intake had non-significant association on the risk of ovarian cancer (RR = 0.95, 95%CI = 0.81-1.11, I2 = 52.1%, Pfor heterogeneity = 0.008). Subgroup analyses according to characteristics including geographic location and study design showed consistent results with the overall result. In summary, findings from the present study indicated that dietary vitamin C intake is not associated with the risk of ovarian cancer.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Ascorbic Acid; Diet; Female; Humans; Middle Aged; Observational Studies as Topic; Ovarian Neoplasms; Risk Assessment; Risk Factors; Young Adult

Ascorbate (vitamin C) was an early, unorthodox therapy for cancer, with an outstanding safety profile and anecdotal clinical benefit. Because oral ascorbate was ineffective in two cancer clinical trials, ascorbate was abandoned by conventional oncology but continued to be used in complementary and alternative medicine. Recent studies provide rationale for reexamining ascorbate treatment. Because of marked pharmacokinetic differences, intravenous, but not oral, ascorbate produces millimolar concentrations both in blood and in tissues, killing cancer cells without harming normal tissues. In the interstitial fluid surrounding tumor cells, millimolar concentrations of ascorbate exert local pro-oxidant effects by mediating hydrogen peroxide (H(2)O(2)) formation, which kills cancer cells. We investigated downstream mechanisms of ascorbate-induced cell death. Data show that millimolar ascorbate, acting as a pro-oxidant, induced DNA damage and depleted cellular adenosine triphosphate (ATP), activated the ataxia telangiectasia mutated (ATM)/adenosine monophosphate-activated protein kinase (AMPK) pathway, and resulted in mammalian target of rapamycin (mTOR) inhibition and death in ovarian cancer cells. The combination of parenteral ascorbate with the conventional chemotherapeutic agents carboplatin and paclitaxel synergistically inhibited ovarian cancer in mouse models and reduced chemotherapy-associated toxicity in patients with ovarian cancer. On the basis of its potential benefit and minimal toxicity, examination of intravenous ascorbate in combination with standard chemotherapy is justified in larger clinical trials.

Topics: Animals; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Ascorbic Acid; Carboplatin; Cell Death; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Synergism; Female; Infusions, Parenteral; Mice; Ovarian Neoplasms; Paclitaxel; Xenograft Model Antitumor Assays

Topics: Antioxidants; Ascorbic Acid; beta Carotene; Diet; Female; Follow-Up Studies; Humans; Ovarian Neoplasms; Prospective Studies; Risk Factors; Vitamin A; Vitamin E; Vitamins

Vitamin C is essential for the proper functioning of the human body and plays a crucial role in many biological processes as a cofactor for enzymes. The anticancer activity of vitamin C has been indicated for years. Hyperthermia used in clinics allows increasing the effectiveness of anticancer therapies and may also be useful in enhancing the action of other substances. The purpose of this study was to enhance the anticancer activity of vitamin C through hyperthermia against ovarian cancer cells.. The ovarian cancer cell lines Caov-3, NIH:OVCAR-3, and human fibroblasts CCD-1064Sk were tested in the present study. Vitamin C was used in the following concentrations: 0.24, 2.50 and 5.25 mM. Each of the selected concentrations was combined with the different temperatures (37°C, 40°C and 43°C). Cell survival, adhesion and changes at the molecular level were assessed.. The obtained results revealed that hyperthermia enhances the anticancer activity of vitamin C. Ovarian cancer cells showed greater sensitivity to vitamin C at elevated temperatures. Cells may have different sensitivity to vitamin C due to the activation of different gene signatures associated with redox reactions and apoptosis, therefore we examined the following genes: BCAP31, BCL2L13, BID, CASP7, FADD and HTRA2. The increase in expression of these genes in cancer cells generated a stronger proapoptotic response.. The present study showed that hyperthermia enhanced the anticancer activity of vitamin C in vitro.

Topics: Antineoplastic Agents; Apoptosis; Ascorbic Acid; Carcinoma, Ovarian Epithelial; Cell Line, Tumor; Female; Humans; Hyperthermia, Induced; Membrane Proteins; Ovarian Neoplasms

Topics: Apoptosis; Ascorbic Acid; Caspase 3; Cell Line, Tumor; Dietary Supplements; Female; Humans; Ovarian Neoplasms; Pharmaceutical Preparations; Tumor Microenvironment

The bromoalkane, 1-bromopropane (1-BP), may damage the reproductive system though oxidative stress, while the transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays an important role in regulating intracellular antioxidant levels against oxidative stress. This study explored the role of oxidative stress and the Nrf2 signaling pathway in mediating the reproductive toxicity of 1-BP using the ovarian carcinoma cell line OVCAR-3 as an

Topics: Antioxidants; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Cell Survival; Female; Humans; Hydrocarbons, Brominated; NF-E2-Related Factor 2; Ovarian Neoplasms; Oxidative Stress; Signal Transduction

