Rat Ovarian Cancer Research Articles

Identification and evaluation of UR238, a first-in-field small molecule inhibitor of HE4, in a syngeneic rat ovarian cancer model

Identification and evaluation of UR238, a first-in-field small molecule inhibitor of HE4, in a syngeneic rat ovarian cancer model

Trichostatin A-modified vaccine provides superior protection against ovarian cancer formation and development.

More attention has been paid to immunotherapy for ovarian cancer and the development of tumor vaccines. We developed a trichostatin A (TSA)-modified tumor vaccine with potent immunomodulating activities that can inhibit the growth of ovarian cancer in rats and stimulate immune cell response in vivo. TSA-treated Nutu-19 cells inactivated by X-ray radiation were used as a tumor vaccine in rat ovarian cancer models. Prophylactic and therapeutic experiments were performed with TSA-modified tumor vaccine in rats. Flow cytometry and ELISpot assays were conducted to assess immune response. Immune cell expression in the spleen and thymus were detected by immunohistochemical staining. GM-CSF, IL-7, IL-17, LIF, LIX, KC, MCP-1, MIP-2, M-CSF, IP-10/CXCL10, MIG/CXCL9, RANTES, IL-4, IFN-γ, and VEGF expressions were detected with Milliplex Map Magnetic Bead Panel immunoassay. TSA vaccination in therapeutic and prophylactic models could effectively stimulate innate immunity and boost the adaptive humoral and cell-mediated immune responses to inhibit the growth and tumorigenesis of ovarian cancer. This vaccine stimulated the thymus into reactivating status and enhanced infiltrating lymphocytes in tumor-bearing rats. The expression of key immunoregulatory factors were upregulated in the vaccine group. The intensities of infiltrating CD4+ and CD8+ T cells and NK cells were significantly increased in the vaccine group compared to the control group (P<0.05). This protection was mainly dependent on the IFN-γ pathway and, to a much lesser extent, by the IL-4 pathway. The tumor cells only irradiated by X-ray as the control group still showed a slight immune effect, indicating that irradiated cells may also cause certain immune antigen exposure, but the efficacy was not as significant as that of the TSA-modified tumor vaccine. Our study revealed the potential application of the TSA-modified tumor vaccine as a novel tumor vaccine against tumor refractoriness and growth. These findings offer a better understanding of the immunomodulatory effects of the vaccine against latent tumorigenesis and progression. This tumor vaccine therapy may increase antigen exposure, synergistically activate the immune system, and ultimately improve remission rates. A vaccine strategy designed to induce effective tumor immune response is being considered for cancer immunotherapy.

Cisplatin effect on digital cytomorphometric and bioinformatic tumor cell characteristics in rat ovarian cancer model-a preliminary study.

Ovarian cancer is one of the most common diseases of the female reproductive system. The aim of this study was the investigation of the antitumor cisplatin effect on ascitic fluid tumor cells in the ovarian cancer experimental model by digital cytomorphometry and cell bioinformatic analysis. Female Wistar rats were inoculated by ovarian cancer strain. After ovarian cancer transplantation rats were divided into two groups: control group-without cisplatin treatment, the experimental group-under cisplatin treatment. The ascitic fluid was taken on the 9-th day after tumor cell inoculation. Digital cytomorphometric and cytobioinformatic analysis were used to study ascitic fluid cancer cell morphofunctional changes under cisplatin treatment. Digital cytomorphometric characteristics of rat ovarian cancer ascitic cells were obtained. Tumor cells were classified into four groups according to their geometric size: small, medium, large, "gigantic". The algorithm and the computer program based on tumor cell morphometric characteristics were created to calculate such cell bioinformatic characteristic as information redundancy coefficient R. Three parameters were determined as the criteria of cisplatin effect on cancer cells: cell number, nuclear/cytoplasmic ratio, R-value. Data obtained suggest that cisplatin reduces the total cell number, the nuclear/cytoplasmic ratio and R-value thus indicates a decrease in cellular resistance and adaptive potential. The digital cytomorphometry and bioinformatics could be recommended as a testing system in the experimental or clinical study.

