Gene therapy for ovarian cancer

Kimball, Kristopher J.; Numnum, T. Michael; Rocconi, Rodney P.; Alvarez, Ronald D.

doi:10.1007/s11912-006-0073-x

Cited by 23 publications

(20 citation statements)

References 43 publications

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“…Standard therapeutic options, such as cytoreductive surgery followed by adjuvant chemotherapy, have poor long-term outcomes for the treatment of ovarian cancer. Therefore, new therapeutic strategies, such as gene therapy, were explored in recent years [2]. Gene therapy inhibits the expression of oncogenes or replaces the activated tumor suppressor genes with their wild-type copies.…”

Section: Introductionmentioning

confidence: 99%

Targeted microbubbles for ultrasound mediated gene transfection and apoptosis induction in ovarian cancer cells

Chang

Guo

Sun

et al. 2013

Ultrasonics Sonochemistry

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Ultrasound-targeted microbubble destruction (UTMD) technique can be potentially used for non-viral delivery of gene therapy. Targeting wild-type p53 (wtp53) tumor suppressor gene may provide a clinically promising treatment for patients with ovarian cancer. However, UTMD mediated gene therapy typically uses non-targeted microbubbles with suboptimal gene transfection efficiency. We synthesized a targeted microbubble agent for UTMD mediated wtp53 gene therapy in ovarian cancer cells. Lipid micro-bubbles were conjugated with a Luteinizing Hormone–Releasing Hormone analog (LHRHa) via an avidin– biotin linkage to target the ovarian cancer A2780/DDP cells that express LHRH receptors. The microbubbles were mixed with the pEGFP-N1-wtp53 plasmid. Upon exposure to 1 MHz pulsed ultrasound beam (0.5 W/cm2) for 30 s, the wtp53 gene was transfected to the ovarian cancer cells. The transfection efficiency was (43.90 ± 6.19)%. The expression of wtp53 mRNA after transfection was (97.08 ± 12.18)%. The cell apoptosis rate after gene therapy was (39.67 ± 5.95)%. In comparison with the other treatment groups, ultrasound mediation of targeted microbubbles yielded higher transfection efficiency and higher cell apoptosis rate (p < 0.05). Our experiment verifies the hypothesis that ultrasound mediation of targeted microbubbles will enhance the gene transfection efficiency in ovarian cancer cells.

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Section: Introductionmentioning

confidence: 99%

Targeted microbubbles for ultrasound mediated gene transfection and apoptosis induction in ovarian cancer cells

Chang

Guo

Sun

et al. 2013

Ultrasonics Sonochemistry

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“…These studies have used specific transgenes, most of which induce apoptosis or cell cycle arrest, introduced into tumors through plasmid or viral vector systems using tumor-specific promoters. [7][8][9] Despite these efforts, the levels of transgene expression have been insufficient to eradicate tumors, mainly because of the unfavorable characteristics of adenoviral vectors, in which the E1 gene is deleted to inhibit the replicative capacity of the vector. These non-replicative vectors have limited distribution within the tumor mass after injection and are therefore not suitable for advanced ovarian cancers, as this tumor type frequently has multiple disseminated lesions throughout the whole peritoneal cavity.…”

