Hyperthermic intraperitoneal chemotherapy as consolidation treatment of advanced stage ovarian cancer.

OBJECTIVE: To investigate the therapeutic efficacy of hyperthermic intraperitoneal chemotherapy (HIPEC) as consolidation treatment after completing first-line treatment in patients with advanced ovarian cancer. METHODS: A retrospective chart review was conducted on patients treated at the Comprehensive Gynecologic Cancer Center between January 2014 and 2019. Based on the inclusion criteria, 24 eligible patients who received HIPEC (paclitaxel 175 mg/m2, for 90 minutes, at 42°C) (HIPEC group) as consolidation treatment after terminating the adjuvant chemotherapy were identified. Another 24 patients who met the inclusion criteria and did not receive HIPEC were matched, representing the non-HIPEC group. Disease-free survival (DFS) and overall survival (OS) were examined between the two groups. RESULTS: The median DFS was 28.7 and 24.2 months in the HIPEC and non-HIPEC groups, respectively (P=0.688). The 3-year DFS rates in the HIPEC and non-HPEC groups were 39.5% and 32.6%, respectively. However, the median OS was not determined. The 5-year OS rates in the HIPEC and non-HIPEC groups were 86.2% and 81.3%, respectively (P=0.850). One patient developed grade 3 neutropenia. Other patients experienced mild adverse events after HIPEC. CONCLUSION: This study suggests that consolidation HIPEC could not support the survival benefit after completing the first-line treatment for patients with advanced ovarian cancer, although no severe specific safety issues were found. Therefore, randomized trials evaluating consolidation HIPEC for the management of ovarian cancer are warranted.

Oncologic and obstetric outcomes of conservative surgery for borderline ovarian tumors in women of reproductive age.

OBJECTIVE: To compare the oncologic and obstetric outcomes in reproductive-age females with borderline ovarian tumors (BOTs) treated with cyst enucleation (CE) or unilateral salpingo-oophorectomy (USO). METHODS: The medical records of patients with BOTs treated between 1998 and 2014 were retrospectively reviewed. The recurrence rates in the USO and CE groups were compared, and the postoperative obstetric outcomes were assessed via telephone survey. RESULTS: Eighty-nine patients with BOTs underwent USO, and 19 underwent CE. Of these, six patients had recurrent BOTs. The recurrence rate was significantly lower in the USO group (3/89, 3.4%) than in the CE group (3/19, 15.8%) (P=0.032). All patients with recurrent disease were successfully treated with further surgery. Of the 76 patients interviewed by telephone, 71 (93.4%) resumed regular menstruation after surgery. Twenty-six of the 32 patients (81.3%) who attempted to conceive had successful pregnancies. USO (19/24, 79.2%), like CE (7/8, 87.5%), resulted in favorable pregnancy rates for patients with BOTs. CONCLUSION: USO is a suitable fertility-preserving surgery for women with BOTs. CE is also an acceptable option for select patients.

Placental Site Trophoblastic Tumors: Analysis of the Clinicopathologic Characteristics of 20 Cases in Korea.

OBJECTIVES: The aim of this study was to evaluate the clinicopathologic features of placental site trophoblastic tumors (PSTTs) in Korea. METHODS/MATERIALS: Twenty patients given a diagnosis of PSTT in Korea (1990-2013) were evaluated retrospectively, including 14 patients identified through a literature review and 6 patients identified through a medical chart review of a single institution. The analysis included patient age, antecedent pregnancies, time since antecedent pregnancy, presenting symptoms, serum ß-human chorionic gonadotropin level, International Federation of Gynecology and Obstetrics stage, treatment, outcome, and follow-up. RESULTS: The mean age of the 20 patients was 32 years (range, 25-53 years). The antecedent pregnancies included 8 term pregnancies, 8 abortions, and 2 molar pregnancies. The time since the antecedent pregnancy was less than 1 year in 16 patients (80%). Nineteen patients (95%) presented with abnormal vaginal spotting or amenorrhea. Serum ß-human chorionic gonadotropin levels ranged from normal to 13,480 mIU/mL, although most patients (80%) had a level less than 1000 mIU/mL. Seventeen patients (85%) presented with stage I disease. Ten patients (50%) underwent hysterectomy, and 14 patients (70%) were treated with chemotherapy with or without hysterectomy. In 11 evaluated patients, the median mitotic count index was 3.4 (0.4-10) per 10 high-power fields. The median follow-up time was 17 months (range, 1-68 months). There was no recurrence or death from disease. CONCLUSIONS: Korean patients with PSTT often have early-stage disease, which has a favorable prognosis even with fertility-preserving therapy. However, international studies are necessary to determine the optimal treatment and prognostic factors.

