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Induction of apoptosis by the kinase inhibitor flavopiridol in human ovarian cancer cell lines.

Korean Journal of Gynecologic Oncology.2008;19(1):26-39. doi:10.3802/kjgo.2008.19.1.26

OBJECTIVE: Flavopiridol that inhibits cyclin-dependent kinase, can cause cell cycle arrest, induce apoptosis in human tumor cell lines. In the present study, we investigated apoptotic effects of flavopiridol and the underlying molecular mechanisms in human ovarian cancer cell lines. METHODS: We used TOV-21G and TOV-112D cell lines. The cell viability was tested by MTT assay and apoptosis was assessed by TUNEL assay and annexin-V binding. Western blot was used to examine apoptosis related protein levels. MAP kinase activity was analyzed by non-radioactive MAP kinase assay kit. RESULTS: Treatment of TOV-21G and TOV-112D cells with flavopiridol (50 nM to 1000 nM) led to a dose- and time-dependent inhibition of cell growth and survival. Dose-related induction of apoptosis was also observed in these cell lines. Flavopiridol (500 nM) induced striking decreases in the levels of the antiapoptic proteins Mcl-1, Bcl-X(L), and XIAP in both cell lines. In contrast, expression of Bax, Bcl-2, and AIF was not significantly influenced by flavopiridol. Although flavopiridol resulted in accumulation of p53 in both cells, flavopiridol mediated apoptosis was p53 independent because it occurred to the same degree in TOV-112D cells in which p53 was inactivated by mutation. Flavopiridol treatment resulted in enhanced cleavage of pro-caspase 9 and activation of caspase 3. Apoptosis was associated with suppression of ERK activity. CONCLUSION: Although the precise mechanisms of flavopiridol mediated cytotoxicity have not been fully defined, these data suggest that flavopiridol has activity against ovarian cancers in vitro and is worthy of continued clinical development in the treatment of ovarian cancer.
Apoptosis ; Blotting, Western ; Caspase 3 ; Cell Cycle Checkpoints ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Flavonoids ; Humans ; In Situ Nick-End Labeling ; Ovarian Neoplasms ; Phosphotransferases ; Piperidines ; Proteins ; Strikes, Employee

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Analysis of expression of survivin, caspase 3, and p53 protein in cervical neoplasia comparing with Ki-67 index.

Ji Young CHA ; Tai Il CHO ; Tae Yang PARK ; Jae Sung SO ; Se Kyoung CHOI ; Eon Sub PARK

Korean Journal of Gynecologic Oncology.2008;19(1):17-25. doi:10.3802/kjgo.2008.19.1.17

OBJECTIVE: The aim of this study was to determine the role of survivin, caspase 3, p53 and Ki-67 expression in the carcinogenesis of cervical carcinoma and aggressiveness of cervical intraepithelial neoplasia (CIN). METHODS: The pathology specimens of 94 patients with a diagnosis of Low grade CIN (31 cases), High grade CINL (32 cases) and squamous cell carcinoma (31 cases) were evaluated immunohistochemically for the expression of survivin, caspase 3, p53 and Ki-67 in paraffin sections. RESULTS: Survivin, p53 and Ki-67 expressions were progressively increased in accordance with the increasing degree of malignancy, but caspase 3 immunoreactivity was higher in high grade CIN than in low grade CIN and invasive cervical cancers. There was no significant difference between Ki-67 index and survivin, caspase 3 and p53 expression with the increasing degree of malignancy. The Ki-67 index was closely related to p53 overexpression in invasive cervical carcinoma group. CONCLUSION: A sequential increase of survivin, p53, and Ki-67 was observed in paralleling the progression of grade of CIN and cervical cancer. In addition, caspase 3 expression increased proportionally to the low-grade CIN to high grade CIN.
Carcinoma, Squamous Cell ; Caspase 3 ; Cervical Intraepithelial Neoplasia ; Humans ; Paraffin ; Uterine Cervical Neoplasms

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Expression of MTA1 and nm23-H1 protein in ovarian carcinomas in relation to lymph node metastasis.