Ovarian cancer is the deadliest gynecological malignancy in women, and fifth leading cause of death. Despite advances made in chemotherapy and surgery, the average time of clinical remission is approximately 2 years and the 5-year survival rate is 45%. Thus, there is an urgent need for the development of a novel therapeutic approach to ovarian cancer treatment. We investigated the effect of a specific nutrient mixture (EPQ) containing ascorbic acid, lysine, proline, green tea extract, and quercetin on human ovarian cancer cell A-2780 in vivo and in vitro. Athymic female nude mice (n = 12) were all inoculated intraperitoneally (IP) with 2 × 10⁶ cells in 0.1 mL of phosphate buffered saline (PBS) and randomly divided into two groups. Upon injection, the Control group (n = 6) was fed a regular diet and the EPQ group (n = 6) a regular diet supplemented with 0.5% EPQ. Four weeks later, the mice were sacrificed and tumors that developed in the ovary were excised, weighed, and processed for histology. Lungs were inspected for metastasis. In vitro, A-2780 cells were cultured in Dulbecco modified Eagle medium supplemented with 10% FBS and antibiotics. At near confluence, cells were treated with EPQ in triplicate at concentrations between 0 and 1000 μg/mL. Cell proliferation was measured via MTT assay, MMP-9 secretion via gelatinase zymography, invasion through Matrigel and morphology via hematoxylin and eosin (H & E) staining. All Control mice developed large ovarian tumors, whereas 5 out of 6 mice in the EPQ group developed no tumors, and one, a small tumor. Control mice also showed lung metastasis in 6 out of 6 mice, while no lung metastasis was evident in EPQ mice. Zymography demonstrated only MMP-9 expression, which EPQ inhibited in a dose-dependent fashion, with virtual total block at 250 μg/mL concentration. EPQ significantly inhibited invasion through Matrigel with total block at 250 μg/mL concentration. MTT showed dose-dependent inhibition of cell proliferation with EPQ, and H & E staining showed no morphological changes below 500 μg/mL EPQ. These results suggest that EPQ has therapeutic potential in the treatment of ovarian cancer by significantly suppressing ovarian tumor incidence and growth and lung metastasis, and by inhibiting MMP-9 secretion and invasion of A-2780 ovarian cancer cells.

Topics: Animals; Antioxidants; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Dietary Supplements; Dose-Response Relationship, Drug; Female; Humans; Lung Neoplasms; Lysine; Matrix Metalloproteinase 9; Mice; Mice, Nude; Micronutrients; Neoplasm Metastasis; Ovarian Neoplasms; Plant Extracts; Proline; Quercetin; Tea; Xenograft Model Antitumor Assays

Nonporous silica nanoparticles (SNPs) with an external shell containing primary amino groups were proposed as potential delivery systems for Pt(iv) antitumor prodrugs. Spherical SNPs containing two different external arms, i.e. 3-aminopropyl and N-(6-aminohexyl)aminomethylene, of around 125 nm hydrodynamic diameter were loaded with two different cisplatin-based Pt(iv) complexes, namely (OC-6-44)-diamminedichloridoethoxidosuccinatoplatinum(iv) and (OC-6-44)-diamminedichloridoacetylamidosuccinatoplatinum(iv), through the formation of amide bonds between the pendant amino groups on SNPs and the free carboxylic group of the complexes. In the presence of the N-(6-aminohexyl)aminomethylene arm, the Pt(iv)-SNP conjugates showed a negligible (unwanted) Pt release by hydrolysis, whereas in the presence of ascorbic acid the reduction of Pt(iv) → Pt(ii) caused the substantial release of the active metabolite cisplatin. Conjugate Pt(iv)-SNP exhibited better antiproliferative activity on the Pt-sensitive A2780 human ovarian cancer cell line than the parent cisplatin and their free Pt(iv) precursors, due to their more efficient cellular uptake, likely by endocytosis.

Topics: Antineoplastic Agents; Ascorbic Acid; Cell Line, Tumor; Cell Proliferation; Cisplatin; Drug Carriers; Endocytosis; Female; Humans; Hydrolysis; Nanoparticles; Organoplatinum Compounds; Ovarian Neoplasms; Prodrugs; Silicon Dioxide

The concept of Pt(IV) prodrug design is one advanced strategy to increase the selectivity for cancer cells and to reduce systemic toxicity in comparison to established platinum-based chemotherapy. Pt(IV) complexes are thought to be activated by reduction via physiological reductants, such as ascorbic acid or glutathione. Nevertheless, only few investigations on the link between the reduction rate, which is influenced by the reductant, and the ligand sphere of the Pt(IV) metal centre have been performed so far. Herein, we investigated a set of Pt(IV) compounds with varying rates of reduction with respect to their cytotoxicity and drug accumulation in A2780 and A2780cis ovarian cancer cell lines, their influence on the cell cycle, efficiency of triggering apoptosis, and ability to interfere with plasmid DNA (pUC19). The effects caused by Pt(IV) compounds were compared without or with extracellularly added ascorbic acid and glutathione (or its precursor N-acetylcysteine) to gain understanding of the impact of increased levels of the reductant on the activity of such complexes. Our results demonstrate that reduction is required prior to plasmid interaction. Furthermore, the rate of reduction is crucial for the efficiency of this set of Pt(IV) compounds. The substances that are reduced least likely showed similar performances, whereas the fastest reducing substance was negatively affected by an increased extracellular level of reducing agents, with reduced cytotoxicity and lower efficiency in inducing apoptosis and G2/M arrest. These results confirm the connection between reduction and activity, and prove the strong impact of the reduction site on the activity of Pt(IV) complexes.