Octreotide therapy for the management of refractory chylous ascites after a staging operation for endometrial adenocarcinoma.

Chylous ascites after para-aortic lymphadenectomy is caused by a rupture in the retroperitoneal lymphatic channels. The incidence of postoperative chylous ascites is increasing as para-aortic lymphadenectomy for the management of gynecologic malignancies becomes more common. However, management of this condition remains unsatisfactory because some patients do not respond to conservative methods and have to undergo surgical intervention, even though they may be malnourished and immunosuppressed. We report the case of a patient who underwent a standard staging operation for endometrial cancer and experienced a large amount of lymphatic leakage, in spite of treatment with total parenteral nutrition and a low-fat diet for over 40 days. As a step-up approach, octreotide, a somatostatin analog, was added and the disease resolved completely. This case demonstrated that octreotide therapy is highly effective in refractory cases of chylous ascites where a large amount of leakage is observed and cases that are otherwise indicated for surgical intervention.

The prognostic impact of duration of anemia during chemotherapy in advanced epithelial ovarian cancer.

OBJECTIVE: To propose a measure of anemia to be used as a prognostic factor for progression-free survival and overall survival in advanced epithelial ovarian cancer patients. PATIENTS AND METHODS: Seventy-six patients with International Federation of Gynecology and Obstetrics stage III and stage IV epithelial ovarian cancer who had received at least six courses of platinum- and taxane-based systemic chemotherapy and achieved clinical or pathologic complete response were included. A novel prognostic factor based on the duration of anemia was proposed and the impact of anemia on progression-free and overall survival times was analyzed by a log-rank test and a Cox proportional hazards model. RESULTS: We introduce a binary variable, Hb1020, that takes a value of 1 if the duration of a hemoglobin (Hb) level <10 g/dL is ≥20% of the total duration of chemotherapy. We propose Hb1020 as a potential prognostic factor for epithelial ovarian cancer. The 5-year progression-free survival rates were 48.4% in the Hb1020 = 0 group (duration of Hb <10 g/dL <20% of total duration) and 17.7% in the Hb1020 = 1 group (p = .026). The 5-year overall survival rates were 64.6% and 45.0%, respectively (p = .015). CONCLUSIONS: Hb1020, based on the duration of anemia, is a potential prognostic factor for epithelial ovarian cancer. Using Hb1020, we will be able to administer highly optimized treatment for anemia to improve patient survival. Further independent studies are needed to confirm its prognostic role.

Consolidation hyperthermic intraperitoneal chemotherapy using paclitaxel in patients with epithelial ovarian cancer.

BACKGROUND: We evaluated the efficacy and feasibility of hyperthermic intraperitoneal chemotherapy (HIPEC) using paclitaxel as consolidation therapy in patients with epithelial ovarian cancer. METHODS: Between November 1999 and January 2004, 18 patients with a negative second-look and 1 patient with positive peritoneal cytology only with stage Ic-IIIc epithelial ovarian cancer received consolidation intra-operative HIPEC using paclitaxel. The HIPEC was performed with open-abdomen technique, using 6 L of lactated Ringer's solution containing paclitaxel 175 mg/m(2), for 90 min in hyperthermic phase (43-44 degrees C). The survival rates were compared with 24 patients treated with conventional therapy (control group). RESULTS: The 8-year progression-free survival rates were 63.16% in the HIPEC-paclitaxel group and 29.17% in the control group (P = 0.027). The 8-year overall survival rates were 84.21% in the HIPEC-paclitaxel group and 25.00% in the control group (P = 0.0004). The time interval between initial treatment and HIPEC was statistically significant with respect to progression-free and overall survival in the HIPEC-paclitaxel group. CONCLUSION: HIPEC with paclitaxel during 2nd-look laparotomy is feasible and relatively safe and showed a good effect on survival. In patients with epithelial ovarian cancer who have a complete pathologic response, HIPEC with paclitaxel should be considered as a consolidation treatment option.

Identification of large-scale characteristic genes of Müllerian inhibiting substance in human ovarian cancer cells.

