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)

Uroplakins (UPs) are a group of integral membrane proteins that are synthesized as the major differentiation products of mammalian urothelium. UPII gene expression is bladder specific and differentiation dependent, but very little is known about its transcription response elements. To identify the promoter elements, a DNA fragment of 2239 bp upstream of the UPII gene was amplified by PCR and linked to a promoterless firefly luciferase reporter gene. Transient transfection experiments showed that the DNA segment located between -1809 and +1 bp resulted in preferential expression in bladder carcinoma cells with negligible expression in nonurothelial cells. This promoter was engineered into adenovirus (Ad) type 5 to drive the expression of the E1A and E1B genes and to create an attenuated replication-competent Ad variant, termed CG8840. Viral replication and the cytopathic effect of CG8840 were evaluated by virus yield and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays in bladder transitional cell carcinoma (TCC) cell lines RT4 and SW780; nonbladder cancer cell lines G361 (melanoma), LNCaP (prostate cancer), PA-1 (ovarian cancer), and U118 (brain cancer); and human primary cells including lung fibroblasts, bladder smooth muscle cells, and mammary epithelial cells. CG8840 replicated in and eliminated bladder TCC efficiently with high specificity (10,000:1) in comparison with nonbladder cells. The antitumor activity of CG8840 was examined in BALB/c nu/nu mice carrying s.c. human TCC xenografts. Intratumoral and i.v. administration of CG8840 in RT4 human bladder cancer xenografts caused significant (P < 0.01) inhibition of tumor growth. Synergistic antitumor efficacy was observed when CG8840 was combined with docetaxel, resulting in significant regression of RT4 bladder cancer xenograft tumors within 6 weeks after i.v. administration of CG8840 (3.33 x 10(9) plaque-forming units/animal on day 1) and docetaxel (20 mg/kg on days 2, 6, and 9). These results demonstrate the utility of the UPII promoter in the generation of urothelium-specific adenoviral vectors and provide a potential foundation for the development of bladder tumor-specific oncolytic viral therapies.
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PMID:Identification of human uroplakin II promoter and its use in the construction of CG8840, a urothelium-specific adenovirus variant that eliminates established bladder tumors in combination with docetaxel. 1209 84

DX-8951f or exatecan mesylate ((1S,9S)-1-amino-9-ethyl-5-fluoro-2,3-dihydro-9-hydroxy-4-methyl-1H,12H-benzo[de]pyrano[3',4':6,7]indolizino[1,2-b]quinoline-10-13(9H,15H)-dione methanesulfonate dihydrate), is a new water-soluble derivative of camptothecin. We determined the activity of DX-8951f in experimental human colon cancer and ovarian cancer, being tumor types sensitive to camptothecins. With the use of the MTT assay, DX-8951f was more potent than SN-38 in four out of five human colon cancer cell lines and three out of four human ovarian cancer cell lines (P<0.05). DX-8951f was considerably more potent than topotecan in all cell lines tested (P<0.05). Prolonged exposure to DX-8951f resulted in a greater increase in inhibition of cell proliferation as compared to that obtained with SN-38 or topotecan (P<0.05). Overexpression of Pgp, MRP1, and LRP did not affect the in vitro activity of DX-8951f. DX-8951f administered daily x 5 or weekly x 2 resulted in growth inhibition <50% in two human colon cancer xenografts grown s.c. in nude mice. In three human ovarian cancer xenografts, however, >50% growth inhibition was observed at both schedules. In the OVCAR-3 human ovarian cancer model, DX-8951f showed considerably greater activity than topotecan (P<0.01). DX-8951f combined with cisplatin or paclitaxel did not indicate the presence of a pharmacological interaction. In OVCAR-3 xenografts the combination was clearly more effective than DX-8951f alone, as the number of complete remissions increased substantially. In conclusion, this study shows that DX-8951f is highly potent in vitro and highly effective in experimental human ovarian cancer in vivo. Prolonged exposure to DX-8951f in vitro greatly increased the antiproliferative effects, which may be a rationale for testing a continuous infusion schedule in the clinic. Addition of cisplatin or paclitaxel improved the in vivo antitumor effects of DX-8951f.
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PMID:The activity profile of the hexacyclic camptothecin derivative DX-8951f in experimental human colon cancer and ovarian cancer. 1223 7