Topics: Antineoplastic Agents; Apoptosis; Ascorbic Acid; Cell Cycle Checkpoints; Cell Line, Tumor; Female; Glutathione; Humans; Organoplatinum Compounds; Ovarian Neoplasms; Ovary; Oxidative Stress; Reducing Agents

Vitamins A, C, and E and folate have anticarcinogenic properties and thus might protect against cancer. Few known modifiable risk factors for ovarian cancer exist. We examined the associations between dietary and total (food and supplemental) vitamin intake and the risk of invasive epithelial ovarian cancer.. The primary data from 10 prospective cohort studies in North America and Europe were analyzed. Vitamin intakes were estimated from validated food frequency questionnaires in each study. Study-specific relative risks (RRs) were estimated using the Cox proportional hazards model and then combined using a random-effects model.. Among 501,857 women, 1,973 cases of ovarian cancer occurred over a median follow-up period of 7-16 years across studies. Dietary and total intakes of each vitamin were not significantly associated with ovarian cancer risk. The pooled multivariate RRs [95% confidence intervals (CIs)] for incremental increases in total intake of each vitamin were 1.02 (0.97-1.07) for vitamin A (increment: 1,300 mcg/day), 1.01 (0.99-1.04) for vitamin C (400 mg/day), 1.02 (0.97-1.06) for vitamin E (130 mg/day), and 1.01 (0.96-1.07) for folate (250 mcg/day). Multivitamin use (vs. nonuse) was not associated with ovarian cancer risk (pooled multivariate RR = 1.00, 95% CI 0.89-1.12). Associations did not vary substantially by study, or by subgroups of the population. Greater vitamin intakes were associated with modestly higher risks of endometrioid tumors (n = 156 cases), but not with other histological types.. These results suggest that consumption of vitamins A, C, and E and folate during adulthood does not play a major role in ovarian cancer risk.

Topics: Adult; Ascorbic Acid; Carcinoma, Ovarian Epithelial; Cohort Studies; Dietary Supplements; Europe; Female; Folic Acid; Humans; Middle Aged; Neoplasms, Glandular and Epithelial; North America; Ovarian Neoplasms; Prospective Studies; Risk; Vitamin A; Vitamin E; Vitamins

Estradiol 17β (E2β) and ascorbic acid (AA) have been implicated in cancer progression. However, little is known about the actions of biologically active metabolites of E2β, 2-hydroxyestradiol (2OHE2), 4-hydroxyestradiol (4OHE2), 2-methoxyestradiol (2ME2), and 4-methoxyestradiol (4ME2) synthesized sequentially by cytochrome P450, family 1, subfamily A (CYP1A1) and B (CYP1B1), polypeptide 1, and catechol-O-methyltransferase (COMT) on ovarian cancer. Herein, we examined the expression of CYP1A1, CYP1B1, COMT, and estrogen receptor α (ERα) and β (ERβ) in human ovarian surface epithelial (IOSE-385) and cancer cell lines (OVCAR-3, SKOV-3, and OVCA-432). We also investigated the roles of E2β, 2OHE2, 4OHE2, 2ME2, and 4ME2 in cell proliferation, and their interactive effects with AA on ovarian cells. We found the expression of CYP1A1, CYP1B1, COMT, ERα, and ERβ in most cell lines tested. Treating cells with physiological concentrations of E2β and its metabolites promoted (13%-42% of the control) IOSE-385 and OVCAR-3 proliferation. The ER blockade inhibited IOSE-385 (∼76%) and OVCAR-3 (∼87%) proliferative response to E2β but not to its metabolites. The ERα blockade inhibited (∼85%) E2β-stimulated OVCAR-3 proliferation, whereas ERβ blockade attenuated (∼83%) E2β-stimulated IOSE-385 proliferation. The AA at ≥250 μmol/L completely inhibited serum-stimulated cell proliferation in all cell lines tested; however, such inhibition in IOSE-385, OVCAR-3, and OVCA-432 was partially (∼10%-20%) countered by E2β and its metabolites. Thus, our findings indicate that E2β and its metabolites promote cell proliferation and antagonize the AA-suppressed cell proliferation in a subset of ovarian cancer cells, suggesting that blocking the actions of E2β and its metabolites may enhance AA's antiovarian cancer activity.

Topics: 2-Methoxyestradiol; Aryl Hydrocarbon Hydroxylases; Ascorbic Acid; Catechol O-Methyltransferase; Cell Line, Tumor; Cell Proliferation; Cytochrome P-450 CYP1A1; Cytochrome P-450 CYP1B1; Dose-Response Relationship, Drug; Drug Interactions; Estradiol; Estrogen Antagonists; Estrogen Receptor alpha; Estrogen Receptor beta; Estrogens, Catechol; Female; Humans; Ovarian Neoplasms; Time Factors

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Female; Infusions, Parenteral; Ovarian Neoplasms

Topics: Administration, Intravenous; Antineoplastic Agents; Ascorbic Acid; Chemotherapy, Adjuvant; Dose-Response Relationship, Drug; Female; Humans; Ovarian Neoplasms

Ascorbic acid (Vitamin C) administration has been used to prevent infectious diseases in public or as a therapeutic agent by the physicians in treatment of several diseases. Ascorbic acid is also involved in immune cell functions and immune responses, although the mechanisms by which it exerts effects on immune cells against cancer cells are not fully understood at the normal plasma level. In this study, we used the mice lacking l-gulono-γ-lactone oxidase (Gulo), the enzyme required for the biosynthesis of ascorbic acid, to characterize the effects of ascorbic acid on NK cell cytotoxicity against ovarian cancer cells, MOSECs (murine ovarian surface epithelial cells). Gulo(-/-) mice depleted of ascorbic acid survived for a shorter time than the normal control or Gulo(-/-) mice supplemented with ascorbic acid after tumor challenge regardless of treatment with IL-2. CD69 and NKG2D expression was clearly reduced in NK cells isolated from mice depleted of ascorbic acid as compared to that in the normal control and the mice supplemented with ascorbic acid. We also observed that IFN-γ secretion by NK cells isolated from Gulo(-/-) mice depleted of ascorbic acid was decreased after NK cells were co-cultured with MOSECs. Furthermore, the mRNA expression of perforin and granzyme B genes was also significantly decreased in NK cells isolated from mice depleted of ascorbic acid. Taken together, our results suggest that ascorbic acid at the normal plasma concentration has an essential role in maintaining the NK cytotoxicity against cancer cells.