A Novel Rat Ovarian Cancer Model Developed to Examine Chemotherapy-Related Cognitive Impairments

OBJECTIVES: To describe a novel method of developing an ovarian cancer intraperitoneal (IP) and subcutaneous (SC) xenograft model with the purpose of extrapolating chemotherapy-related cognitive impairments (CRCI) in tumor-bearing rats.

Molecular imaging-monitored radiofrequency hyperthermia-enhanced intratumoral herpes simplex virus-thymidine kinase gene therapy for rat orthotopic ovarian cancer

Objective To establish the technique of intratumoral combination therapy of radiofrequency hyperthermia (RFH) with herpes simplex virus-thymidine kinase/ganciclovir (HSV-TK/GCV) gene therapy for rat ovarian cancers. Material and methods This study consisted of three parts: (1) in vitro experiments to establish the ‘proof of principal’ that combination of RFH and HSV-TK gene therapy has the synergistic effect on human ovarian cancer cells; (2) creation of bioluminescence imaging-detectable rat ovarian cancer model; and (3) in vivo experiments using this rat model to validate the technical feasibility of the combination therapy. Cells and nude rats were divided into four groups: (i) combination therapy (HSV-TK/GCV + RFH); (ii) RFH; (iii) HSV-TK/GCV; and (iv) phosphate-buffered saline (PBS). Data were analyzed using Dunnett t-test or Kruskal–Wallis test. Results Cell proliferation assay demonstrated significantly greater reduction in viable cells with the combination therapy [0.52 (0.43, 0.61)] compared to other treatments [RFH 0.90 (0.84, 0.96), HSV-TK/GCV 0.71 (0.53, 0.88), PBS 1 (1, 1); p < .05]. For 24 rat models with bioluminescence imaging-detectable orthotopic ovarian cancer (n = 6 per group), optical imaging demonstrated significantly decreased relative bioluminescence signal with the combination therapy [0.81 (0.52, 1.08)] compared to other treatments [RFH 3.60 (2.34, 4.86), HSV-TK/GCV 2.21 (1.71, 2.71), PBS 3.74 (3.19, 4.29); p < .001]. Ultrasound imaging demonstrated the smallest relative tumor volume with the combination therapy [0.78 (0.45, 1.11) versus 3.50 (2.67, 4.33), 2.10 (0.83, 3.37), 3.70 (1.79, 5.61); p < .05]. Conclusion The feasibility of intratumoral RFH-enhanced HSV-TK/GCV gene therapy was established on a unique rat model with molecular imaging-detectable orthotopic ovarian cancer.

Both heat and new chemotherapeutic drug dioxadet in hyperthermic intraperitoneal chemoperfusion improved survival in rat ovarian cancer model

Hyperthermic Intraperitoneal Chemotherapy (HIPEC) at the time of Cytoreductive Surgery (CRS) is an actively researched treatment in patients with advanced ovarian cancer. Relative contribution of heat and chemotherapeutic agents during HIPEC as well as efficacy of a new agent dioxadet for regional chemotherapy in a rat model of ovarian cancer was studied. Sixty rats were divided into three groups: no treatment control group (n = 19), hyperthermia without chemotherapy (HIPEP) (n = 14), HIPEC + cisplatin (n = 14), HIPEC + dioxadet (n = 13). The intra-abdominal tumor was not resected. End points were: median survival (primary), cause of death (secondary). The median survival of the animals in the control group, HIPEP group, HIPEC + cisplatin, HIPEC + dioxadet were 9 (CI; 8-23), 22.5 (CI; 12-43), 25.5 (CI; 13-62), 49 (Cl; 28-70) days, respectively. The P-values control versus HIPEP, HIPEC + cisplatin versus HIPEC + dioxadet were 0.006, 0.002, and 0.001, respectively. During HIPEC both the heat and the cytotoxic drug had antitumor effects in a rat ovarian cancer model. Dioxadet showed potential as a drug for regional chemotherapy. J. Surg. Oncol. 2016;113:438-442. © 2015 Wiley Periodicals, Inc.