Seo Yun TONG ; Yun Young KIM ; Kyung Do KI ; Jong Min LEE ; Yong Gu PARK ; Seon Kyung LEE

Korean Journal of Gynecologic Oncology.2008;19(1):9-16. doi:10.3802/kjgo.2008.19.1.9

OBJECTIVE: Cancer metastasis is a complex process involving a sequential series of multi-step genetic events, which produces an imbalance between stimulatory and inhibitory genes for metastasis. Presently, we examined the expression of metastatic tumor antigen 1 (MTA1) and nonmetastatic protein 23 homologue H1 (nm23-H1) proteins in metastasized epithelial ovarian cancer cells. METHODS: Fifty-one primary epithelial ovarian tumors and corresponding lymph nodes (LNs) were examined immunohistochemically for expression of MTA1 and nm23-H1. Expression of these proteins was statistically evaluated. RESULTS: The frequency of MTA1 expression was 30.3% (10/33) in stage III/IV LNs but was absent (0/18) in stage I/II LNs (p=0.01). MTA1 expression was observed in 50% (6/12) of metastasizing LNs but in only 10.3% (4/39) of non-metastasizing LNs (p=0.01). In contrast with MTA1, nm23-H1 expression was evident in 16 of 18 (88.9%) stage I/II ovarian cancer tissue samples but only in 20 of 33 (60.6%) stage III/IV tissues (p=0.05), and nm23-H1 production was also observed in 75.6% (34/45) of ovarian cancer tissue with residual tumors under 2 cm in diameter, but in 2/6 (33.3%) of cancer tissue with residual tumors exceeding 2 cm in diameter (p=0.03). CONCLUSION: The degree of expression and imbalance of MTA1 and nm23H1 are correlated with ovarian cancer LN metastasis.
Lymph Nodes ; Lymphatic Metastasis ; Neoplasm Metastasis ; Neoplasm, Residual ; Neoplasms, Glandular and Epithelial ; Ovarian Neoplasms ; Proteins

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Major clinical research advances in gynecologic cancer 2007.

Kidong KIM ; Jae Weon KIM ; Soon Beom KANG

Korean Journal of Gynecologic Oncology.2008;19(1):1-8. doi:10.3802/kjgo.2008.19.1.1

Major clinical research advances in gynecologic cancer in 2007 are as follows. Human papillomavirus (HPV) vaccines were shown to be effective in preventing cervical intraepithelial neoplasia (CIN). In treating cervical cancer, the intensity-modulated radiotherapy (IMRT) was suggested to be less toxic than the conventional radiotherapy was. Minimally invasive surgery, especially robot surgery is expected to be more popular in future. Adjuvant radiotherapy did not increase the survival rate in early endometrial cancer. Adjuvant chemoradiation was demonstrated to be superior to adjuvant radiation in the treatment of early endometrial cancer. Hormone therapy in endometrial cancer was effective but has high recurrence rate. Pelvic/abdominal pain, increased abdominal size/bloating, difficulty eating/feeling full, urinary frequency/urgency could be the symptoms of ovarian cancer. Serial CA-125 measurement or combining ultrasonography and CA-125 could be effective screening strategies of ovarian cancer. Molecules interfering vascular-endothelial growth factor (VEGF) were shown to be effective in the treatment of ovarian cancer.
Cervical Intraepithelial Neoplasia ; Endometrial Neoplasms ; Female ; Gynecology ; Humans ; Mass Screening ; Ovarian Neoplasms ; Radiotherapy, Adjuvant ; Radiotherapy, Intensity-Modulated ; Recurrence ; Survival Rate ; Urogenital Neoplasms ; Uterine Cervical Neoplasms ; Vaccines

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A case of retroperitoneal huge smooth muscle tumor misleading to ovarian cancer.

