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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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Rb pathway alteration and E2F-1 expression in epithelial ovarian cancer.

Sung Hee KIM ; Soo Hyeon MOON ; Su Il SHIN ; Dong Soo SUH ; Man Soo YOON ; Kyung Un CHOI

Korean Journal of Gynecologic Oncology.2007;18(4):299-307.

OBJECTIVE: To evaluate the clinicopathological implications of Rb pathway alteration and E2F-1 expression in Epithelial ovarian cancer using immunohistochemical staining. METHODS: Tissue samples (n=72) were collected after staging operation between 1998 and 2004. RESULTS: In 72 cases, the overall expression of pRb, and E2F-1 were 59.7% (43/72), and 58.3% (42/72), respectively. pRb expression was inversely correlated with stage, histologic grade and mitotic index. E2F-1 expression was correlated with advanced stages, high grade, mitotic index, Ki-67 labeling index (LI). CONCLUSION: We suggest that Rb pathway alteration and E2F-1 expression could play roles as a new prognostic factors in Epithelial ovarian cancer.
Mitotic Index ; Ovarian Neoplasms*

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Development of a therapeutic method in the HPV-related cervical lesion using pH/temperature sensitive polymer spray formulation.

Chan Joo KIM ; Byeong Moon JEONG ; Tae Woo KIM ; Tae Heung KANG ; Kyung Hee NOH ; Myoung Ok KIM ; Zae Young RYOO ; Hy Sook KIM ; Jong Sup PARK

Korean Journal of Gynecologic Oncology.2007;18(4):289-298.

OBJECTIVE: The causal link between oncogenic HPV(Human Papilloma Viruses) and the development of CIN (rvical intraepithelial neoplasia) and cervical cancer are now well established. Several medical therapeutic candidates aimd at the treatment of precancerous lesions and invasive carcinoma of the cervix. The objective of this study was to develop the pH-sensitive chitosan/alginate gels (pH=3.8-4.5) and temperature sensitive multiblock copolymers of PEG/PLA (poly (L-lactic acid)/polyethylene glycol) gels (temperature=37 degrees C) for controlled delivery of the paclitaxel (PTX). We had also evaluated whether PTX entrapped in chitosan/alginate gels or multiblock copolymers of PEG/PLA 1 could inhibit tumor growth in vivo. METHODS: PTX entrapped as microsphere in Chitosan/Alginate Microspheres were obtained using a spray-drying method. PTX-entrapped PEG/PLA gels were prepared by the solvent displacement method. We had prepared the multiblock copolymers of PEG/PLA which has the sol-gel-sol transition temperature at body temperature. The in-vivo efficacy of PTX in chitosan microphere or PTX in PEG/PLA mutiblock copolymer micelle were conducted in HeLa-tumor bearing Balb/c Nu/Nu athymic mice at an equivalent paclitaxel dose of 10 mg/kg with 48 hr interval. The inhibition of tumor growth was evaluated after 8 days of treatment. RESULTS: On 8 days after the transcutaneous treatment of PTX-containing chitosan microphere or PTX in PEG/PLA mutiblock copolymer micelle. significant inhibition in tumor growth was observed in balb/c nu/nu nude mouse carrying xenograft tumors (HeLa cells; HPV-18 positive state). Among these formulations, PTX in PEG/PLA mutiblock copolymer have shown improved therapeutic efficacy as compared to PTX-ivgroup. CONCLUSION: PTX-containing chitosan microphere or PTX in PEG/PLA mutiblock copolymer nanoparticles are a unique pH-sensitive and temperature sensitive drug delivery system. These formulations elicits enhanced efficacy as an effective and minimally invasive treatment in mice bearing human cervical cancer (HeLa Cells) xenograft.
Animals ; Body Temperature ; Cervix Uteri ; Chitosan ; Drug Delivery Systems ; Female ; Gels ; Heterografts ; Human papillomavirus 18 ; Humans ; Mice ; Mice, Nude ; Microspheres ; Nanoparticles ; Paclitaxel ; Papilloma ; Polymers* ; Transition Temperature ; Uterine Cervical Neoplasms

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Expression of c-Met in ovarian epithelial tumor.

Bo Seop KIM ; Il Soo PARK ; Yoon Soon LEE ; Tae Bon KOO ; Tae In PARK

Korean Journal of Gynecologic Oncology.2007;18(4):284-288.

OBJECTIVE: This study was performed to evaluate the expression of c-Met in epithelial ovarian carcinoma. METHODS: Paraffin-embedded tissues from 50 epithelial ovarian adenocarcinomas were stained immunohistochemically for c-Met expression. The expression of c-Met was correlated with clinicopathologic parameters including, histologic type, tumor size, and tumor stage. RESULTS: c-Met expression was found in 29 cases (58%) among 50 ovarian cancers. In clinicopathologic study, c-Met expression of epithelial ovarian carcinomas did not show the correlation with clinicopathologic parameters such as histologic type, tumor size and stage. CONCLUSION: c-Met expression might be a potential prognostic marker for patients with advanced stage epithelial ovarian cancers. However, larger population-based studies should be performed to determine the prognostic potential of c-Met expression in advanced ovarian carcinoma.
Adenocarcinoma ; Humans ; Ovarian Neoplasms ; Prognosis

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Recommendation guideline of Korean Society of Gynecologic Oncology and Colposcopy for quadrivalent human papillomavirus vaccine.