Synthesis, characterization and preliminary in vitro cellular uptake studies of 67Ga(III) thiosemicarbazones

Abstract Preliminary experiments were conducted using the radiometal 67 Ga and a select series of thiosemicarbazones. A series of five monothiosemicarbazone ligands was synthesized via a Schiff-base condensation reaction. Radiolabelling studies were performed using 67 GaCl 3 . The successfully radiolabelled complexes (with labelling efficiencies ranging from 87% to more than 99%) were tested for their radiochemical stability in saline and foetal bovine serum. While all the complexes are stable in saline, only one compound showed some degree of radiochemical stability in serum. In vitro cellular uptake of the radiochemically stable complex was evaluated against rat ovarian cancer (DMBA OC1R) cells, human breast cancer (MCF 7) cells and non-cancerous brain endothelial (bEND5) cells. A clear correlation between cellular uptake of the radiolabelled complex and cell count was observed.

Antitumor effect and toxicity of Lipusu in rat ovarian cancer xenografts

Paclitaxel has yielded superior therapeutic effects in treating ovarian cancer after intraperitoneal (i.p.) injection. However, the dose-limiting toxicity of Cremophor-based paclitaxel was severe abdominal pain, likely caused by the excipients (Cremophor/ethanol). Lipusu, a paclitaxel liposome, has been widely applied for the treatment of ovarian cancer by intravenous administration in China. In order to find potential benefits of i.p. administration of Lipusu, we suppose that Lipusu could modulate paclitaxel toxicity without affecting antitumor activity compared with Cremophor-based paclitaxel (PTX). Antitumor effects, bone marrow toxicity, cardiotoxicity and biodistributions in NuTu19 ovarian cancer-bearing rats, as well as the abdominalpain in normal mice were evaluated. Lipusu exerted similar antitumor effects similar to PTX, but much lower bone marrow toxicity and cardiotoxicity. Furthermore, Lipusu exhibited similar plasma drug exposure, higher exposure in tumor and pelvic lymph nodes and lower exposure in bone marrow and heart compared with PTX. Additionally, Lipusu induced notably lighter abdominalpain than PTX. These data suggested that Lipusu has similar antitumor effect and superior lymphatic targeting with reduced toxicities compared with PTX via i.p. route, which could be related with altered biodistributions. Therefore, Lipusu could be attractive for further evaluation of treating ovarian cancer by i.p. administration in clinic.

Efficacy of a Non-Hypercalcemic Vitamin-D2 Derived Anti-Cancer Agent (MT19c) and Inhibition of Fatty Acid Synthesis in an Ovarian Cancer Xenograft Model

BackgroundNumerous vitamin-D analogs exhibited poor response rates, high systemic toxicities and hypercalcemia in human trials to treat cancer. We identified the first non-hypercalcemic anti-cancer vitamin D analog MT19c by altering the A-ring of ergocalciferol. This study describes the therapeutic efficacy and mechanism of action of MT19c in both in vitro and in vivo models.Methodology/Principal FindingAntitumor efficacy of MT19c was evaluated in ovarian cancer cell (SKOV-3) xenografts in nude mice and a syngenic rat ovarian cancer model. Serum calcium levels of MT19c or calcitriol treated animals were measured. In-silico molecular docking simulation and a cell based VDR reporter assay revealed MT19c–VDR interaction. Genomewide mRNA analysis of MT19c treated tumors identified drug targets which were verified by immunoblotting and microscopy. Quantification of cellular malonyl CoA was carried out by HPLC-MS. A binding study with PPAR-Y receptor was performed. MT19c reduced ovarian cancer growth in xenograft and syngeneic animal models without causing hypercalcemia or acute toxicity. MT19c is a weak vitamin-D receptor (VDR) antagonist that disrupted the interaction between VDR and coactivator SRC2-3. Genome-wide mRNA analysis and western blot and microscopy of MT19c treated xenograft tumors showed inhibition of fatty acid synthase (FASN) activity. MT19c reduced cellular levels of malonyl CoA in SKOV-3 cells and inhibited EGFR/phosphoinositol-3kinase (PI-3K) activity independently of PPAR-gamma protein.SignificanceAntitumor effects of non-hypercalcemic agent MT19c provide a new approach to the design of vitamin-D based anticancer molecules and a rationale for developing MT19c as a therapeutic agent for malignant ovarian tumors by targeting oncogenic de novo lipogenesis.