Topics: Animals; Antigens, CD; Antigens, Differentiation, T-Lymphocyte; Antioxidants; Apoptosis; Ascorbic Acid; Cell Line, Tumor; Cell Transformation, Neoplastic; Cytotoxicity, Immunologic; Disease Models, Animal; Female; Granzymes; Killer Cells, Natural; Lectins, C-Type; Lymphocyte Activation; Mice; Mice, Inbred BALB C; Mice, Knockout; NK Cell Lectin-Like Receptor Subfamily K; Ovarian Neoplasms; Perforin

The potential of arsenic trioxide (As2O3) as a novel therapy against ovarian cancer has been progressively recognized. Its prospective usefulness for treatment of this malignancy either alone or in combination with other chemotherapeutic agents has been increasingly explored. In this study, we attempted to enhance the cytotoxicity of As2O3 in ovarian cancer cells through manipulation of cellular glutathione (GSH) levels using either buthionine sulfoximine (BSO) or ascorbic acid (AA). Results from our studies showed that combinatorial therapies using As2O3 with either low dose BSO or only pharmacological doses of AA acted synergistically to enhance the cytotoxicity of As2O3 in ovarian tumor cells. With these regimens, therapeutic selectivity was observed with preferential killing of ovarian tumor cells over normal fibroblast controls. Furthermore, contrary to previous reports, enhancement of As2O3-mediated cell killing by these two agents was propagated through different effects. With BSO, apoptotic and non-apoptotic cell death enhancement were mediated through increased arsenic accumulation and GSH depletion that occurred independently of reactive oxygen species. With pharmacological doses of AA, increase in cell death proceeded through non-apoptotic routes via an oxidative stress-related pathway independent of GSH levels. Taken together, these results indicate that GSH depleting agents or pro-oxidative chemicals have capabilities of improving the utility of As2O3 in ovarian cancer management.

Topics: Antineoplastic Agents; Apoptosis; Arsenic Trioxide; Arsenicals; Ascorbic Acid; Buthionine Sulfoximine; Cell Death; Cell Line, Tumor; Drug Synergism; Female; Fibroblasts; Glutathione; Glutathione Peroxidase; Humans; Intracellular Space; Ovarian Neoplasms; Oxidative Stress; Oxides

Antioxidant nutrients and carotenoids have been inconsistently associated with ovarian cancer risk. We examined the relationship between intake of dietary and supplemental antioxidant nutrients including vitamins C, E, and selenium as well as carotenoids and vitamin A and ovarian cancer in 133,614 postmenopausal women enrolled in the Women's Health Initiative (WHI) study. Dietary intake was assessed using a food frequency questionnaire, and ovarian cancer endpoints were centrally adjudicated. Cox regression models were used to estimate the risk for invasive ovarian cancer in relation to each of the antioxidant nutrients and carotenoids under consideration using models stratified for a WHI study component. A total of 451 cases of invasive ovarian cancer were diagnosed over 8.3 yr of follow-up. Dietary intake at baseline was not significantly different for cases vs. controls. Cases reported greater intake of supplemental vitamin C (358.0 mg/day vs. 291.6 mg/day, respectively; P = 0.024). Multivariate modeling (P for trend) of the risk for developing ovarian cancer did not suggest any significant relationships among dietary factors and ovarian cancer risk. The results from this prospective study of well-nourished, postmenopausal women suggest that intake of dietary antioxidants, carotenoids, and vitamin A are not associated with a reduction in ovarian cancer risk.

Topics: Aged; Antioxidants; Ascorbic Acid; Carotenoids; Female; Humans; Middle Aged; Ovarian Neoplasms; Prospective Studies; Vitamin A

Topics: Adult; Antioxidants; Ascorbic Acid; Canada; Carotenoids; Diet Surveys; Female; Humans; Longitudinal Studies; Middle Aged; Multivariate Analysis; Ovarian Neoplasms; Proportional Hazards Models; Prospective Studies; Risk; Vitamin A; Vitamin E; Vitamins

Based on the poor prognosis associated with ovarian cancer and reported anticancer properties of specific nutrients, we investigated the effect of a nutrient mixture (NM) containing lysine, proline, arginine, ascorbic acid and epigallocatechin gallate on human ovarian cancer cells SK-OV-3 by measuring: cell proliferation, modulation of matrix metalloproteinase (MMP)-2 and -9 expression, and cancer cell invasive potential.. Cell proliferation was evaluated by MTT assay, MMP activity by gelatinase zymography, and invasion through Matrigel.. Human ovarian cancer cell growth was not significantly affected by the NM. Zymography demonstrated inhibition of MMP-2 secretion in a dose-dependent fashion with virtual total inhibition at 50 microg/mL NM concentration. Invasion of human ovarian cancer cells through Matrigel decreased in a dose-dependent fashion, with 90% inhibition at 500 microg/mL NM and 100% inhibition at 1000 microg/mL NM (P < 0.0001).. The combination of lysine, proline, arginine, ascorbic acid and green tea extract tested inhibited critical steps in cancer development and spread, such as MMP expression and invasion, indicating its potential as a treatment modality against ovarian cancer.