The purpose of this study was to investigate the large-scale characteristic molecular signature of Müllerian inhibiting substance (MIS) in human ovarian cancer cells through expression genomics. To understand the comprehensive molecular mechanisms by which MIS inhibits ovarian cancer cell growth, we identified the large-scale characteristic molecular changes elicited by MIS in the human ovarian cancer cell line OVCAR-8, using DNA microarray analysis. Combined serial gene expression analysis from 0 to 96 h after MIS treatment of OVCAR-8 cells resulted in 759 genes which showed at least a 2-fold change in overexpression or underexpression compared to non-treatment groups. Of the 759 outlier genes, 498 genes were mapped to known biological cellular processes, and the resultant major pathways included metabolism, signal transduction, cell growth and apoptosis. Among these pathways, 68 genetic elements were dissected as cell cycle-related genes induced by MIS. Although cellular phenotypic changes by MIS were observed after 24 h of treatment, the characteristic large-scale molecular changes were observed from 48 to 96 h of exposure to MIS. This finding may imply that the suppressive role of MIS on ovarian cancer cells could be cumulative in that the metabolic disturbance of MIS is followed by arrest at the G1/S cell cycle checkpoint. We suggest 759 outlier genes comprise the characteristic molecular signature of MIS, which may be responsible for the suppressive effect on OVCAR-8 cells. Although the precise biological mechanisms underlying these outlier genes should be validated, the genetic elements described herein provide promising therapeutic interventions for ovarian cancer.

Treatment of ovarian cancer with paclitaxel- or carboplatin-based intraperitoneal hyperthermic chemotherapy during secondary surgery.

OBJECTIVE: We aimed to evaluate the efficacy and feasibility of treating advanced ovarian cancer with paclitaxel or carboplatin in intraperitoneal hyperthermic chemotherapy (IPHC) during secondary surgery. METHODS: We reviewed clinical data of 96 eligible patients with stage Ic-IIIc epithelial ovarian cancer. After primary staging operation and 6-12 cycles of adjuvant chemotherapy, 22 patients were treated with IPHC-paclitaxel (175 mg/m(2)) and 45 patients were treated with IPHC-carboplatin (350 mg/m(2)) during secondary surgery. Survival rates were compared with those of 29 patients treated with only conventional therapy (control group). RESULTS: In stage III diseases, 5-year survival rates were 84.6% in IPHC-paclitaxel, 63.0% in IPHC-carboplatin (P=0.4098) and 32.8% in control group (vs. IPHC, P=0.0003). Three-year progression-free survival rates in stage III diseases were both 56.3% in IPHC-paclitaxel and IPHC-carboplatin (P=0.8911) and 16.7% in control group (vs. IPHC, P=0.0028). For the relative risk of disease progression yielded from multivariate analyses, hazard ratio of IPHC-paclitaxel was 0.281 (P=0.0039) and that of IPHC-carboplatin was 0.443 (P=0.0083). Like carboplatin (hazard ratio: 0.396, P=0.0004), IPHC-paclitaxel considerably decreased the risk of death (hazard ratio: 0.197, P=0.0253). CONCLUSION: In advanced ovarian cancer, IPHC using paclitaxel or carboplatin during secondary surgery could be a candidate for regional consolidation therapy to prolong survival and hinder disease progression.

18F-fluorodeoxyglucose positron emission tomography in patients with recurrent ovarian cancer: in comparison with vascularity, Ki-67, p53, and histologic grade.

The aim of this study was to assess the correlation between 18F-fluorodeoxyglucose positron emission tomography (FDG PET) positivity of tumor recurrence and vascularity, Ki-67, p53, and histologic grade in patients with ovarian cancer. Nineteen patients with recurrent ovarian cancer underwent FDG PET before second-look surgery. Archival paraffin-embedded tissue materials were used to assess histologic grade including architectural pattern, mitotic activity, and nuclear pleomorphism; intratumor microvessel density (MVD); Ki-67; and p53. Univariate analysis was used to evaluate the correlation between FDG PET positivity and each biomarker. Stepwise logistic regression analysis was used to determine the best parameter to explain FDG PET positivity. MVD revealed significant positive correlation with FDG PET positivity (p=0.0341). There was no significant correlation between FDG PET positivity and Ki-67 or p53 (p=0.4040, p=0.6027). Mitotic activity yielded statistically significant positive correlations with FDG PET positivity (p=0.0448) although histologic grade revealed no positive correlation (p=1). Stepwise logistic regression analysis revealed MVD to be the strongest parameter for FDG PET positivity (OR=0.696, 95% CI 0.487-0.993, p=0.0458). In conclusion, FDG PET positivity revealed positive correlation with MVD and mitotic activity. MVD was the strongest parameter in predicting positive tumor recurrence on FDG PET.