Tumor cells lysates pulsed dendritic cells for immunotherapy of ovarian cancer in rats: in-vitro study

To study the feasibility of ovarian tumor cells lysates pulsed dendritic cells (DCs) in the immunotherapy of tumor prevention via cytotoxic test in-vitro. Forty rats were randomly divided into 2 groups: experimental and control groups. Ten rats from each group were killed and DCs were isolated and cultured. Frozen-thawed antigen of in the study group, rat's Ovarian cancer cells of the line NuTu-19 were cultured, freeze-melt antigens were added at day 3. Two groups co-cultured with T lymphocytes from the other rat's spleen on the 14th day. Then observed the shape of DCs, contrasted the proliferation and killing rate. In the study group, DCs could significantly stimulate T lymphocytes multiplication and produce tumor specific cytotoxic T lymphocytes (CTL). When the ratios of stimulating cells (SC) to reaction cells (RC) were 1:3, 1:10, 1:30 and 1:100, the stimulating index (SI) in the study group were much higher than those in control group (P<0.01). When the ratios of SC is the same with RC (SC:RC=3:1, 10:1, 30:1): the killing and wounding rate to tumor cells of study group [(40.9+/-1.2)%, (69.8+/-1.8)%, (89.0+/-0.4%)] is significantly higher than those of control group [(30.9+/-1.9)%, (34.4+/-2.1)%, (51.0+/-1.5)%] (P < 0.01). DC could activate T lymphocytes proliferation and produce CTL to kill and wound tumor cells in-vitro.

Protoporphyrin IX fluorescence photobleaching is a useful tool to predict the response of rat ovarian cancer following hexaminolevulinate photodynamic therapy

Accurate dosimetry was shown to be critical to achieve effective photodynamic therapy (PDT). This study aimed to assess the reliability of in vivo protoporphyrin IX (PpIX) fluorescence photobleaching as a predictive tool of the hexaminolevulinate PDT (HAL-PDT) response in a rat model of advanced ovarian cancer. Intraperitoneal 10(6) NuTu 19 cells were injected in 26 female rats Fisher 344. Peritoneal carcinomatosis was obtained 26 days post-tumor induction. Four hours post-intraperitoneal HAL (Photocure ASA, Oslo, Norway) injection, a laparoscopic procedure (D-light AutoFluorescence system, Karl Storz endoscope, Tuttlingen, Germany) and a fluorescence examination were made for 22 rats. The first group (LASER group, n=26) was illuminated with laser light using a 532 nm KTP laser (Laser Quantum, Stockport, UK) on 1 cm(2) surface at 45 J/cm(2). The second group (NO LASER group, n=26) served as controls. Biopsies were taken 24 hours after PDT. Semi-quantitative histology was performed and necrosis value was determined: 0--no necrosis to 4--full necrosis. Fluorescence was monitored before and after illumination on complete responders (NV=3-4; n=20) and non-responders (NV=0-2; n=6). High PpIX photobleaching corresponded with complete responders whereas low photobleaching corresponded with non-responders (P<0.05). A direct linear correlation was shown between photobleaching and necrosis (R(2)=0.89). In vivo PpIX fluorescence photobleaching is useful to predict the tissue response to HAL-PDT.

Iron(III)-Salophene: An Organometallic Compound with Selective Cytotoxic and Anti-Proliferative Properties in Platinum-Resistant Ovarian Cancer Cells

BackgroundIn this pioneer study to the biological activity of organometallic compound Iron(III)-salophene (Fe-SP) the specific effects of Fe-SP on viability, morphology, proliferation, and cell-cycle progression on platinum-resistant ovarian cancer cell lines were investigated.Methodology/Principal FindingsFe-SP displayed selective cytotoxicity against SKOV-3 and OVCAR-3 (ovarian epithelial adenocarcinoma) cell lines at concentrations between 100 nM and 1 µM, while the viability of HeLa cells (epithelial cervix adenocarcinoma) or primary lung or skin fibroblasts was not affected. SKOV-3 cells in contrast to fibroblasts after treatment with Fe-SP revealed apparent hallmarks of apoptosis including densely stained nuclear granular bodies within fragmented nuclei, highly condensed chromatin and chromatin fragmentation. Fe-SP treatment led to the activation of markers of the extrinsic (Caspase-8) and intrinsic (Caspase-9) pathway of apoptosis as well as of executioner Caspase-3 while PARP-1 was deactivated. Fe-SP exerted effects as an anti-proliferative agent with an IC50 value of 300 nM and caused delayed progression of cells through S-phase phase of the cell cycle resulting in a complete S-phase arrest. When intra-peritoneally applied to rats Fe-SP did not show any systemic toxicity at concentrations that in preliminary trials were determined to be chemotherapeutic relevant doses in a rat ovarian cancer cell model.Conclusion/SignificanceThe present report suggests that Fe-SP is a potent growth-suppressing agent in vitro for cell lines derived from ovarian cancer and a potential therapeutic drug to treat such tumors in vivo.