Young Eun JEON ; Su Ran CHOI ; Seung Woo LEE ; Jung Un CHOI ; Jeong Bae KANG ; Pong Rheem JANG ; Young Han PARK ; Sung Joo KIM ; Chae Chun RHIM ; Soo Kee MIN

Korean Journal of Gynecologic Oncology.2005;16(2):177-181.

Smooth muscle tumors are very common tumors in the uterus and related adjacent structures but occur rarely in the retroperitoneum. Traditionally, most retroperitoneal smooth muscle tumor are believed to be malignant. But well-differentiated smooth muscle tumors with lack of atypia, necrosis, and significant mitotic activity appear to have a benign behaviors. Laparotomy revealed a huge solid tumor in the retroperitoneal space, about 50 cm in diameter, and histologically diagnosed as a smooth muscle tumor of uncertain malignant potential (STUMP). We report a case of primary retroperitoneal smooth muscle tumor with a brief review of literatures.
Laparotomy ; Muscle, Smooth* ; Necrosis ; Ovarian Neoplasms* ; Retroperitoneal Space ; Smooth Muscle Tumor* ; Uterus

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A clinical study on gestational trophoblastic disease.

Jong Hyun KIM ; Kwan Sik KIM ; Yoon Jeong YANG ; Cheol Min TAE ; Seok Keun YOON ; Yoon Soo HUR ; Jeong Heon LEE ; Sung Nam CHO ; Byung Chan OH ; Jong Duk KIM

Korean Journal of Gynecologic Oncology.2005;16(2):169-176.

OBJECTIVE: To evaluate the clinical characteristics and the outcome of the management for gestational trophoblastic disease (GTD) patients diagnosed at our hospital and to report the current situation of GTD in Korea. METHODS: Between January, 1991, and December, 2000, One hundred and eleven women were diagnosed as GTD and managed in our hospital. Patients were classified according to clinical diagnosis and their medical records were investigated. RESULTS: Cases of benign, malignant nonmetastatic, malignant metastatic low risk and malignant metastatic high risk GTDs were 62, 36, 2 and 11 respectively. The mean age (year), gravidity and parity (number) of GTD patients were 33.3+/-9.9 (range: 19-54), 3.2+/-3.0 (range: 0-16) and 1.7+/-1.8 (range: 0-7) overall. About 75% of GTD patients were women in their 20s and 30s, and 85% occurred in patients with parity of 3 or less. The most common prior gestational event was abortion (37.1%) for molar pregnancy and molar pregnancy (61.2%) for persistent gestational trophoblastic tumor (PGTT). The progression rate of molar pregnancies to PGTT was 38.0%. MTX (16.3%) was mainly used as a single agent, and EMACO (28.6%) or MAC (22.4%) were primarily used for multidrug chemotherapy for the treatment of PGTT. In the treatment of PGTT, overall remission rate was 95.9% (n=47/49). CONCLUSION: The trends for GTD in Korea revealed significant changes, not only a decrease in the incidence of GTD, but also an improvement in the outcome of the management. There is a necessity of further community-based surveys for GTD.
Diagnosis ; Drug Therapy ; Female ; Gestational Trophoblastic Disease* ; Gravidity ; Humans ; Hydatidiform Mole ; Incidence ; Korea ; Medical Records ; Parity ; Pregnancy ; Trophoblastic Neoplasms

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The efficacy of paclitaxel based combination chemotherapy in recurrent endometrial cancer.

Eun Sun CHOI ; Min Hyung JUNG ; Gin Young MA ; Soo Jung LEE ; Dae Yeon KIM ; Jong Hyeok KIM ; Yong Man KIM ; Young Tak KIM ; Joo Hyun NAM ; Jung Eun MOK

Korean Journal of Gynecologic Oncology.2005;16(2):163-168.

