Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C1140680 (ovarian cancer)
 28,141 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ascites from ovarian cancer patients contain potent growth-promoting activity toward human ovarian cancer cells both in vitro and in vivo. This activity is associated with rapid increases in cytosolic free calcium ([Ca2+]i) as a consequence of phosphoinositide hydrolysis. In this study, we describe the purification, characterization, and identification of an ovarian cancer activating factor (OCAF) from ascites of ovarian cancer patients. We have isolated OCAF by a combination of solvent extraction, silica gel chromatography, and TLC. Mass spectral analysis, phospholipase sensitivity, and gas chromatographic behavior of purified OCAF indicate that OCAF is composed of various species of lysophosphatidic acid (LPA), including LPAs with polyunsaturated fatty acyl chains (linoleic, arachidonic, and docosahexaenoic acids). However, OCAF is more potent than sn-1 palmitoyl, oleoyl, or stearoyl LPA in increasing [Ca2+]i in ovarian cancer cells. The ability of OCAF to alter [Ca2+]i is sensitive to the effects of lipoxidase, whereas the activity of sn-1 oleoyl, stearoyl, or palmitoyl LPA is not, suggesting that polyunsaturated bonds in the fatty acyl chain of OCAF may account for its increased ability to activate ovarian cancer cells. Furthermore, a sn-2 linoleoyl LPA generated by phospholipase A1 treatment of synthetic phosphatidic acid is much more active than are sn-1 palmitoyl, stearoyl, or oleoyl LPA in increasing [Ca2+]i in ovarian cancer cells. Taken together, these data suggest that the ability of OCAF to increase cellular calcium may reside in the structure and/or location of the fatty acyl chain of LPA. Purified OCAF, at concentrations similar to those present in ascites from ovarian cancer patients, was sufficient to induce proliferation of ovarian cancer cells, as indicated by thymidine incorporation, reduction of 3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide, or colony formation. However, even at optimal concentrations of OCAF, proliferation was lower than that induced by FCS or ascites from ovarian cancer patients, indicating that, although OCAF may be a major regulator of ovarian cancer cells in vivo, it is not the sole mediator present in ascites, and it likely functions in concert with other growth factor activities.
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PMID:Characterization of an ovarian cancer activating factor in ascites from ovarian cancer patients. 981 16

The current treatment concept of ovarian cancer consists of radical surgery with subsequent chemotherapy. We have shown that adenovirus (ADV) mediated thymidine kinase (TK) gene transduction of cisplatin-resistant human ovarian cancer xenotransplanted into nude mice followed by ganciclovir (GCV) administration leads to prolongation of survival or cure. In this study the interaction of ADV-TK gene therapy and selected chemotherapeutic agents commonly used for the treatment of ovarian cancer was investigated in three ovarian cancer cell lines with different growth patterns. Toxicity and cell killing efficacy of gene therapy, chemotherapy and their combinations with different concentrations and time intervals were measured by a 3-(4,5- dimethylthiazol)-2,5-diphenyl tetrazolium bromide (MTT) based assay. A slightly increased resistance to gene therapy was observed in cells pretreated with chemotherapy. Removal of the drugs restored the previous susceptibility of the cells to gene therapy. No antagonism was observed with gene therapy followed by chemotherapy. The concomitant application of gene therapy and chemotherapy resulted in a higher rate of cell death than the interval therapy. A dose dependent synergistic interaction was observed only for the combination of gene therapy and the topoisomerase 1 inhibitor topotecan. This synergistic effect was still seen even if the chemotherapeutic agent was added 72 hours later. Our data demonstrate that in addition to its own therapeutic efficacy, ADV-TK based gene therapy may enhance the effect of subsequent chemotherapy while up-front chemotherapy was disadvantageous.
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PMID:Adenovirus mediated thymidine kinase gene therapy may enhance sensitivity of ovarian cancer cells to chemotherapeutic agents. 985 18

Paclitaxel and methotrexate are active against a variety of solid tumors. Because of differences in their mechanisms of action and toxicity profiles, the combination of these two agents has clinical potential. Clinical studies of this combination are in progress. We studied the optimal schedule of paclitaxel and methotrexate in combination at various schedules in vitro using human lung cancer A549, breast cancer MCF7, ovarian cancer PA1, and colon cancer WiDr cells. Cells were simultaneously exposed to paclitaxel and methotrexate for 24 h and sequentially exposed to paclitaxel for 24 h followed by methotrexate for 24 h or vice versa. Cell growth inhibition after 5 days was determined by a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. The effects of drug combinations at the concentration of drug that produced 80% cell growth inhibition (the IC80 level) were analyzed by the isobologram method. The simultaneous exposure to paclitaxel and methotrexate produced additive to antagonistic effects in the A549 and PA1 cells, and antagonistic effects in the MCF7 and WiDr cells. The sequential exposure to paclitaxel followed by methotrexate produced additive effects in all four cell lines. The reverse sequence produced synergistic effects in the A549, MCF7, and WiDr cells, and additive effects in the PA1 cells. These findings suggest that a sequential administration of methotrexate followed by paclitaxel may be the appropriate schedule for this combination. On the basis of the observed in vitro synergism, further in vivo and clinical studies are necessary to clarify the toxicity and proposed antitumor effects of this schedule.
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PMID:Schedule-dependent synergism and antagonism between paclitaxel and methotrexate in human carcinoma cell lines. 1006 68