Immunization with adenoviral vectors carrying recombinant IL-12 and E7 enhanced the antitumor immunity to human papillomavirus 16-associated tumor.

OBJECTIVE: Human papillomavirus (HPV) infection play a significant role in cervical carcinogenesis, and HPV oncoprotein E7 has important functions in the formation and maintenance of cervical cancers. Interleukin-12 (IL-12) has been reported to induce cellular immune responses, and has also been demonstrated to suppress the growth of tumors and the expression of E7. Here, we investigate the utility of adenovirus E7 (AdE7) and adenovirus IL-12 (AdIL-12) for protection against TC-1 tumor using an animal model. METHODS: The antitumor effects induced by AdIL-12 and/or E7 were assessed by measurements of tumor size. E7-specific antibody and INF-gamma production in sera were measured, as were T-helper cell proliferative responses. Cytotoxic T-lymphocytes (CTL) and T cell subset depletion studies were also performed. RESULTS: Infection of tumor sites with a combination of AdIL-12 and AdE7 resulted in an antitumor effect which was significantly more profound than that which resulted from singular infections with either AdIL-12 or AdE7. Combined infection resulted in regression of 9-mm-sized tumors in approximately 80% of our experimental animals as compared to the PBS group. Serum levels of E7-specific antibody and INF-gamma production, as well as T-helper cell proliferative responses, were found to be significantly higher in coinfected with AdIL-12 and AdE7 group than in single infection with either AdIL-12 or AdE7 group. CTL responses only exhibited by the AdIL-12 and AdE7 coinjected group suggested that these tumor suppression effects were mediated primarily by CD8+ and, to a lesser degree, by CD4+ T cells. CONCLUSION: Combined injection with adenovirus carrying IL-12 and E7 induced significant antitumor immunity against TC-1 tumors. They may prove useful in clinical applications for the treatment of HPV-associated tumors.

New approaches to pathogenic gene function discovery with human squamous cell cervical carcinoma by gene ontology.

PURPOSE: This study utilized mRNA differential display and the Gene Ontology (GO) analysis to characterize the multiple interactions of a number of genes with gene expression profile involved in squamous cell cervical carcinoma. METHODS: mRNA differential displays were used to identify potential transcripts that were differentially expressed between cervix cancers of 13 patients (invasive cancer stages Ib-IIb) and universal reference RNAs comprised of 17 different normal cervixes. Aberrant bands were excised and used to make cDNA, which was sequenced. DNA sequences were compared to other nucleic acids in the NCBR database for homology. Transcript expression was verified in select samples using RT-PCR and North blotting. The specific functions were correlated with gene expression patterns via gene ontology. RESULTS: Fifty-eight genes were up- or down-regulated above 2-fold and organized into reciprocally dependent sub-function sets depending on the cervical cancer pathway. The GO analysis showed that squamous cell cervical carcinogenesis underwent complete up-regulation of cell cycle, transport, epidermal differentiation, protein biosynthesis, and RNA metabolism. Also, genes belonging to protein metabolism and catabolism activity were significantly up-regulated. In contrast, significant down-regulation was shown in muscle development, cell adhesion, and damaged DNA binding activity. CONCLUSION: The GO analysis can overcome the complexity of the gene expression profile of the squamous cell cervical carcinoma-associated pathway and identify several cancer-specific cellular processes as well as genes of unknown function. Also, GO analysis can serve as a powerful basis for a molecular classification of carcinogenesis.

Immunization with adenoviral vectors carrying recombinant IL-12 and E7 enhanced the antitumor immunity against human papillomavirus 16-associated tumor.