Iron chelators deferoxamine and diethylenetriamine pentaacetic acid induce apoptosis in ovarian carcinoma

Objectives. Ovarian cancer remains a leading cause of death in women and development of new therapies is essential. Deprivation of iron (Fe), an essential micro-nutrient, by chelation is known to inhibit proliferation of several human cancers but its potential in ovarian cancer treatment remains unknown. We have evaluated the anti-proliferative activities of iron chelators, deferoxamine (DFO), and diethylenetriamine pentaacetic acid (DTPA), in human and rat ovarian cancer cells. Methods. The effect of DFO and DTPA on CaOV-3 (human) and NUTU-19 (rat) ovarian cancer cells was determined by cell proliferation and apoptosis assays (Hoechst staining, DNA fragmentation, and caspase activation), cell cycle analysis, and Fe supplementation studies. Results. DFO and DTPA were cytotoxic to ovarian cancer cells in a dose- and time-dependent manner. DFO inhibited proliferation of NUTU-19 and CaOV-3 cells (IC 50 at 45 and 280 μM, respectively), while DTPA inhibited proliferation of only NUTU-19 cells (IC 50 at 50 μM), at 48 h. DNA synthesis was inhibited in CaOV-3 cells by DFO (>90% at 200 μM) and in NUTU-19 by both DFO and DTPA (>90% at 50 μM). Fe supplementation effectively reversed the cytotoxic effects of DFO and DTPA. Cell cycle analysis showed a G0/G1- and S-phase block with increased apoptosis. DNA fragmentation analysis confirmed apoptosis. Increase in caspase-3, -8, and -9 activities (∼2.4-fold) was associated with apoptosis. Conclusions. Our studies show that Fe chelators suppress ovarian cancer growth by inhibiting proliferation and inducing apoptosis. Therefore, Fe chelators can be potentially developed as novel therapeutic agents to treat ovarian cancer.

Antiproliferative effect of mimosine in ovarian cancer

3200 Objective: Iron plays a critical role in cell proliferation and survival making it a potential target for cancer therapy. Iron chelators have recently been shown to possess selective anti-neoplastic properties. Mimosine, a plant amino acid, acts as a potent iron chelator, but its use in gynecologic malignancies has yet to be tested. It is a naturally occurring plant amino acid known to arrest cell-cycle progression at the G1-S border in cultured cells. The objective of our study was to evaluate the anti-proliferative and pro-apoptotic effects of mimosine on human and rat ovarian cancer cells. Methods: Human (CaOV-3 & OvCAR) and rat (NuTu 19) ovarian cancer cell lines were treated for 24–72 hours with mimosine at varying doses ranging from 50 to 800 micro-molar concentrations. Untreated cells were used as a control. Cell viability was measured by MTS reduction assay and cell proliferation was determined by BrdU incorporation. Apoptosis was analyzed by DNA fragmentation. Iron challenge studies were performed to determine the role of iron in the cytotoxic effect of mimosine. Results: Mimosine demonstrated dose dependent anti-proliferative effects on all the ovarian cancer cells tested. Cell viability was inhibited over 70% at a dose of 200μM mimosine. Mimosine also inhibited DNA synthesis as revealed by BrdU incorporation assay. Fifty percent inhibition in DNA synthesis was observed at 100 μM dose level of mimosine. Addition of ferric ion effectively reversed the effects of mimosine, indicating that the effect of mimosine is mediated by iron chelation. In addition, mimosine induced apoptosis. DNA fragmentation analysis confirmed apoptosis. Further testing revealed mimosine to have significant dose-dependent antiproliferative effects on vulvar and cervical cancer cell lines and only a minimal effect on endometrial and colorectal cells. Conclusions: Mimosine, an iron chelator, has potent cytotoxic and anti-proliferative effects on a human and rat ovarian cancer cells. Iron challenge studies imply that the anti-proliferative effect of mimosine is mediated by iron chelation. Mimosine induced apoptosis. No significant financial relationships to disclose.