Topics: Amino Acids; Arginine; Ascorbic Acid; Cell Division; Cell Line, Tumor; Enzyme Inhibitors; Female; Humans; Lysine; Matrix Metalloproteinase 2; Matrix Metalloproteinase Inhibitors; Neoplasm Invasiveness; Ovarian Neoplasms; Proline; Tea

Ovarian cancer is the leading cause of death due to gynecological malignancies among women. The extent of free radical induced oxidative stress can be exacerbated by the decreased efficiency of antioxidant mechanisms. The present study was conducted to investigate the extent of oxidative stress and the levels of antioxidants in the circulation of ovarian cancer patients.. Plasma thiobarbituric acid reactive substances (TBARS) and conjugated dienes (CD) and the levels of antioxidants such as superoxide dismutase (SOD), catalase (CAT), vitamin C and vitamin E were estimated in the circulation of 30 ovarian cancer patients and an equal number of age-matched normal subjects as control.. Significantly increased concentrations of plasma TBARS and CD and significantly lowered levels of SOD, CAT, vitamin C and vitamin E were observed in ovarian cancer patients as compared with normal subjects.. The low levels of SOD, CAT, vitamin C and vitamin E in the plasma of ovarian cancer patients may be due to their increased utilization to scavenge lipid peroxides as well as their sequestration by tumor cells. Increased levels of lipid peroxidation may be due to excessive oxidative stress caused by incessant ovulation or epithelial inflammation.

Topics: Antioxidants; Ascorbic Acid; Catalase; Female; Humans; Lipid Peroxidation; Ovarian Neoplasms; Oxidative Stress; Superoxide Dismutase; Thiobarbituric Acid Reactive Substances; Vitamin A

Microscopic aspects, densitometric evaluation of Feulgen-stained DNA, and gel electrophoresis of total DNA have been used to elucidate the effects of 1, 2, and 3 h VC (ascorbic acid), VK3 (menadione), and combined VC:VK3 treatments on the cellular and nuclear morphology and DNA content of a human ovarian carcinoma cell line (MDAH 2774). Optical densitometry showed a significant decrease in cancer cell DNA content directly related to VC and VC:VK3 treatments while VK3 and VC:VK3 treated cells exhibited cytoskeletal changes that included self-excision of cytoplasmic pieces with no membranous organelles. Nuclei decreased in size and exhibited poor contrast consistent with progressive decondensation of their chromatin. Degraded chromatin was also detected in cytoplasmic autophagosomes. Nucleoli segregated their components and fragmented into small pieces. Gel electrophoretic analysis of total DNA revealed evidence of generalized DNA degradation specific to treated tumor cells. These results are consistent with previous observations [Scanning 20 (1998a) 564; Ultrastruct. Pathol. 25 (2001b) 183; J. Histochem. Cytochem. 49 (2001) 109] which demonstrated that the VC:VK3 combination induced autoschizic cell death by a series of cytoplasmic excisions without organelles along with specific nuclear ultrastructural damage.

Topics: Antineoplastic Agents; Ascorbic Acid; Cell Death; Cell Line; Cell Line, Tumor; Cell Nucleus; Cell Proliferation; Chromatin; Chromatin Assembly and Disassembly; Cytoskeleton; DNA Fragmentation; DNA, Neoplasm; Female; Humans; Intracellular Membranes; Ovarian Neoplasms; Reactive Oxygen Species; Vitamin K 3

Ultrasound could potentiate cytotoxicity of adriamycin on cancer cell line as a result of increased intracellular accumulation ascribed to cavitation. In order to determine which free radical led to increase of drug content, effects of the free radical scavenger and antioxidant on increased intracellular adriamycin accumulation by ultrasound were investigated. The intracellular drug content of adriamycin was lower in the group where histidine was administrated before ultrasound exposure and in the group where mannitol was added after sonication. Drug accumulation was also decreased in groups in which vitamin C administrated either before or after ultrasonic exposure. These results suggested that hydroxyl radical play the leading role in synergism between ultrasound and adriamycin.

Topics: Antineoplastic Agents; Antioxidants; Ascorbic Acid; Doxorubicin; Drug Synergism; Female; Free Radical Scavengers; Histidine; Humans; Intracellular Fluid; Mannitol; Ovarian Neoplasms; Tumor Cells, Cultured; Ultrasonics

Hypoxia-inducible factor (HIF) plays an important role in determining patterns of gene expression in cancer. HIF is down-regulated in oxygenated cells by a series of Fe (II) and 2-oxoglutarate dependent dioxygenases that hydroxylate specific residues in the regulatory HIF-alpha subunits. Because these enzymes require ascorbate for activity in vitro we analyzed the effects of ascorbate on HIF in human cancer cell lines. Ascorbate at physiological concentrations (25 micro M) strikingly suppressed HIF-1alpha protein levels and HIF transcriptional targets, particularly when the system was oncogenically activated in normoxic cells. Similar results were obtained with iron supplementation. These results indicate that both ascorbate and iron availability have major effects on HIF, and imply that the system is commonly regulated by limiting hydroxylase activity under normoxic tissue culture conditions.