Section: Introductionmentioning

confidence: 99%

Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination

et al. 2009

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Despite tremendous development in chemotherapy for ovarian cancer over the past few decades, the prognosis of advanced cases with massive peritoneal dissemination is still unsatisfactory, and novel treatment modalities that can combine with chemotherapy are urgently needed. We recently developed virotherapy for solid tumors using telomerase-specific replication-selective adenoviruses (Telomelysin: OBP-301), in which the human telomerase reverse transcriptase (hTERT) gene promoter has been inserted to direct tumor-specific E1 gene expression. In this study, we investigated the anti-tumor effects of OBP-301, combined with cisplatin (CDDP), on ovarian cancer cells. In vitro treatment of SKOV3 cells with OBP-301 at a multiplicity of infection (MOI) of 0.01-100 induced significant cell death in a dose-dependent manner, with moderate cytotoxicity at an MOI of 1-10 and maximal cytotoxicity at an MOI of 100. In contrast, OBP-301 treatment of normal human cells showed no significant cell death at an MOI of 1-10 and exhibited modest cytotoxicity at an MOI of 100. The effects of low-dose CDDP at 0.5-1 mM, which induced only 20% cell death, were significantly augmented by combination with OBP-301 at an MOI of 1-10, finally achieving 40% cell death. Such enhancement of CDDP sensitivity was also observed in CDDP-resistant ovarian cancer cells. The combinatorial effects were further tested using a xenograft mouse model of SKOV3 with peritoneal dissemination. After intraperitoneal administration of OBP-301, we confirmed that injected OBP-301 fused with the green fluorescent protein (GFP) gene (OBP-401) was preferentially localized to peritoneal disseminations, as determined by fluorescence imaging. Treatment of mice with CDDP at low dose (0.5 mg kg -1 ) had modest effects, showing a 10% decrease in disseminations, whereas combination with intraperitoneal administration of OBP-301 at an MOI of 10 led to enhanced effects, achieving an approximately 80% decrease in disseminations. Kaplan-Meier analysis showed improved overall survival of mice treated with CDDP plus OBP-301 compared with CDDP alone. These findings support the therapeutic potential of intraperitoneal administration of OBP-301 to sensitize ovarian cancer cells to CDDP.

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“…These electrophilic aldehyde or ketone groups act as trap for Ser195 of the catalytic triade and form a covalent bond to its side chain hydroxyl group, which strongly contributes to thrombin affinity. Other first generation electrophilic inhibitors were developed from arginine-, and lysine-derived poly-fluorinated ketones (5, 6), α-keto-amides (7), -acids and -esters (8,9), α-keto-heterocycles (10, 11) and boronic acids (12) reviewed previously [12,[34][35][36][37]. Most of these inhibitors are highly potent in vitro but are often plagued with poor selectivity towards other trypsin-like proteases, slow-binding kinetics and chemical instability (e. g. racemization, cyclization).…”

Section: Electrophilic Inhibitorsmentioning

confidence: 99%

“…Additional physiological inhibitors are α1-protease inhibitor, α2-macroglobulin, and heparin cofactor II, however they inactivate thrombin more slowly than antithrombin. It is assumed that these inhibitors can control low levels of free thrombin in the circulation but are not sufficiently potent to block higher amounts of activated thrombin formed during severe thrombotic conditions [12].…”

Section: Introductionmentioning

confidence: 99%

Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

Steinmetzer

Stürzebecher²

2004

CMC

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The trypsin-like serine protease thrombin is a multifunctional key enzyme at the final step of the coagulation cascade and is involved in the regulation of hemostasis and thrombosis. An increased activation of coagulation can result in severe thromboembolic disorders, one of the major reasons responsible for mortality and morbidity in western world. Therefore, an effective, safe, and orally available thrombin inhibitor could be a useful anticoagulant drug for the daily prophylaxis of venous and arterial thrombosis and prevention of myocardial infarction for high-risk patients. Synthetic thrombin inhibitors have a long history; initial compounds were derived from electrophilic ketone- and aldehyde-analogs of arginine. First potent leads of non-covalent inhibitors were developed in the early eighties, which were further optimised in the nineties, after the X-ray structure of thrombin became available. In the meantime a huge number of highly active and selective inhibitors has been published, however, only a few of them have an appropriate pharmacokinetic and pharmacodynamic overall profile, which could justify their further development. Very recently, with Ximelagatran a first orally available thrombin inhibitor has been approved in France for the prevention of venous thromboembolic events in major orthopaedic surgery after successful clinical phase III. However, it still has to be awaited, whether the extensive clinical use of Ximelagatran can demonstrate for the first time that direct thrombin inhibitors offer a real benefit in terms of efficacy and safety over established antithrombotic therapies. This review summarizes the current status of synthetic thrombin inhibitors with a focus on more recently published and promising new compounds.

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Gene therapy for ovarian cancer

Cited by 23 publications

References 43 publications

Targeted microbubbles for ultrasound mediated gene transfection and apoptosis induction in ovarian cancer cells

Targeted microbubbles for ultrasound mediated gene transfection and apoptosis induction in ovarian cancer cells

Intraperitoneal administration of telomerase-specific oncolytic adenovirus sensitizes ovarian cancer cells to cisplatin and affects survival in a xenograft model with peritoneal dissemination

Progress in the Development of Synthetic Thrombin Inhibitors as New Orally Active Anticoagulants

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