Enhanced efficiency and specificity of ovarian cancer gene therapy in rats with a novel nonviral gene delivery system (GE7) via intraovarian artery perfusion approach

Transfer of the herpes simplex virus type I-thymidine kinase gene, followed by the administration of ganciclovir (HSV1-tk/GCV) into ovarian cancer-derived cell line either in vitro or transplanted into nude mice has been shown to provide a potential strategy for the gene therapy of ovarian cancer. We investigated the antitumor effects of HSV1-tk/GCV strategy with a chemically induced rat ovarian cancer model and a tumor-selective gene delivery by a novel nonviral gene delivery system (GE7) through the ovarian artery and tail vein. We demonstrated the expression of a reporter gene, beta-gal gene, as well as HSV1-tk gene in tumors and other organs, evaluated the overall antitumor effects after the GCV treatment and analyzed the tumor cell cycle phase distribution. Via the ovarian artery route, the expressions of beta-gal and HSV1-tk in tumors were significantly stronger than those expressed in such organs as the hearts, livers, spleens, lungs and kidneys. However, no beta-gal and HSV1-tk were detected in the tumor tissues when administrated via the tail vein, and little was found in other organs. The cell cycle analysis showed that the total S-phase of tumor cells in the test intra-arterial treatment group was considerably higher than that of the controls. The weight of the tumor tissues in the group treated by the intra-arterial route (4.06+/-2.12 g) was much less than the group treated intravenously (18.25+/-8.34 g) (P<.01). These findings indicated that the administration of GE7/HSV1-tk complex via the ovarian artery route could be a promising avenue of future human ovarian cancer treatment.

Suppression of Ovarian Cancer Cell Tumorigenicity and Evasion of Cisplatin Resistance Using a Truncated Epidermal Growth Factor Receptor in a Rat Model

The overexpression of the epidermal growth factor receptor (EGFR) is associated with a poor prognosis in ovarian cancer. The dominant-negative EGFR (EGFR-DNR) is a truncated receptor that lacks the tyrosine kinase domain and is devoid of signaling capability. This study tested the effects of a EGFR-DNR approach in ovarian cancer cells. NuTu-19, a rat ovarian cancer cell line was rendered resistant to cisplatin. Both NuTu-19 and resistant cells were infected with a retroviral vector containing the EGFR-DNR. NuTu-19 and NuTu-DNR (NuTu-19 cells expressing the EGFR-DNR) were injected into Fisher 344 immunocompetent rats. Western blot analyses were used to assess signal transduction pathways. All rats injected with NuTu-DNR cells remained healthy following tumor injection. In contrast, 100% of the rats injected with the NuTu-19 and NuTu-Sham (NuTu-19 cells expressing an empty vector) died of disease progression at the end of 15 weeks (P = 0.00009). On Western blot analysis, both NuTu-19 and NuTu-Sham cells showed a strong activation of mitogen-activated protein kinase (MAPK) after exposure to EGF. Cisplatin-resistant cell lines showed an enhanced EGF stimulatory effect via the MAPK pathway compared with parental cells. The EGFR-DNR significantly reduced the ability of EGF to induce cell signaling through the MAPK pathway. Lastly, the EGFR-DNR can partially reverse cisplatin resistance in drug-resistant cells. The EGFR-DNR approach suggests that EGFR confers a growth advantage to NuTu-19 cells in vivo. Thus, EGFR blockade may ultimately prove to be a useful therapeutic tool in the treatment of cisplatin-sensitive and cisplatin-resistant ovarian cancers.