In vitro studies showed that decorin, a small proteoglycan that is a normal component of the cell matrix involved in tissue scaffolding, effectively inhibited the growth of two ovarian cancer lines, SKOV3 and 2774. Using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay to measure cell growth, IC50s for decorin ranged from 150 to 400 microg/ml for the two cell lines. In contrast, the growth of tumor cells grown on an artificial cell matrix (Matrigel) was unaffected by decorin treatment, perhaps because of the decorin being irreversibly bound by matrix-associated collagen. Decorin-induced inhibition of ovarian tumor cells appeared to be associated with the increased expression of the cyclin-dependent kinase inhibitor p21Waf1/Cip1. Up-regulation of p21 expression was shown by Western blot analysis in decorin-treated ovarian cancer cells. No decorin-induced up-regulation of c-myc was seen, although decorin was reported to activate the epidermal growth factor receptor. Decorin was also shown to synergize with carboplatin to inhibit the growth of ovarian tumor cells. Additional studies are warranted to determine the role of decorin in the treatment of ovarian cancer.
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PMID:In vitro growth inhibition of ovarian cancer cells by decorin: synergism of action between decorin and carboplatin. 1062 12

Docetaxel, a novel member of the taxoid family, has shown greater potency than paclitaxel in the treatment of advanced breast cancer and certain other solid tumors. The promising clinical activity of docetaxel has also promoted considerable interest in combining this drug with other antitumor agents. In this study, we assessed the cytotoxic interaction between docetaxel and doxorubicin administered at various schedules to human breast and ovarian cancer cells. Through a series of in vitro assays including DNA fragmentation analyses, 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assays, and flow cytometric analyses, we found that the antagonistic interaction occurred when tumor cells were exposed to the two drugs simultaneously or exposed to doxorubicin before docetaxel. However, no antagonism was observed when docetaxel was added before doxorubicin. Further analyses demonstrated that doxorubicin could interfere with the cytotoxic effect of docetaxel on both mitotic arrest and apoptotic cell death. In addition, biochemical examinations revealed that docetaxel could induce phosphorylation of both bcl-2 and c-raf-1, but these changes were inhibited when tumor cells were pretreated or simultaneously treated with doxorubicin. These results indicate that the interaction between docetaxel and doxorubicin is highly schedule dependent. Exposure of tumor cells to doxorubicin before docetaxel could result in pronounced antagonism. The optimal schedule for this combination might be sequential exposure to docetaxel followed by doxorubicin.
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PMID:In vitro evaluation of schedule-dependent interactions between docetaxel and doxorubicin against human breast and ovarian cancer cells. 1099 71

In a systematic effort to identify a potent anticancer agent against human ovarian cancer, we synthesized 15 oxovanadium(IV) complexes, and examined their cytotoxic activity against human ovarian cancer cell lines PA-1, SKOV-3, ES-2 and OVCAR-3 using a MTT [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyletetrazolium bromide]-based assay. The apoptosis-inducing ability of the oxovanadium compounds was evaluated by the two-color flow cytometric terminal deoxynucleotidyl transferase-based assay that labels 3'-hydroxyl ends of fragmented DNA (TUNEL) assay and confocal laser scanning microscopy. Notably, all eight oxovanadium complexes of 1,10 phenanthroline exhibited significant cytotoxicity and induced apoptosis within 24 h. The mono-chelated, VO(NO2-phen) and bis-chelated, VO(Me2-phen)2, VO(Cl-phen)2 and VO(NO2-phen)2 complexes were the most potent oxovanadium compounds, and killed target cancer cells at low micromolar concentrations. The marked differences in the cytotoxic activity of oxovanadium(IV) complexes containing different heterocyclic ancillary ligands suggest that the cytotoxic activity of these compounds is determined by the identity of the five-member bidentate ligands, as well as the nature of the substituents on the heterocyclic aromatic rings. Our results presented herein provide experimental evidence that oxovanadium compounds induce apoptosis in human ovarian cancer cells. The lead compounds, VO(Me2-phen)2 and VO(NO2-phen)2, may be useful in the treatment of ovarian cancer.
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PMID:Apoptosis-inducing oxovanadium(IV) complexes of 1,10-phenanthroline against human ovarian cancer. 1114 93