We report on the use of shock waves delivered by a shock-tube to permeabilize cancer cells and potentiate the cytotoxicity of the type-1 ribosome-inactivating protein, saporin. We studied human colorectal cancer HT29 and ovarian cancer OVCAR-5 cells, and used two different cytotoxicity assays, colony formation and loss of mitochondrial activity. A single shock wave and saporin (10(-9) M) produced significant toxicity not seen with either shock wave or drug alone. Increasing the number of shock waves up to five further increased cytotoxicity. Higher toxicity was seen with the clonogenic assay compared to MTT assay. Shock waves may have applications in promoting cytoplasmic delivery of toxins into cancer cells after intratumoral injection.
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PMID:Delivery of ribosome-inactivating protein toxin into cancer cells with shock waves. 1244 79

The role of vascular endothelial growth factor (VEGF) during peritoneal dissemination of ovarian carcinoma and the association with tumor microvessel density (MVD) and matrix metalloproteinase (MMP) activity was investigated. To this end, MVD, tumor tissue and ascitic fluid levels of VEGF, and MMP activity of ascitic fluid were examined in patients with ovarian cancer and benign ovarian tumor. The effect of ascites on cell growth, cell invasion activity and angiogenesis was investigated in vitro. Ascitic fluid and tumor tissue samples were obtained from 15 patients with benign ovarian tumor and 24 patients with ovarian carcinoma. Tissue extract and ascitic fluid levels of VEGF were measured using enzyme immunoassay. Tumor microvessels were detected immunohistochemically. MMP activity was measured by gelatin zymography. For the in vitro experiment, the SKOV-3 human ovarian carcinoma cell line was utilized. Cell growth was examined using MTT-assay, cell invasion activity was measured by Matrigel in vitro invasion assay, and neovascularization was assessed using an angiogenesis kit. VEGF levels in tissue extract and ascitic fluid, MVD, expression of active form MMP-2 in ascitic fluid and ascites volume were higher in ovarian cancer patients than in benign ovarian tumor patients. In addition, these were elevated in stage III and IV diseases compared to stage I and II diseases in ovarian cancer patients. MVD and expression of active form MMP-2 in ascitic fluid were closely correlated with VEGF level in tissue extracts, and MVD and ascites volume were closely correlated with VEGF level in ascitic fluid. Cell invasive activity and angiogenesis activity increased when cells were exposed to ascites. These increases were apparent when exposed to ascites obtained from ovarian cancer patients and were related to VEGF concentrations of ascitic fluid and expression of active form MMP-2 in ascitic fluid. The increased VEGF secreted from tumor cells is suggested to enhance tumor growth through angiogenesis, to produce ascites and to elevate ascitic VEGF concentrations and expression of active form MMP-2. The progression of peritoneal involvement may be induced by elevated VEGF and expression of active form MMP-2, followed by increased VEGF in the primary tumor. Control of VEGF in the primary tumor may become an effective strategy against peritoneal dissemination of ovarian carcinoma.
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PMID:Vascular endothelial growth factor activating matrix metalloproteinase in ascitic fluid during peritoneal dissemination of ovarian cancer. 1246 50

We have found the short-term MTT assay to be a simple, reproducible chemosensitivity technique, suitable for use throughout the time course of disease. We now have 12 years' experience of using this method in a variety of tumour types, both haematological and solid malignancies. Tumour cells are isolated from bone marrow, malignant effusions or solid biopsies and subjected to drug exposure for 48-96 h. Cell survival is measured by re-incubation in MTT for 4 h. We have found a significant correlation of in vitro results with in vivo outcome for acute myeloid leukaemia (AML) and for ovarian cancer (both p < 0.0001) with an assay sensitivity of 98% for AML and 81% for ovarian cancer. Furthermore, the 5-year survival of ovarian cancer patients treated with a drug found sensitive in vitro is significantly higher than that for patients treated with a drug found resistant in vitro (p = 0.033). We have correlated assay results with drug resistance markers. For example, expression of the newly described half transporter BCRP is related to daunorubicin resistance (p < 0.05). The MTT assay is also suitable for screening for modulation of drug resistance. We have found that the DNA polymerase inhibitor aphidicolin markedly increases in vitro sensitivity to the platinum drugs in ovarian cancer and cytosine arabinoside in AML in the majority of patients. The greatest effect was seen for patients deemed resistant in vitro to these agents. We have identified novel drug combinations which demonstrate significant synergism using this methodology and have also used it to study the emergence of drug resistance in cell line models with a view to its prevention. In conclusion, we have found the MTT assay to be a simple, repeatable, adaptable technique which produces accurate information to help the clinician select suitable treatment for individual cases.
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PMID:The use of the MTT assay to study drug resistance in fresh tumour samples. 1252 95