Influence of surgical trauma on tumor establishment in a rat ovarian cancer model

There is a strong debate regarding the influence of laparoscopic surgery on tumor dissemination and prognosis, especially in ovarian cancer. In murine mammary cancer cell line models, the incidence of surgical metastasis was influenced by the type of surgical trauma. We investigated the influence of surgical trauma on tumor establishment in a synergetic rat ovarian cancer model in 6- to 8-week-old female BD-IX rats using the rat ovarian cancer cell line O-342. The animals underwent i.p. injection of tumor cells, laparoscopy or midline laparotomy with different surgical procedures at the right uterine horn (grasping with a forceps, incision of the uterine horn after coagulation or partial resection of the uterine horn by ligation). Intraperitoneal tumor establishment was then determined 14 days after the surgical procedure, using cancer index scoring (0, no tumor; 1, tumor diameter less than 0.5 cm; 2, between 0.5 and <1.0 cm; 3, between 1.0 and <2.0 cm). No macroscopically visible tumor growth was observed in the uterine horn, which was unaffected by any surgical procedure. Alternatively, for the right uterine horn that underwent grasping by forceps, coagulation or ligation, the cancer index score was found to be 0.2, 2.5 and 3.0, respectively. The present study shows that surgical trauma favors the establishment of tumor lesions in the rat ovarian cancer model.

Analysis of proapoptotic tumor suppressor function of BARD1 (BRCA1 Associated RING domain protein) in rat ovarian cancer model

Analysis of proapoptotic tumor suppressor function of BARD1 (BRCA1 Associated RING domain protein) in rat ovarian cancer model

Expression of Cyclin D1 and CDK4 in DMBA-Induced Rat Ovarian Cancer.

Ovarian cancer is a common gynecologic malignancy and the leading cause of death in women. It is typically not diagnosed until it has reached the advanced stages. We performed this study to investigate the roles of the proteins related to the G1 cell cycle in ovarian carcinogenesis. Immunohistochemistry and Western blot were used to analyse the expression of cyclin Dl and CDK4 in 7, 12-dimethylbenzanthracene- induced ovarian cancer in rats. The Cyclin D1 and CDK4 labelling index was significantly higher in the ovarian cancers than in the normal ovarian surface epithelium of rats. There was no difference among the cancer types. In Western blot analyses, the expression of cyclin Dl and CDK4 in the ovarian cancers was higher than that in the normal ovarian surface epithelium. A positive correlation was observed between the expressions of the CDK4 and Cyclin D1. The upregulation of cyclin Dl and CDK4 that occurs in DMBA-induced rat ovarian carcinogenesis is likely to be associated with tumor progression. Further studies are needed to investigate the role and function of cyclin Dl and CDK4 in human ovarian cancer.

Monitoring tumor response during photodynamic therapy using near-infrared photon-migration spectroscopy.

Benzoporphyrin-derivative (BPD)-monoacid-ring A photodynamic therapy (PDT) was performed on subcutaneous tumor implants in a rat ovarian cancer model. In order to assess PDT efficacy the tumor and normal tissue optical properties were measured noninvasively prior to and during PDT using frequency-domain photon migration (FDPM). FDPM data were used to quantify tissue absorption and reduced scattering properties (given by the parameters mu a and mu's, respectively) at four near-infrared (NIR) wavelengths (674, 811, 849 and 956 nm). Tissue physiologic properties, including the in vivo concentration of BPD, deoxy-hemoglobin (Hb), oxy-hemoglobin (HbO2), total hemoglobin (TotHb), water (H2O) and percent tissue hemoglobin oxygen saturation (%StO2), were calculated from optical property data. PDT efficacy was also determined from morphometric analysis of tumor necrosis in histologic specimens. All the measured tumor properties changed significantly during PDT. [Hb] increased by 9%, while [HbO2], [TotHb] and %StO2 decreased by 18, 7 and 12%, respectively. Using histologic data we show that long-term PDT efficacy is highly correlated to mean BPD concentration in tumor and PDT-induced acute changes in [HbO2], [TotHb] and %StO2 (correlation coefficients of 0.829, 0.817 and 0.953, respectively). Overall, our results indicate that NIR FDPM spectroscopy is able to quantify noninvasively and dynamically the PDT-induced physiological effects in vivo that are highly correlated with therapeutic efficacy.