We studied the effect of arsenic trioxide (As2O3) on prostate and ovarian carcinoma cell lines. As2O3 has been shown to be effective in leukemia, and acute promyelocytic leukemia in particular, both in vitro and in vivo. As model cell lines, we used DU145 and PC-3 for prostate cancer and MDAH 2774 for ovarian cancer. New modalities of treatment are essential in these kinds of cancers, which produce a high death toll. The 3-(4,5-dimethyl-thiazoyl-2-yl)-2,5-diphenyl-tetrazolium bromide assay was used to evaluate cytotoxicity. Flow cytometric analysis and mono-oligo nucleosome detection-based ELISA were used to determine the apoptosis. Isobologram analysis was used to evaluate synergism and/or the additive effects of As2O3 and conventional chemotherapeutic agents. We clearly demonstrated that As2O3 has significant cytotoxic effect on both prostate and ovarian carcinoma cell lines. The dose range of As2O3 in all three cell lines was approximately 10(-6) M. The mechanism underlying cytotoxicity of As2O3 was shown to be apoptosis. The experiments by butylated hydroxyanisole showed that the cytotoxic effect of As2O3 was not through superoxide generation. There was no synergism, but the additive effects of As2O3 were demonstrated with cisplatin, adriamycin, and etoposide. We strongly suggest that As2O3 alone or in combination with conventional chemotherapeutic agents be evaluated further as a new agent for the treatment of prostate and ovarian cancers.
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PMID:Arsenic trioxide-mediated cytotoxicity and apoptosis in prostate and ovarian carcinoma cell lines. 1115 57

Kallikrein gene 5 (KLK5, also known as KLK-L2), located on chromosome 19q13.4, is one of the newly identified members of the kallikrein gene family, which is a subgroup of the serine protease enzyme family. In normal human tissues, KLK5 is highly expressed in skin, mammary gland and testis. Preliminary RT-PCR analysis has indicated that KLK5 is expressed in a subset of ovarian tumours. We have thus hypothesized that KLK5 may be a new prognostic indicator in ovarian cancer. We have examined the mRNA expression of KLK5 in 142 malignant ovarian tissues. Tumours were pulverized, total RNA was extracted, and cDNA was prepared by reverse transcription. KLK5 was amplified by PCR using gene specific primers, and the identity of the PCR product was verified by sequencing. Ovarian tissues were then classified as KLK5 positive or negative, based on ethidium bromide staining of the PCR product on agarose gels. KLK5 was found to be highly expressed in 58/142 (41%) of ovarian cancer samples while its level of expression was very low in normal ovarian tissues. We found a strong positive relation between KLK5 expression and tumour grade (P = 0.006) and disease stage (P = 0.027). Univariate survival analysis revealed that patients with ovarian tumours positive for KLK5 expression had an increased risk for relapse and death (P = 0.018 and 0.022, respectively). In multivariate analysis, KLK5 expression showed independent prognostic value only in the subset of tumours with lower grade disease (grades I and II). We conclude that KLK5 expression is associated with more aggressive forms of epithelial ovarian carcinoma and has indepdent prognostic value in low grade tumours.
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PMID:Human kallikrein gene 5 (KLK5) expression is an indicator of poor prognosis in ovarian cancer. 1123 85

The 3-(4,5 dimethylthiazol-2-yl)-2,5 diphenyltetrazolium bromide (MTT) assay is used successfully to estimate the number of viable cells in drug screening trials. We used the MTT assay to assess the viability of a rodent ovarian carcinoma cell line (DMBA-OC-1R) after exposure to combinations of cisplatin and 5-fluorouracil as free drug and in encapsulated (conjugated and unconjugated) forms. After 48 h of exposure to free drugs, a significant trend towards cell cytotoxicity could be observed and this was well established by 120 h. Cells treated with drug-containing immuno-microspheres showed a similar initial decrease in cell viability after 96 h, and this was maintained for 128 h. These results suggest that immuno-microspheres loaded with chemotherapeutic drugs have the potential to be successfully used in the treatment of ovarian cancer.
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PMID:Assessment of the antitumour activity of targeted immunospecific albumin microspheres loaded with cisplatin and 5-fluorouracil: toxicity against a rodent ovarian carcinoma in vitro. 1123 8

The aim of this study was to assess the use of the MTT assay for chemosensitity testing to identify drug resistance and predict survival in patients with advanced ovarian cancer. Samples of ascitic fluid and/or solid biopsies were taken from 120 patients with FIGO stage III or IV ovarian adenocarcinoma at presentation. Cells were exposed for 48 hours to four concentrations of clinically relevant drugs including platinums, anthracyclines and alkylating agents. Cell survival was measured using the 3-4,5-dimethyl-2, 5-diphenyl tetrazolium bromide (MTT) assay allowing patients to be grouped as "sensitive" or "resistant" in vitro. Clinical data including age, residual disease, histological grade, treatment, response after initial treatment and overall survival were collected. There was a highly significant (p<0.0001) correlation of in vitro sensitivity with in vivo response in the patients who completed their therapy, with an 83% positive predictive accuracy for resistance. This translated in the longer term to an increased survival for the patients found to be sensitive in vitro to their therapy with a 5-year survival rate of 24% compared to 12% for the resistant group (p=0.033). These results suggest that MTT chemonsensitivity testing can predict response in ovarian cancer leading to the prospect of increased survival in this devastating disease by customising therapy to individual patients.
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PMID:Chemosensitivity testing predicts survival in ovarian cancer. 1169 9


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