PURPOSE: Human papillomavirus (HPV) infection has a significant role in cervical carcinogenesis, and HPV oncoprotein E7 plays an important part in the formation and maintenance of cervical cancer. Interleukin-12 (IL-12) has been reported to induce a cellular immune response, and to suppress the tumor growth and the E7 production. Here we describe the use of adenoviral delivery of the HPV 16 E7 subunit (AdE7) along with adenoviral delivery of IL-12 (AdIL-12) in mice with HPV-associated tumors. MATERIALS AND METHODS: Mice were injected with TC-1 cells to establish TC-1 tumor, and then they were immunized with AdIL-12 and/or AdE7 intratumorally. The anti tumor effects induced by AdIL-12 and/or E7 were evaluated by measuring the size of the tumor. E7-specific antibody and INF-gamma production in sera, and the T-helper cell proliferative responses were then measured. Cytotoxic T-lymphocyte (CTL) and T cell subset depletion studies were also performed. RESULTS: Combined AdIL-12 and AdE7 infection at the tumor sites significantly enhanced the antitumor effects more than that of AdIL-12 or AdE7 single infection. This combined infection resulted in regression of the 9 mm sized tumors in 80% of animals as compare to the PBS group. E7-specific antibody and INF-gamma production in the sera, and the T-helper cell proliferative responses were significantly higher with coinfection of AdIL-12 and AdE7 than with AdIL-12 or AdE7 alone. CTL response induced by AdIL-12 and AdE7 in the coinjected group suggested that tumor suppression was mediated by mostly CD8+ and only a little by the CD4+ T cells. CONCLUSION: IL-12 and E7 application using adenovirus vector showed antitumor immunity effects against TC-1 tumor, and this system could be use in clinical applications for HPV-associated cancer.

Anticancer effects of (-)-epigallocatechin-3-gallate on ovarian carcinoma cell lines.

PURPOSE: A constituent of green tea, (-)-epigallocatechin-3-gallate (EGCG), has been known to possess anti-cancer properties. In this study, we investigated the time-course anticancer effects of EGCG on human ovarian cancer cells to provide insights into the molecular-level understanding of growth suppression mechanism involved in EGCG-mediated apoptosis and cell cycle arrest. METHODS: Three human ovarian cancer cell lines (p53 negative, SKOV-3 cells; mutant type p53, OVCAR-3 cells; and wild type p53, PA-1 cells) were used. The effect of EGCG treatment was studied via cell count assay, cell cycle analysis, FACS, Western blot, and macroarray assay. RESULTS: EGCG exerts a significant role in suppressing ovarian cancer cell growth. Also, EGCG showed growth inhibitory effects in each cell line in a dose-dependent fashion and induced apoptosis and cell cycle arrest. The cell cycle was arrested at the G(1) phase by EGCG in SKOV-3 and OVCAR-3 cells. In contrast, the cell cycle was arrested in the G(1)/S phase arrest in PA-1 cells. EGCG differentially regulated the expression of genes and proteins (Bax, p21, Retinoblastoma, cyclin D1, CDK4, Bcl-X(L)) more than 2-fold, showing a possible gene regulatory role of EGCG. The continual expression in p21WAF1 suggests that EGCG acts in the same way with p53 proteins to facilitate apoptosis after EGCG treatment. And Bax, PCNA, and Bcl-X are important in EGCG-mediated apoptosis. In contrast, CDK4 and Rb are not important in ovarian cancer cell growth inhibition. CONCLUSION: EGCG can inhibit ovarian cancer cell growth through induction of apoptosis and cell cycle arrest as well as regulation of cell cycle-related proteins. Thereby, the EGCG-mediated apoptosis can be applied to an advanced strategy in the development of a potential drug against ovarian cancer.

Effects of intraperitoneal hyperthermic chemotherapy in ovarian cancer.

OBJECTIVES: To evaluate the clinical effect of intraperitoneal hyperthermic chemotherapy (IPHC) in ovarian cancer patients. PATIENTS AND METHODS: We retrospectively reviewed 117 stages Ic-III ovarian cancer patients, who were diagnosed at the Gynecology Department of Kangnam St. Mary's Hospital between January 1994 and January 2000. Of these, 57 patients underwent cytoreductive surgery (conventional treatment) with IPHC and 60 patients (control group) underwent conventional treatment only. IPHC consisted of administering a mixture of 350 mg/m(2) of carboplatin and 5,000,000 IU/m(2) of interferon-alpha, and maintaining the intraperitoneal temperature at 43-44 degrees C during surgery. RESULTS: The overall 5-year survival rate was 58.6%; that of the IPHC group was 63.4% vs. 52.8% in the control group, with significantly higher survival in the IPHC group (P = 0.0078). Considering stage III ovarian cancer patients only (n = 74), the survival rate was 53.8% in the IPHC group (n = 35) and 33.3% in the control group (n = 39) and was significantly higher in the IPHC group (P = 0.0015). For stage III ovarian cancer patients whose tumor was reduced to less than 1 cm during a second procedure (n = 53), the 5-year survival rate was 65.6% in patients who underwent IPHC (n = 26) and 40.7% in the control patients (n = 27) (P = 0.0046). IPHC was an independent prognostic factor that was not affected by surgical staging, tumor size after second surgery, or patient age, according to a multivariate analysis (Hazard ratio = 0.496, P = 0.0176). CONCLUSION: Our study suggests that IPHC is a promising new treatment modality in ovarian cancer.