Topics: Adenocarcinoma; Ascorbic Acid; Breast Neoplasms; Cell Hypoxia; Endothelial Growth Factors; Female; Ferrous Compounds; Glucose Transporter Type 1; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Intercellular Signaling Peptides and Proteins; Lymphokines; Male; Monosaccharide Transport Proteins; Neoplasms; Ovarian Neoplasms; Procollagen-Proline Dioxygenase; Prostatic Neoplasms; RNA, Messenger; Transcription Factors; Transcriptional Activation; Transferrin; Tumor Cells, Cultured; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors

Human ovarian carcinoma cells (MDAH 2774) were treated with sodium ascorbate (VC), menadione (VK3), or with a VC:VK3 combination for 1 h and then studied using light microscopy (LM) and scanning (SEM) and transmission electron (TEM) microscopy. Plasma membrane damage (blisters and blebs, hairy aspect) results from vitamin C (VC) treatment, while cytoskeletal damage and self-morsellation are caused by vitamin K3 (VK3) treatment. VC:VK3-treated cells exhibit exacerbated injuries characteristic of both VC and VK3 treatment as well as a significant decrease in cell diameters from 20-35 microm for control cells to 7-12 microm for VC:VK3 treatment. Moreover, after a 1-h exposure to the vitamin combination, autoschizis (43%), apoptosis (3%), and oncosis (1.9%) are observed at the percentages indicated. All cellular changes associated with autoschizis observed with SEM were confirmed by LM and TEM observations and are consistent with cell death by autoschizis: decrease in cell size, cytoplasmic self-excisions, degradation of the nucleus and nucleolus without formation of apoptotic bodies and, ultimately, karyorrhexis and karyolysis. These results also suggest that the vitamin combination may find clinical use in the treatment of ovarian cancer.

Topics: Ascorbic Acid; Cell Death; Drug Combinations; Female; Humans; Microscopy; Microscopy, Electron, Scanning; Ovarian Neoplasms; Tumor Cells, Cultured; Vitamin K 3

Antioxidant vitamins may decrease risk of cancer by limiting oxidative DNA damage leading to cancer initiation. Few prospective studies have assessed relations between antioxidant vitamins and ovarian carcinoma.. The authors prospectively assessed consumption of vitamins A, C, and E and specific carotenoids, as well as fruit and vegetable intake, in relation to ovarian carcinoma risk among 80,326 participants in the Nurses' Health Study who had no history of cancer other than nonmelanoma skin carcinoma. Women reported on known and suspected ovarian carcinoma risk factors including reproductive factors, smoking, and use of vitamin supplements on biennial mailed questionnaires from 1976 to 1996. Food frequency questionnaires were included in 1980, 1984, 1986, and 1990. The authors confirmed 301 incident cases of invasive epithelial ovarian carcinoma during 16 years of dietary follow-up (1980-1996). Pooled logistic regression was used to control for age, oral contraceptive use, body mass index, smoking history, parity, and tubal ligation.. The authors observed no association between ovarian carcinoma risk and antioxidant vitamin consumption from foods, or foods and supplements together. The multivariate relative risks (95% confidence intervals [CIs]) for ovarian carcinoma among women in the highest versus lowest quintile of intake were 1.04 (95% CI, 0.72-1.51) for vitamin A from foods and supplements; 1.01 (95% CI, 0.69-1.47) for vitamin C; 0.88 (95% CI, 0.61-1.27) for vitamin E; and 1.10 (95% CI, 0.76-1.59) for beta-carotene. Among users of vitamin supplements, the authors found no evidence of an association between dose or duration of any specific vitamin and ovarian carcinoma risk, although the authors had limited power to assess these relations. No specific fruits or vegetables were associated significantly with ovarian carcinoma risk. The authors found no association between ovarian carcinoma and consumption of total fruits or vegetables, or specific subgroups including cruciferous vegetables, green leafy vegetables, legumes, or citrus fruits. Women who consumed at least 2.5 total servings of fruits and vegetables as adolescents had a 46% reduction in ovarian carcinoma risk (relative risk, 0.54, 95% CI, 0.29-1.03; P value for trend 0.04).. These data do not support an important relation between consumption of antioxidant vitamins from foods or supplements, or intake of fruits and vegetables, and incidence of ovarian carcinoma in this cohort. However, modest associations cannot be excluded, and the authors' finding of an inverse association for total fruit and vegetable intake during adolescence raises the possibility that the pertinent exposure period may be much earlier than formerly anticipated.

Topics: Adolescent; Adult; Ascorbic Acid; Carotenoids; Cohort Studies; Diet; Dietary Supplements; DNA Damage; Female; Fruit; Humans; Middle Aged; Ovarian Neoplasms; Prospective Studies; Risk Assessment; Vegetables; Vitamin A; Vitamin E

Several studies of dietary and serum antioxidant micronutrients (vitamins A, C, and E and beta-carotene) suggest that higher levels may be protective for ovarian cancer. None of these has examined supplements. We used a food frequency questionnaire and additional questions on supplements to study 168 histologically confirmed epithelial ovarian cancer cases, 159 community controls, and 92 hospital-based controls. Antioxidant consumption from diet or supplements was calculated in milligrams or international units per day. In multivariate analyses using only community controls, the highest levels of intake of vitamins C and E from supplements were protective: odds ratio (OR) = 0.40 [95% confidence interval (CI) = 0.21-0.78] and OR = 0.33 (95% CI = 0.18-0.60), respectively. Consumption of antioxidants from diet was unrelated to risk. In analyses combining antioxidant intake from diet and supplements, vitamins C (> 363 mg/day) and E (> 75 mg/day) were associated with reduced risks: OR = 0.45 (95% CI = 0.22-0.91) and OR = 0.44 (95% CI = 0.21-0.94), respectively. Results were similar, with some attenuation toward the null, in analyses combining both control groups. The levels of vitamins C and E associated with the protective effect were well above the current US Recommended Dietary Allowances. These findings support the hypothesis that antioxidant vitamins C and E from supplements are related to a reduced risk of ovarian cancer.