Tafluposide (F 11782), a novel epipodophylloid with a unique mechanism of interaction with both topoisomerase I and II, has shown outstanding antitumor activity in vivo against a panel of experimental human tumor xenografts. The aim of this study was to evaluate its cytotoxicity against fresh tumor cells taken from patients. Cells derived from bone marrow, peripheral blood, malignant effusions or solid biopsies from 84 patients with either hematological or solid tumors were exposed continuously to 0.8-100 nuM tafluposide for 48 h, 96 h or 7 days. Cell survival was measured using an MTT assay or the ATP assay and LC(50) values (drug concentration required for 50% cell kill) were calculated. Tafluposide showed significant cytotoxicity against cells derived from either hematological or solid tumors, with a marked inter-patient variation. There was no significant difference between the effect of tafluposide in samples from untreated or previously treated patients (p>0.05 for all cancer types). Whilst tafluposide appeared to show weak (p<0.05) cross-resistance with the topoisomerase II inhibitor etoposide in acute myeloid leukemia (AML), there did not appear to be any correlation with the effect of the topoisomerase I inhibitor topotecan (p>0.05) in either hematological or solid malignancies. True synergism was identified when combining tafluposide with cisplatin in ovarian cancer [combination index (CI)=0.14, 0.79] and with etoposide in AML (CI=0.49, 0.63 and 0.78). Our results suggest that tafluposide is a strong candidate for inclusion in clinical trials, particularly in hematological malignancies.
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PMID:Ex vivo effects of the dual topoisomerase inhibitor tafluposide (F 11782) on cells isolated from fresh tumor samples taken from patients with cancer. 1285 90

Artemisinin derivatives artesunate (ART) and dihydroartemisinin are remarkable anti-malarial drugs with low toxicity to humans. In the present investigation, we find they also inhibited tumor cell growth and suppressed angiogenesis in vitro. The anti-cancer activity was demonstrated by inhibition (IC(50)) of four human cancer cell lines: cervical cancer Hela, uterus chorion cancer JAR, embryo transversal cancer RD and ovarian cancer HO-8910 cell lines growth by the MTT assay. IC(50) values ranged from 15.4 to 49.7 microM or from 8.5 to 32.9 microM after treatment with ART or dihydroartemisinin for 48 h, indicating that dihydroartemisinin was more effective than ART in inhibiting cancer cell lines. The anti-angiogenic activities were tested on in vitro models of angiogenesis, namely, proliferation, migration and tube formation of human umbilical vein endothelial (HUVE) cells. We investigated the inhibitory effects of ART and dihydroartemisinin on HUVE cells proliferation by cell counting, migration into the scratch wounded area in HUVE cell monolayers and microvessel tube-like formation on collagen gel. The results showed ART and dihydroartemisinin significantly inhibited angiogenisis in a dose-dependent form in range of 12.5-50 microM and 2.5-50 microM, respectively. They indicated that dihydroartemisinin was more effective than ART in inhibiting angiogenesis either. These results and the known low toxicity are clues that ART and dihydroartemisinin may be promising novel candidates for cancer chemotherapy.
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PMID:Inhibition of human cancer cell line growth and human umbilical vein endothelial cell angiogenesis by artemisinin derivatives in vitro. 1286 Apr 39