Comparison of effects of As2O3 and As4O6 on cell growth inhibition and gene expression profiles by cDNA microarray analysis in SiHa cells.

An arsenical compound, As2O3 has been reported to be effective for treating acute leukemia and induce apoptosis in many different tumor cell types. In this study we designed a novel arsenical compound, As4O6, and compared its ability to induce cell growth inhibition as well as gene expression profiles along with As2O3 in HPV16 infected SiHa cervical cancer cells. Both As2O3 and As4O6 induced apoptosis in SiHa cells, as determined by a DNA ladder formation. As4O6 was more effective in suppressing the growth of SiHa cells in vitro, as compared to As2O3. To further compare gene expression profiles between these two drugs, we used a 384 cDNA microarray system. The gene expression profiles were also classified into the Gene Ontology (GO) to investigate apoptosis-related cellular processes. In the case of As2O3, 41 genes were up- or down-regulated at least 2-fold, as compared to non-treatment, whereas, 65 genes were up- or down-regulated by As4O6 treatment. In particular, 27 genes were commonly regulated by both arsenic compounds. The GO analysis also indicated that down-regulation of cell-regulatory functions, such as cell cycle, protein kinase activity and DNA repair, induces an anti-tumor effect. Taken together, these data support that As4O6 could be more effective than As2O3 in inhibiting the growth of HPV16 infected cervical cancer cells. This appears to be mediated through a unique but overlapping regulatory mechanism(s), suggesting that the regulated genes and cellular processes could be used for a new potential drug approach for treating cervical cancer in clinical settings.

Searching for pathogenic gene functions to cervical cancer.

OBJECTIVES: Molecular pathology of cervical cancers associated with human papillomavirus (HPV) infection is presently unclear. In an effort to clarify this issue, we investigated gene expression profiles and pathogenic cellular processes of cervical cancer lesions. METHODS: Tissues of 11 patients (invasive cancer stages Ib-IIIa) were investigated by a cDNA microarray of 4700 genes, hierarchical clustering and the Gene Ontology (GO). RESULTS: We identified 74 genes showing a more than 2-fold difference in their expression in at least 8 out of 11 patients. Among these, 33 genes were up-regulated, in contrast, 41 genes were down-regulated. The gene expression profiles were classified into mutually dependent 345 function sets, resulting in 611 cellular processes according to the GO. The GO analysis showed that cervical carcinogenesis underwent complete down-regulation of cell death, protein biosynthesis, and nucleic acid metabolism. Also, genes belonging to nucleic acid binding and structural molecule activity were significantly down-regulated. In contrast, significant up-regulation was shown in skeletal development, immune response, and extracellular activity. CONCLUSIONS: These data suggest that the regulated genes and cellular processes could be further used for predicting prognosis and diagnosis of cervical cancer patients, and further investigation and functional characterization of the identified genes is warranted.

Recombinant adenovirus-p53 gene transfer and cell-specific growth suppression of human cervical cancer cells in vitro and in vivo.