Topics: Adult; Aged; Analysis of Variance; Antioxidants; Ascorbic Acid; Case-Control Studies; Diet; Dietary Supplements; Female; Humans; Logistic Models; Middle Aged; Nutrition Policy; Odds Ratio; Ovarian Neoplasms; Risk Factors; Surveys and Questionnaires; Vitamin E

A fast and high yielding method of 188Re radiolabelling DD-3B6/22 Fab' is described. An inert atmosphere [N2(g)] and ascorbic acid was essential for preparation and storage of therapeutic levels (< or =2 GBq/mg) for up to 24 h. Immunoreactivity was greater than 75%. Pharmacokinetic studies in nu/nu mice demonstrated localisation of 188Re DD-3B6/22 Fab' was equivalent and correlated well with the behaviour observed for 99mTc DD-3B6/22 Fab' used to image ovarian cancer. Excellent stability at the target site in vivo supports the potential use of 188Re DD-3B6/22 Fab' in the therapy of ovarian cancer.

Topics: Animals; Ascorbic Acid; Female; Gluconates; Immunoglobulin Fab Fragments; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Ovarian Neoplasms; Oxidation-Reduction; Radioimmunodetection; Radioisotopes; Radiopharmaceuticals; Radiotherapy; Rhenium; Technetium

In a hospital-based case-control study of common malignant epithelial tumors of the ovary, conducted in Athens (1989-1991), 189 cases were compared with 200 hospital visitor controls. Personal interviews were conducted in all cases and diet was ascertained through a semi-quantitative food frequency questionnaire. Nutrient intakes for individuals were estimated by multiplying the nutrient content of a typical portion size for each specified food item by the frequency at which the food was consumed per month and summing these estimates for all food items. Data were analyzed using logistic regression, controlling for non-dietary confounding factors, total energy intake and, among nutrients, mutual confounding influences. Adjusted odds ratios (rate ratios) for ovarian cancer, associated with particular nutritional variables, were expressed in terms of increments approximately equal to the standard deviations of (the residual of) the respective nutrients, on a daily basis. The adjusted odds ratios (and 95% confidence intervals) were 0.80 (0.65-0.99) for mono-unsaturated fat and 0.73 (0.61-0.87) for crude fiber. No substantial, statistically significant or consistent independent associations were noted for total energy, total protein, saturated fat, polyunsaturated fat, dietary cholesterol, total carbohydrates, sucrose, vitamin C, vitamin A, riboflavin or calcium. These associations, if causal, could explain to some extent the relatively low incidence of ovarian cancer in Greece and other Mediterranean countries as well as the increasing incidence trends noted in these countries during the last few decades.

Topics: Adult; Aged; Ascorbic Acid; Case-Control Studies; Cholesterol, Dietary; Diet; Dietary Fats; Dietary Fiber; Feeding Behavior; Female; Greece; Humans; Middle Aged; Ovarian Neoplasms; Vitamin A

The deuterated benzaldehyde derivative zilascorb(2H), 5,6-O-benzylidene-d-L-ascorbic acid, was administered once daily by i.v. injection in nude mice with grafted tumours of a human malignant melanoma (E.E.) and ovarian carcinoma (OVCAR-3) origins. Like benzaldehyde, zilascorb(2H) has been shown to induce protein synthesis inhibition at otherwise non-toxic doses in cells grown in vitro, and acts reversibly in the sense that protein synthesis returns to normal shortly after removal of the drug. The present data indicate that daily injections with zilascorb(2H) induce a tumour volume growth inhibitory effect in both tumour xenografts studied. Furthermore, from histological examinations of each single tumour it was found that tumours of drug-treated animals, although smaller than those of placebo-treated (i.e. control) animals, had, on average, a higher necrotic fraction than control tumours. Thus, it is concluded that zilascorb(2H) induces tumour necrotisation and not just inhibition of the rate of tumour cell production. Continued measurement of tumour volume after ended treatment with zilascorb(2H) indicated that surviving tumour cells resumed their normal growth rate immediately. The reversibility of the effect induced by this compound, earlier observed in vitro only, is therefore here confirmed to be valid also in two different tumour xenografts in vivo. The present data accords well with the assumption that protein synthesis inhibition is the primary cellular effect of zilascorb(2H) in vivo. We therefore conclude that zilascorb(2H)-induced cancer cell lethality in tumour xenografts probably comes as a secondary consequence of prolonged protein synthesis inhibition.

Topics: Animals; Antineoplastic Agents; Ascorbic Acid; Benzylidene Compounds; Cell Division; Deuterium; Dose-Response Relationship, Drug; Female; Humans; Male; Melanoma; Mice; Mice, Inbred BALB C; Mice, Nude; Middle Aged; Necrosis; Neoplasm Proteins; Neoplasm Transplantation; Ovarian Neoplasms; Transplantation, Heterologous

The role of oxygen-derived free radicals in the cytotoxicity of doxorubicin (Dox) was studied in a Dox sensitive human ovarian cancer cell line (A2780) and its multidrug resistant counterpart (2780AD) using reactive oxygen scavengers. In both cell lines, a significant inhibition of Dox toxicity was found after treatment with the hydroxyl radical scavengers, N-acetylcysteine, sodium benzoate and dimethyl sulfoxide, but not with mannitol. The protection was similar in sensitive and resistant cells: 13-39% less growth inhibition was found at Dox concentrations of 0.2 and 0.5 microM for A2780 as well as at 20 and 50 microM for 2780AD. This protection was not due to effects of the scavengers on Dox accumulation, as shown by uptake experiments with radio-labelled Dox. The superoxide anion free radical scavenger ascorbic acid or the enzyme superoxide dismutase as well as the hydrogen peroxide scavenger catalase did not protect cells against Dox-induced cell growth inhibition. Preloading the cells with the enzymes, a treatment which resulted in a two to nine-fold increase in their cellular contents, was not effective either. It is concluded that hydroxyl radicals, but not superoxide anion or hydrogen peroxide likely play a role in the antitumor activity of Dox in sensitive and resistant human ovarian cancer cells.