OBJECTIVE: This study was performed to evaluate the efficacy of paclitaxel based combination chemotherapy by response rate and survival time in the treatment of recurrent endometrial cancer. METHODS: From May 1995 to February 2004, 27 out of 301 cases of endometrial cancer treated at the Asan Medical Center in Seoul were recurrent. We identified 11 patients treated with paclitaxel based combination chemotherapy and 7 patents treated with other combination chemotherapy, and then retrospectively estimated the survival times from the chemotherapy after recurrence to the death or last visit. RESULTS: The non-paclitaxel based combination chemotherapy group showed partial response in 1 case (14.3%) and disease progression in 4 (57.1%). In contrast, the paclitaxel group showed 7 cases (63.6%) of partial response. The median survival time for total study patients was 18.0 months, 22.0 months for paclitaxel group and 15.0 months for the non-paclitaxel group, the difference being statistically significant (p=0.047). Side effect of chemotherapy such as leukopenia, neutropenia and thrombocytopenia showed no difference between the two groups. CONCLUSION: Paclitaxel-based combination chemotherapy may be the first-line chemotherapeutic agent in recurrent endometrial cancer patients if it's more effective than other combination chemotherapy in prolonging survival times.
Chungcheongnam-do ; Disease Progression ; Drug Therapy ; Drug Therapy, Combination* ; Endometrial Neoplasms* ; Female ; Humans ; Leukopenia ; Neutropenia ; Paclitaxel* ; Recurrence ; Retrospective Studies ; Seoul ; Thrombocytopenia

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Analysis of prognostic factor and survival in patients with epithelial ovarian cancer treated with combination chemotherapy.

Il Jung CHOI ; Bong Gyu KWAK ; Myoung Seok HAN ; Moon Seok CHA ; Hyun Ho KIM ; Goo Hwa JE

Korean Journal of Gynecologic Oncology.2005;16(2):154-162.

OBJECTIVE: The purpose of this retrospective study is to identify and to discuss the clinical relevance of prognostic factors and survival rate in patients with epithelial ovarian cancer treated with combination chemotherapy. METHODS: A total of 98 histologically verified patients with epithelial ovarian cancer who were treated at Dong-A Medical Center between 1997 and 2002 were used for analysis. The 30 patients having borderline tumor were excluded. Kaplan-Meier survival curves were computed and tested statistically by the log rank test. A multivariable Cox proportional hazard model was applied to access the prognostic significance of the different covariates. RESULTS: The median age of the patients with epithelial ovarian cancer was 46.6 years and FIGO stage distribution was 38.2% for stage I, 5.9% for stage II, 44.1% for stage III, 11.8% for stage IV. The histopathologic type distribution were serous type (45.6%), mucinous type (36.8%), endometriod type (8.8%), clear cell type (7.4%), mixed type (1.4%). Residual tumor volume size of less than 1 cm or 1 cm was identified in 50 patients (73.5%) and more than 1 cm in 18 patients (26.5%) after primary cytoreductive surgery. The overall 5-year survival rate was 55.7%. According to univariate analysis, FIGO stage (p<0.0001), residual volume (p<0.0001), ascitic fluid volume (p=0.0001), menopause (p=0.0021), CA125 (p=0.0058), tumor size (p=0.0099), age (p=0.0113) were significant prognostic factors affecting survival. However, multivariate analysis in this study demonstrated that FIGO stage (p=0.011), residual tumor volume (p=0.026), ascitic fluid volume (p=0.031) were found to be the most significant independent prognostic factors. CONCLUSION: In this retrospective study, the overall 5-year survival rate of patients with epithelial ovarian cancer treated with combination chemotherapy was 55.7% and 5-year survival rate of stage I/II was 95.8%, stage III 28.4%, stage IV 0%. The overall survival of stage I/II were 90 months, stage III 39 months, stage IV 17 months. In multiple analysis, FIGO stage, residual volume, ascitic fluid volume were identified as three most significant independent prognostic factors.
Ascitic Fluid ; Drug Therapy, Combination* ; Female ; Humans ; Kaplan-Meier Estimate ; Menopause ; Mucins ; Multivariate Analysis ; Neoplasm, Residual ; Ovarian Neoplasms* ; Proportional Hazards Models ; Residual Volume ; Retrospective Studies ; Survival Rate

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L-myc single nucleotide polymorphism and epithelial ovarian cancer: susceptibility and prognosis in Korean women.