PURPOSE: We investigated the time-course expression patterns of p53 and E6 on cervical cancer cells to obtain a molecular level understanding of cell-dependent tumor growth suppression effects of recombinant adenovirus expressing p53 in vitro and in vivo. METHODS: Four human papillomavirus (HPV)-infected human cervical cancer cell lines (HPV 16-positive cells, CaSki and SiHa cells; and HPV 18-positive cells, HeLa and HeLaS3 cells) were used. Also, HPV negative C33A and HT3 cell line that has a mutation on p53 gene were used. After infection with AdCMVp53, the cell growth inhibition was studied via cell count assay, MTT assay, and Neutral red assay. After transfecting AdCMVp53 and AdCMVLacZ into the cancer cells-xenografted nude mice, antitumor effects were investigated for 1 month, respectively. RESULTS: For each cervical cancer cell, IC50 was as follows; CaSki (68.5 multiplicity of infection, or MOI), SiHa (43.5 MOI), HeLa (31 MOI), HeLaS3 (42 MOI), C33A (21 MOI), and HT3 (62 MOI). In particular, complete inhibition of cell growth was observed at 125 MOI in both CaSki and SiHa cells. However, the complete inhibition was detected at 62.5 MOI in HeLa and HeLaS3. In contrast, at these MOI, no suppression of cell growth was observed when cells were infected with recombinant adenovirus expressing beta-gal as a negative control. The levels of p53 protein were notably expressed in CaSki and HeLa more than in SiHa and HeLaS3 on days 2 and 4. However, the p53 was only detected in HeLaS3 on day 6. In contrast, p53 expression was continually maintained in C33A and HT3 during the same periods. After transfection AdCMVp53 into CaSki- and SiHa-xenografted nude mice, the size of tumor was remarkably decreased in SiHa cells as compared to AdCMVLacZ transfection. CONCLUSION: The adenovirus-mediated p53 gene transfection was done effectively in vitro and in vivo. Also, the antitumor effects were accomplished via differential role of p53-specific apoptotic cell death, which is dependent upon the cervical cancer cell line.

Activity of green tea polyphenol epigallocatechin-3-gallate against ovarian carcinoma cell lines.

PURPOSE: A constituent of green tea, (-)-epigallocatechin-3-gallate (EGCG), is known to possess anti-cancer properties. In this study, the time-course of the anticancer effects of EGCG on human ovarian cancer cells were investigated to provide insights into the molecular-level understanding of the growth suppression mechanism involved in EGCG-mediated apoptosis and cell cycle arrest. MATERIALS AND METHODS: Three human ovarian cancer cell lines (p53 negative, SKOV-3 cells; mutant type p53, OVCAR-3 cells; and wild type p53, PA-1 cells) were used. The effect of EGCG treatment was studied via a cell count assay, cell cycle analysis, FACS, Western blot and macroarray assay. RESULTS: EGCG exerts a significant role in suppressing ovarian cancer cell growth, showed dose dependent growth inhibitory effects in each cell line and induced apoptosis and cell cycle arrest. The cell cycle was arrested at the G1 phase by EGCG in SKOV-3 and OVCAR-3 cells. In contrast, the cell cycle was arrested in the G1/S phase in PA-1 cells. EGCG differentially regulated the expression of genes and proteins (Bax, p21, Retinoblastoma, cyclin D1, CDK4 and Bcl-X(L)) more than 2 fold, showing a possible gene regulatory role for EGCG. The continual expression in p21WAF1 suggests that EGCG acts in the same way with p53 proteins to facilitate apoptosis after EGCG treatment. Bax, PCNA and Bcl-X are also important in EGCG-mediated apoptosis. In contrast, CDK4 and Rb are not important in ovarian cancer cell growth inhibition. CONCLUSION: EGCG can inhibit ovarian cancer cell growth through the induction of apoptosis and cell cycle arrest, as well as in the regulation of cell cycle related proteins. Therefore, EGCG-mediated apoptosis could be applied to an advanced strategy in the development of a potential drug against ovarian cancer.

Photodynamic effects of Radachlorin on cervical cancer cells.

PURPOSE: Photodynamic therapy (PDT) is a novel treatment modality, which produces local tissue necrosis with laser light following the prior administration of a photosensitizing agent. Radachlorin has recently been shown to be a promising PDT sensitizer. In order to elucidate the antitumor effects of PDT using Radachlorin on cervical cancer, growth inhibition studies on a HPV-associated tumor cell line, TC-1 cells in vitro and animals with an established TC-1 tumor in vivo were determined. MATERIALS AND METHODS: TC-1 tumor cells were exposed to various concentrations of Radachlorin and PDT, with irradiation of 12.5 or 25 J/cm(2) at an irradiance of 20 mW/cm(2) using a Won-PDT D662 laser at 662 nm in vitro. C57BL/6 mice with TC-1 tumor were injected with Radachlorin via different routes and treated with PDT in vivo. A growth suppression study was then used to evaluate the effects at various time points after PDT. RESULTS: The results showed that irradiation of TC-1 tumor cells in the presence of Radachlorin induced significant cell growth inhibition. Animals with established TC-1 tumors exhibited significantly smaller tumor sizes over time when treated with Radachlorin and irradiation. CONCLUSION: PDT after the application of Radachlorin appears to be effective against TC-1 tumors both in vitro and in vivo.