Topics: Acetylcysteine; Ascorbic Acid; Benzoates; Benzoic Acid; Catalase; Cell Division; Cell Survival; Doxorubicin; Drug Resistance; Female; Free Radicals; Humans; Hydroxides; Hydroxyl Radical; Kinetics; Mannitol; Ovarian Neoplasms; Oxygen; Superoxide Dismutase; Tumor Cells, Cultured

Topics: Adenocarcinoma; Adult; Aged; Ascorbic Acid; Cell Migration Inhibition; Female; Humans; Leukocyte Adherence Inhibition Test; Leukocytes; Middle Aged; Ovarian Neoplasms; Rosette Formation; Vitamin A

Topics: Adult; Aged; Ascorbic Acid; Carcinoma, Papillary; Female; Humans; Immunoglobulins; Lymphocyte Activation; Middle Aged; Ovarian Neoplasms; Oxidation-Reduction; RNA, Neoplasm

The levels of ascorbic acid were measured in the tissue of 53 ovarian carcinomas and compared to concentrations in normal human ovarian tissue. The mean ascorbic acid concentrations per gram of tissue was 218 microgram in carcinoma tissue and 382 microgram in intact ovarian tissue. The difference was significant, with p less than 0.001. A relationship was found to exist between ascorbic acid concentrations in tumor tissue, on the one hand, stages of the disease, on the other. The importance of ascorbic acid to tumour growth is discussed.

Topics: Adult; Aged; Ascorbic Acid; Female; Humans; Middle Aged; Ovarian Neoplasms; Ovary

Ascorbic acid metabolism is associated with a number of mechanisms known to be involved in host resistance to malignant disease. Cancer patients are significantly depleted of ascorbic acid, and in our opinion this demonstrable biochemical characteristic indicates a substantially increased requirement and utilization of this substance to potentiate these various host resistance factors. The results of a clinical trial are presented in which 100 terminal cancer patients were given supplemental ascorbate as part of their routine management. Their progress is compared to that of 1000 similar patients treated identically, but who received no supplemental ascorbate. The mean survival time is more than 4.2 times as great for the ascorbate subjects (more than 210 days) as for the controls (50 days). Analysis of the survival-time curves indicates that deaths occur for about 90% of the ascorbate-treated patients at one-third the rate for the controls and that the other 10% have a much greater survival time, averaging more than 20 times that for the controls. The results clearly indicate that this simple and safe form of medication is of definite value in the treatment of patients with advanced cancer.

Topics: Adult; Aged; Ascorbic Acid; Breast Neoplasms; Bronchial Neoplasms; Colonic Neoplasms; Female; Humans; Kidney Neoplasms; Male; Middle Aged; Neoplasms; Ovarian Neoplasms; Rectal Neoplasms; Stomach Neoplasms; Terminal Care; Urinary Bladder Neoplasms

The authors report the results of studies on the content of ascorbic acid, pyruvic acid and the activity of malate dehydrogenase decarboxylizing (MDHD) in cell nuclei of uterine fibromyoma, glandular hyperplasia of the endometrium with epithelial proliferation, common ovarian cyst and solid cancer. It was shown that due to the glycolysis inhibited respiration an oxidated form of ascorbic acid is absent in every case, whereas the MDHD activity is not manifested. The amount of a reduced form of ascorbic and pyruvic acid in benign tumors is at the control level, but in malignant growth these indices are markedly increased.

Topics: Ascorbic Acid; Carcinoma; Cell Nucleus; Decarboxylation; Endometrial Hyperplasia; Female; Humans; Hydroxy Acids; Keto Acids; Leiomyoma; Malate Dehydrogenase; Ovarian Cysts; Ovarian Neoplasms; Pyruvates; Uterine Neoplasms

Topics: Acidosis; Adult; Aged; Ascorbic Acid; Female; Glucose; Humans; Insulin; Intestinal Neoplasms; Lung Neoplasms; Male; Middle Aged; Ovarian Neoplasms; Premedication; Pyridoxine; Stomach Neoplasms; Thiamine; Thiamine Pyrophosphate; Uterine Neoplasms

Topics: Androstanes; Androstenols; Ascorbic Acid; Cobalt Isotopes; Convalescence; Cystine; Drug Synergism; Female; Genital Neoplasms, Female; Humans; Ovarian Neoplasms; Pantothenic Acid; Pyridoxine; Radioisotope Teletherapy; Thiamine; Uterine Cervical Neoplasms; Uterine Neoplasms; Vitamin A; Vitamin B 12; Vitamin B Complex

Topics: Ascorbic Acid; Blood Transfusion; Brazil; Breast Neoplasms; Cyclophosphamide; Female; Humans; Neoplasms; Ovarian Neoplasms; Thyroid Hormones; Urethral Neoplasms; Uterine Cervical Neoplasms; Vaginal Neoplasms; Vitamin B 12; Vitamin B Complex