Woong JU ; Jae Weon KIM ; Noh Hyun PARK ; Yong Sang SONG ; Seung Cheol KIM ; Soon Beom KANG ; Hyo Pyo LEE

Korean Journal of Gynecologic Oncology.2005;16(2):148-153.

OBJECTIVE: The aim of this investigation was to analyze the association between a single nucleotide polymorphism (SNP) in L-myc gene (T3109G) and ovarian cancer risk or prognosis in Korean women. METHODS: The blood samples of 98 ovarian cancer patients and 332 non-cancer control subjects who managed at Seoul National University Hospital from 1999 to 2002 were collected. Polymorphism in L-myc (T3109G) was determined using TaqMan method. Allele frequency and genotype distribution in the ovarian cancer group were compared with those of the control group to determine whether this polymorphism elevates the susceptibility of Korean women to ovarian cancer. The relationship between this SNP and cancer invasiveness or prognosis were also evaluated by collating clinicopathologic data of those in the cancer group, such as surgical stage, stromal invasion, histologic type, and survival. RESULTS: In the ovarian cancer group, the allele frequency of G was 51.0%, in the control group 48.5%, showing no significant difference (p=0.569). Similarly the genotypes with TG or GG showed no increased risk for ovarian cancer susceptibility compared with TT genotype. A subgroup analysis of the clinicopathologic parameters in cancer group also showed no significant difference suggesting the lack of an association between SNP of the L-myc and ovarian cancer invasiveness and survival. CONCLUSION: This study shows that Korean women with specific polymorphism in L-myc are neither more susceptible to develop ovarian cancer nor more vulnerable for cancer progression.
Female ; Gene Frequency ; Genes, myc ; Genotype ; Humans ; Ovarian Neoplasms* ; Polymorphism, Single Nucleotide* ; Prognosis* ; Seoul

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Overexpression of p16(INK4A) as a biomarker for ASCUS in ThinPrep(TM) smear.

So Jin YEO ; Kei Hyun NAM ; Ill Koo SHIM ; Tae Hee KIM ; Kwon Hae LEE ; Hyeong Mun KIM ; Hee Jung CHO ; Kye Won KWON

Korean Journal of Gynecologic Oncology.2005;16(2):141-147.

OBJECTIVE: The overexpression of p16(INK4A) is induced by human papillomavirus (HPV) and associated with the carcinogenesis of cervical epithelia. So, immunostaining of p16(INK4A) may be useful biomarker in detecting CIN of cervix uteri in abnormal cervical lesions. The potential of p16(INK4A) as a biomarker for Atypical squamous cells of undetermined significance (ASCUS) examined in liquid-based specimens. METHODS: We collected samples 30 cases of ASCUS in Thinprep(TM) smears between March 2003 and August 2003. 23 control Thinprep(TM) cases were included; 10 negative for intraepithelial lesions, 13 cervical squamous intraepithelial lesions. p16(INK4A) immunochemial staining was performed on 53samples. At the same time, we tested another cervical swabs of patients by the Hybrid Capture II(TM) test. The cut off value was scored positive if it contained above 5 abnormal cells with nuclear and cytoplasmic immunostaining. RESULTS: The results of p16(INK4A) immunochemial staining comparing with one of HC II(TM) showed negative results with low kappa coefficient of 0.034. The sensitivity of p16(INK4A) immunochemial staining were 30.8% and the specificity were 82.4% respectively (p<0.01). p16(INK4A) is a useful marker for the detection of the cervical intraepithelial neoplasia but is not ASCUS. CONCLUSION: Immunostaining of p16(INK4A) is not useful triage test in detecting abnormal lesion of ASCUS in liquid-based specimens.
Carcinogenesis ; Cervical Intraepithelial Neoplasia ; Cervix Uteri ; Cyclin-Dependent Kinase Inhibitor p16* ; Cytoplasm ; Female ; Humans ; Sensitivity and Specificity ; Triage

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