Peritoneal Metastasis Of Ovarian Cancer Research Articles

Folate-targeted nanoparticle delivery of chemo- and radiotherapeutics for the treatment of ovarian cancer peritoneal metastasis

Peritoneal metastasis is a major cause of morbidity and mortality in ovarian cancer. While intraperitoneal chemotherapy and radiotherapy have shown favorable clinical results, both are limited by their non-targeted nature. We aimed to develop a biologically targeted nanoparticle therapeutic for the treatment of ovarian cancer peritoneal metastasis. Folate-targeted nanoparticles encapsulating chemotherapy and/or radiotherapy were engineered. Paclitaxel (Ptxl) was used as the chemotherapeutic and yittrium-90 ( 90Y) was employed as the therapeutic radioisotope. Folate was utilized as the targeting ligand as most ovarian cancers overexpress the folate receptor. Nanoparticle characterization studies showed monodispersed particles with controlled Ptxl release. Folate targeting ligand mediated the uptake of NPs into tumor cells. In vitro efficacy studies demonstrated folate-targeted NPs containing chemoradiotherapy was the most effective therapeutic compared to folate-targeted NPs containing a single therapeutic or any non-targeted NP therapeutics. In vivo efficacy studies using an ovarian peritoneal metastasis model showed that folate-targeted NP therapeutics were significantly more effective than non-targeted NP therapeutics. Among the folate-targeted therapeutics, the NP containing chemoradiotherapy appeared to be the most effective. Our results suggest that folate-targeted nanoparticles containing chemoradiotherapy have the potential as a treatment for ovarian peritoneal metastasis.

LC−MS/MS Analysis of Ovarian Cancer Metastasis-Related Proteins Using a Nude Mouse Model: 14-3-3 Zeta as a Candidate Biomarker

Peritoneal implantation is the most common metastatic pattern of epithelial ovarian cancer, and the five-year survival rate of patients is dramatically decreased when large-scale peritoneal metastasis occurs. This study aimed to determine serum proteins that could be used to detect early peritoneal metastasis of ovarian cancer. The secreted (or shed) proteins of the ovarian cancer cell line SKOV-3 were analyzed using LC-MS/MS, and 97 proteins were identified in the SKOV-3 culture supernatant. After the SKOV-3 cells were xenografted into the peritoneal cavities of nude mice, 3 of the 97 proteins were detected in animal sera. Following enzyme-linked immunosorbent assay (ELISA)-based screening of clinical blood samples, one of the three proteins, 14-3-3 zeta, was identified as a candidate biomarker. The average serum levels of 14-3-3 zeta in patients with epithelial ovarian cancer and benign gynecological diseases were significantly different. The expression of 14-3-3 zeta was associated with the degree of cancer peritoneal metastasis, the emergence of ascites, bilateral involvement, and the clinical stage and substage. Using 14-3-3 zeta, the overall diagnostic accuracy for ovarian cancer was greatly improved. Furthermore, siRNA-based experiments demonstrated that 14-3-3 zeta was responsible for approximately 62, 65, and 30% of the migratory, invasive, and implantation abilities of SKOV-3 cells, respectively. The present results demonstrated that the nude mouse xenograft model is an efficient system for performing function-oriented biomarker discovery, which can be used for a variety of research tasks in future molecular diagnoses, targeted therapies, and ovarian cancer vaccine development.

A Randomized Phase II Trial to Test the Efficacy of Intra-peritoneal Paclitaxel for Gastric Cancer with High Risk for the Peritoneal Metastasis (INPACT Trial)

Owing to its peculiar pharmacological characteristics, paclitaxel attains substantial intra-peritoneal concentration for a prolonged period when delivered intra-peritoneally, and is active against peritoneal metastasis of ovarian cancer. It is also considered promising against disseminated gastric cancer. However, the fact that the intra-peritoneal paclitaxel has not been approved in Japan has rendered its evaluation by a formal clinical trial impossible. The authors designed a randomized phase II trial using the Kodo Iryo Hyoka system, a new system to legally test an yet unapproved mode of treatment. It is hoped that this trial will result in a breakthrough in the treatment of peritoneal carcinomatosis from gastric cancer.

Abstract 2346: Contribution of VLA-4 to ovarian cancer metastasis and platinum resistance

Abstract Ovarian cancer is the fourth leading cause of cancer-related death among women. The relatively poor prognosis for ovarian cancer (5-year survival of 30-40%) reflects 1) the advanced stage of disease at diagnosis and 2) the frequent development of recurrent disease refractory to front line therapy. Ovarian cancers metastasize by attaching to and invading through the mesothelium, a single cell layer of mesothelial cells lining the peritoneal cavity. The presence of invasive peritoneal metastases is associated with a poor prognosis for ovarian cancer (5 yr survival <25%). We identified the integrin VLA-4 and its ligand VCAM-1 as regulators of mesothelial invasion. VLA-4 expression correlates with the ability of ovarian cancer cells to invade mesothelial monolayers. Additionally, VLA-4 is expressed on primary ovarian cancer cells obtained from patient tumors or ascites. The contribution of VLA-4 to ovarian cancer peritoneal metastasis was evaluated using a mouse xenograft model and function-blocking antibodies directed against VLA-4. Mice were injected intraperitoneally with platinum-resistant human ovarian cancer cells; one week later the mice were randomized into four groups and treated with 1) anti-VLA-4 antibodies, 2) carboplatin, 3) anti-VLA-4 and carboplatin, or 4) control IgG. Treatment with either anti-VLA-4 therapy or carboplatin alone had no effect on tumor burden compared to the IgG control group. However, the combined treatment of anti-VLA-4 and carboplatin significantly reduced tumor burden compared to the control or either treatment alone. This study supports a role for the active involvement of VLA-4 expressed by tumor cells in the regulation of ovarian cancer chemoresponsiveness. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2346.