The in vitro cytotoxic activity profile of nine novel phenylarsonic acid (CAS 98-05-5, PAA) compounds against 17 human cancer cell lines including (a) ovarian cancer cell lines ES-2, PA-1, CAOV-3, OVCAR-3, (b) testicular cancer cell lines Ntera-2, Tera-2, N2NICP, 833K, and 64CP, (c) multiple myeloma cell lines ARH77, HS-Sultan, RPMI-8226, and U266, and (d) acute lymphoblastic leukemia (ALL) cell lines NALM-6, MOLT-3, ALL-1, and RS4; 11, was determined by the MTT assay. The lead compounds, 2-methylthio-4-[(4'-aminophenylazo)-phenylarsonic acid] pyrimidine (PHI-370) and 2-methylthio-4-(4'-phenylarsonic acid)-aminopyrimidine (PHI-380) caused apoptotic death in all 17 cancer cell lines at low micromolar concentrations, as documented by TUNEL assays and confocal laser scanning microscopy. PHI-380 was also tested and found to be very active against primary tumor cells isolated from surgical biopsy specimens of 14 patients with therapy-refractory non-small cell lung cancer, breast cancer, colon cancer, lymphoma, hepatoblastoma, or Wilm's tumor as well. Because of their broad-spectrum and potent anticancer activity and ability to induce apoptosis in primary tumor cells from therapy-refractory cancer patients, PAA compounds such as PHI-370 and PHI-380 may provide the basis for effective salvage regimens for patients with recurrent cancer.
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PMID:Phenylarsonic acid compounds with broad-spectrum and potent cytotoxic activity against human cancer cells. 1287 14

OVS1 monoclonal antibody (MAb) produced against ovarian cancer is currently used to identify mucinous cystadenocarcinoma antigen as a tumor marker secreted in serum. The potential of OVS1 MAb in ovarian cancer treatment was studied by evaluating the induction of cytotoxicity and apoptosis of SKOV3 ovarian cancer and BT549 breast cancer cell lines induced by OVS1. Paclitaxel, an antitumor drug, was used as positive control and applied as a combined drug together with OVS1 MAb. OVS1 MAb and paclitaxel were found by MTT assay to induce cytotoxicity against both cell lines. The ED50 of OVS1 MAb were 26.25 and 25.00 microg/ml and of paclitaxel were 21.88 and 9.20 nM against SKOV3 and BT549 cell lines, respectively. The quantitative amount of cells determined by fluorimetric assay was correlated to the results of the MTT assay. The combined application of OVS1 MAb and paclitaxel on these two cell lines resulted in a greater cytotoxicity than observed by either agent alone. OVS1 MAb and paclitaxel applied against both cell lines induced the morphological changes of apoptotic cell death at 24 hours visualized by two color fluorescence dyes, Ho33342 and propidium iodide. Combination of the two substances enhanced the rate of apoptosis compared to either OVS1 MAb or paclitaxel given alone. DNA fragmentation was detected in an agarose gel electrophoresis after treating cells with OVS1 MAb and paclitaxel at 24 hours. These findings on the induction of cytotoxicity and apoptosis by OVS1 MAb on cancer cell lines have implications on the potential application of OVS1 MAb for clinical therapy.
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PMID:Cytotoxicity and apoptosis of ovarian and breast cancer cell lines induced by OVS1 monoclonal antibody and paclitaxel. 1293 49

A series of osteotropic (bone-seeking) [(bis(phosphonomethyl)amino-kappaN)acetato-kappaO(2-)]platinum(II) complexes attached to diammine, ethane-1,2-diamine, cis-R,S-cyclohexane-1,2-diamine, trans-S,S-cyclohexane-1,2-diamine, or trans-R,R-cyclohexane-1,2-diamine has been synthesized in accord with the concept of drug targeting and characterized by elemental analysis, (1)H, (13)C, and (31)P NMR spectroscopy. The in vitro antitumor activity in ovarian cancer cells (CH1) has been determined by means of the MTT assay. In this cisplatin-sensitive cell line the complexes containing cyclohexane-1,2-diamine (chxn) displayed a high activity in comparison to the diammine and ethane-1,2-diamine counterparts. In agreement with structure-activity relationships of other chxn-containing platinum(II) complexes both [(bis(phosphonomethyl)amino-kappaN)acetato-kappaO(2-)](trans-cyclohexane-1,2-diamine)platinum(II) complexes show superior potency than the corresponding cis-congener whereas the trans-R,R isomer displays the highest activity. Within the series of complexes under investigation, potency decreases depending on the coordinated amine ligand in the following order: trans-R,R-chxn > trans-S,S-chxn > NH(3) > or = cis-R,S-chxn > en.
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PMID:Synthesis, characterization, and in vitro antitumor activity of osteotropic diam(m)ineplatinum(II) complexes bearing a N,N-bis(phosphonomethyl)glycine ligand. 1458 45


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