Byoung Gie KIM ; Nak Woo LEE ; Seung Cheol KIM ; Young Tae KIM ; Yong Man KIM ; Chan Joo KIM ; Sang Yoon PARK ; Yong Sang SONG ; Jae Kwan LEE ; Won Chul LEE ; Nam Hoon CHO ; Chi Hum CHO ; Soo Young HUR ; Jong Sup PARK ; Kyu Wan LEE

Korean Journal of Gynecologic Oncology.2007;18(4):259-283.

Genital HPV infection is the most common sexually transmitted infection, but the majority of infections are self-limited. However, persistent infection with high-risk types can cause cervical cancer in women, which is the most common female genital cancer in Korea. In addition, HPV infection is the cause of genital warts and is associated with other anogenital cancers. The HPV vaccine is composed of the HPV L1 protein, the major capsid protein of HPV. Expression of the L1 protein in yeast using recombinant DNA technology produces noninfectious virus-like particles (VLP) that resemble HPV virions. The quadrivalent HPV vaccine is a mixture of four HPV type-specific VLPs prepared from the L1 proteins of HPV 6, 11, 16, and 18 combined with an aluminum adjuvant. Clinical trials indicate that the vaccine has high efficacy in preventing persistent HPV infection, cervical cancer precursor lesions, vaginal and vulvar cancer precursor lesions, and genital warts caused by HPV types 6, 11, 16, or 18 among females who have not already been infected with the respective HPV type. The recommended age for primary vaccination of Korean females is 15-17 years, considering sexual debut and duration of protection of the vaccine. Vaccine can be administered as young as age 9 years. Catch-up vaccination is recommended for females aged 18-26 years who have not been previously vaccinated. Vaccination is not a substitute for routine cervical cancer screening, and vaccinated females should have cervical cancer screening as recommended.
Aluminum ; Capsid Proteins ; Colposcopy* ; Condylomata Acuminata ; DNA, Recombinant ; Female ; Human papillomavirus 6 ; Humans* ; Korea ; Mass Screening ; Uterine Cervical Neoplasms ; Vaccination ; Virion ; Vulvar Neoplasms ; Yeasts

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Malignant lymphoma of the uterine cervix treated by neoadjuvant chemotherapy.

Soon Ho HWANG ; Bo Yeon KIM ; Jin Hee PARK ; Kyung Eun LEE ; Min A LEE ; Ki Hwan LEE ; Heung Tae NOH ; Sung Kyong SON

Korean Journal of Gynecologic Oncology.2007;18(2):160-164.

Non-Hodgkin's lymphoma presented as a malignancy of the uterine cervix is exceedingly rare disease and accounts for approximately only 0.12-0.6% of extranodal lymphomas. There is no consensus on the management and prognosis of the disease because of its extreme rarity. Previously, treatment of this disease has been radiation therapy, surgery or chemotherapy either alone or in combination. We present the case of a 45-year-old woman diagnosed with diffuse, large B-cell non-Hodgkin's lymphoma of the uterine cervix. We administered neoadjuvant chemotherapy according to CHOP protocol (cyclophosphamide, adriamycin, vincristine, and prednisone) followed by hysterectomy and bilateral salpingo-oophorectomy. The patient is alive 20 months after the initial diagnosis. We report the case with a brief review of literature.
B-Lymphocytes ; Cervix Uteri* ; Consensus ; Diagnosis ; Doxorubicin ; Drug Therapy* ; Female ; Humans ; Hysterectomy ; Lymphoma* ; Lymphoma, Non-Hodgkin ; Middle Aged ; Prognosis ; Rare Diseases ; Vincristine

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A case of recurrent aggressive angiomyxoma of the vulva in the adolescence.

Joo Yuen RYU ; Mi Sun PARK ; Chang Jae LEE ; Kyung Rak SON

Korean Journal of Gynecologic Oncology.2007;18(2):155-159.

Aggressive angiomyxoma is a rare, locally infiltrative soft tissue tumor that usually arises in the vulvoperitoneal region of young female. Frequent relapses are common. Clinicians should consider the diagnosis of aggressive angiomyxoma when a patient presents with an atypical vulvoperineal mass, because an incorrect diagnosis may lead to repeated surgical procedures. Treatment is wide surgical excision. Medical management with a GnRH agonist and radiation therapy with total dose of 60 Gy may be helpful adjuvant treatment in recurrent aggressive angiomyxoma. We experienced a case of recurrent aggressive angiomyxoma and report it with a brief review of literatures.
Adolescent* ; Diagnosis ; Female ; Gonadotropin-Releasing Hormone ; Humans ; Myxoma* ; Recurrence ; Vulva*

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