Evaluation of ALA-PDT of ovarian cancer in the Fisher 344 rat tumor model

This study aimed to evaluate aminolevulinic acid-photodynamic therapy (ALA-PDT) in an experimental tumor model to expand the use of PDT in the treatment of ovarian cancer with peritoneal carcinosis. 5-Aminolevulinic acid (ALA) (Photocure ASA, Norway) 60mg/kg was injected in the peritoneum cavity of 45 female rats Fisher with induced peritoneal metastases of ovarian cancer. ALA-PDT was performed 4h later with two different lasers: (1) laser diode (Diomed, Cambridge, UK), at 630nm, 100mW/cm(2), or (2) KTP laser (Laser Quantum, Stockport, UK), 532nm, 30mW/cm(2). The animals were divided into five groups: LASER ALONE group, CTRL group (no cancer), NO LASER group, 1 DOSE group (PDT during 1s) and 1.5 DOSE group (PDT during 1.5s). Biopsies were taken 24h after treatment. A semi-quantitative score called necrosis value (NV) was assigned to each sample that reflected the depth of the peritoneal necrosis. In the first two groups, the peritoneum remained intact irrespective of the wavelength. In the 1 DOSE group, necrosis was observed for 532nm and 630nm. In the 1.5 DOSE group, necrosis was observed for 532nm (NV: 3.22±0.83) and 630nm (NV: 2.67±1.00) (p<0.05). The mesothelium strongly thinned out in the diffuse shape of the tumor. Only ALA-PDT induces tumor necrosis with either 532nm and 630nm and should be considered an effective therapy for micrometastasis of ovarian cancer. This preliminary study deserves further experiments.

Comparison of Aminolevulinic Acid– and Hexylester Aminolevulinate–Induced Protoporphyrin IX Fluorescence for the Detection of Ovarian Cancer in a Rat Model

This study set out to compare the photodetection of peritoneal micrometastases in an ovarian cancer model following administration of two precursors of protoporphyrin IX (PpIX): 5-aminolevulinic acid (ALA) and hexylester aminolevulinate (He-ALA). ALA or He-ALA (100 mg/kg) was injected into the peritoneal cavity of 16 rats with induced peritoneal metastases of ovarian cancer. Two hours later, the tumors were visualized laparoscopically using both white light for standard exploration and blue light for fluorescence. Peritoneal micrometastases were counted. Fluorescence intensities of tumoral and normal surrounding tissues were compared. The distribution of PpIX throughout the peritoneum was studied on frozen biopsies using fluorescence microscopy and correlated with pathological findings. The number of micrometastases detected by the fluorescence blue mode was significantly higher (p < 0.05) than with standard white light for both ALA (235 versus 198) and He-ALA application (248 versus 199). The mean fluorescence intensity ratio between tumor and normal surrounding tissue was significantly (p < 0.05) higher for He-ALA (1.55 +/- 0.1) compared to ALA (1.45 +/- 0.1). Fluorescence microscopy confirmed that the PpIX fluorescence remained limited to cancer cells. Macroscopically fluorescing nodules were histopathologically confirmed as malignant. He-ALA is an excellent precursor for PpIX synthesis, giving the highest PpIX fluorescence contrast between normal and tumoral peritoneal tissues. Imaging with He-ALA improves the detection of peritoneal metastases compared to ALA.

Gonadotropins Activate Proteolysis and Increase Invasion through Protein Kinase A and Phosphatidylinositol 3-Kinase Pathways in Human Epithelial Ovarian Cancer Cells

Despite evidence that gonadotropins may facilitate peritoneal metastasis of ovarian cancer by increasing cell adhesion, the action and molecular mechanism of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in ovarian cancer invasion is not well characterized. In the present study, we investigated the effects of FSH and LH on the invasive activity and the expression of metastasis-related proteinases in human epithelial ovarian cancer by Western blot, zymography, reverse transcription-PCR (RT-PCR), ELISA, and Boyden chamber assay. Treatment with FSH or LH (10, 100, or 1,000 ng/mL) significantly increased the invasion of ovarian cancer cell lines, including BG-1, CaOV-3, and SKOV-3 cells but not OVCAR-3 cells. In addition, treatment of SKOV-3 cells with FSH or LH (100 or 1,000 ng/mL) enhanced the expression and activation of matrix metalloproteinases (MMP-2 and MMP-9) as shown by RT-PCR, gelatin zymography, and ELISA. Pretreatment with [(2R)-2-(hydroxamido-carbonylmethyl)-4-methylpentanoyl]-l-tryptophan methylamide (10 micromol/L), a total MMP inhibitor, and 3-(4-phenoxyphenylsulfonyl)-propylthiirane (20 micromol/L), a specific gelatinase inhibitor, neutralized the proinvasive effect of gonadotropins in SKOV-3 cells. In addition, the secretion of tissue inhibitor of metalloproteinases (TIMP-1 and TIMP-2) and plasminogen activator inhibitor-1 was significantly decreased by FSH and LH (100 or 1,000 ng/mL). We further showed that gonadotropins induced an increase in SKOV-3 invasiveness via the activation of protein kinase A (PKA) and phosphatidylinositol 3-kinase (PI3K) signaling pathways. Taken together, these results suggest that gonadotropins may contribute to ovarian cancer metastasis via activation of proteolysis and increase in invasion through the PKA and PI3K pathways.