Cancer Research and Treatment

The Efficacy and Safety of Docetaxel in Patients with Anthracychne pretreated Metastatic Breast Cancer: A Multicenter Phase II Study: Joong Bae Ahn, Kwang Yong Shim, Joon Oh Park, Hei Chul Jung, Nae Choon Yoo, Hyun Cheol Chung, Joo Hang Kim, Jin Hyuk Choi, Hyun Soo Kim, Hugh Chul Kim, Woo Kun Kim, Jae Kyung Roh; J Korean Cancer Assoc. 2000;32(2):235-243.

Abstract PDF: PURPOSE
Tbis phase II study was performed to evaluate the efficacy and safety of docetaxel in patients with anthracycline-pretreated metastatic breast cancer (MBC).
MATERIALS AND METHODS
From September 1996 to January 1998, 27 patients with metastatic breast cancer from 31 to 63 years of age with a performance status of 0 to 2 were registered in the phase II trial. All patients had metastatic breast cancer which had progressed or relapsed 2 during or after treatment with an anthracycline-based regimen. Docetaxel 75 mg/m2 was ad- ministered over 1 hour every 21 days until disease progression was documented or until toxic effects precluded further therapy. All patients received dexamethasone orally at the dose of 16 mg on days -1, 0, 1 of each cycle.
RESULTS
Objective responses were seen in 9 of 25 assessable patients (two complete and seven partial responses), with an overall objective response rale of 36%. The median duration of response was 36 weeks (range 19.0~40.5). The median time to progression and survival duration were 17.5 and 69 weeks, respectively, for assessable patients. One hundred fifty cycles (median, five) of docetaxel were administered. Among 27 patients assessable for toxicity, the following side effects were reported: nadir neutropenia grade 3 (4 patients) and grade 4 (22 patients); grade 2 stomatitis (6 patients); grade 2 alopecia (5 patients); grade 2 to 3 neurosensory toxicity (4 patients); no hypersensitivity reaction; mild fluid retention (4 patients).
CONCLUSION
Docetaxel is an active agent in patients with antracycline-pretreated metastatic breast cancer. Docetaxel was associated with severe but reversible neutropenia. Dexamethasone prevented hypersensitivity reactions and appeared to ameliorate fluid retention.

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Combination Chemotherapy of Vinorelbine and Epirubicin ( VE ) in Patients with Advanced Breast Cancer: S M Bang, H S Hong, K H Cha, T H Lee, J A Lee, Y S Park, E K Cho, D B Shin, J H Lee; J Korean Cancer Assoc. 2000;32(2):244-252.

Abstract PDF: PURPOSE
This study was performed to evaluate the efficacy and toxicity of vinorelbine in combination with epirubicin as a first-line chemotherapy in patients with advanced breast cancer as well as a second-line chemotherapy in refractory patients after failing to first-line chemotherapy.
MATERIALS AND METHODS
Between March 1997 and July 1999, thirty-seven patients were enrolled. Vinorelbine 25 mg/m2 intravenously (IV) on days 1 and 8, and epirubicin 50 mg/m2 IV on day 1 were given every 3 weeks. Among the evaluable 34 patients, 25 patients received VE chemotherapy as a ""first-line chemotherapy"". 4 patients had initially systemic metastasis, 2 patients relapsed after operation and 19 patients relapsed after adjuvant chemotherapy. Nine patients had progressive diseases after one or more palliative regimens. Among the 9 patients, 1 patient showed the progression during the adjuvant chemotherapy. The median age of the patients was 49 years (range; 31~64), and 68% of patients were premenopausal. Dominant sites of metastasis were viscera in 82% and non-viscera (soft tissue, lymph nodes and bone) in 18%.
RESULTS
Overall response rates (RR) were 64% in first-line group. There was no responder in second-line group. Six patients without any prior chemotherapy obtained 2 CR and 3 PR (RR; 83%), while pre-treated 28 patients showed 1 CR and 10 PR (RR; 39%). Among the second-line group, 6 patients had been exposed to anthracycline. Median number of chemotherapy cycle was 3.5 (2~7). Total 135 cycles of therapy were evaluable for toxicity. The most common dose-limiting toxicity was myelosuppression, mainly leukopenia in 58 cycles (43%). Grade 3 or 4 leukopenia were observed in 10 cycles (7%), of which 3 cycles were associated with infection requiring hospitalization. Anemia were observed in 42 cycles (31%), mostly grade 1 or 2 (28%). The most common non-hematologic toxicity was alopecia (91%) followed by phlebitis (41%). There was no therapy-related mortality.
CONCLUSION
Vinorelbine and epirubicin combination showed significant activity as a first-line regimen in advanced breast cancer. The combinaton showed no activity in patients pretreated with other palliative regimen.

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A Study for Correlation between Bone Marrow Micrometastases and Tumoric Angiogenesis in Breast Cancer: N S Choi, Y J Jaegal, J H Youn, C S Park; J Korean Cancer Assoc. 2000;32(2):253-260.

Abstract PDF: PURPOSE
Since some reports that tumoric angiogenesis in breast cancer is significantly correlated with the presence of local or distant metastases, many clinicians determined the tumoric angiogenesis just as one of the prognostic factors. However, a consistent role of tumoric angiogenesis in metastatic progression was not completely resolved yet. We tried to evaluate the direct relationship between tumoric angiogenesis and bone marrow micrometastases to reveal the actual contribution of tumoric angigenesis to systemic spread of cancer cells in breast cancer patients.
MATERIALS AND METHODS
Seventy patients with breast cancer who underwent curative surgical resection were included in this study. We observed the micrometastases in bone marrow with RT-PCR method targeting to mRNA for cytokeratin and tumoric angiogenesis with image analyzer technique followed by immunohistochemical staining to CD 34 from formalin-fixed, paraffin-embedded specimens.
RESULTS
Incidence of bone marrow micrometastases was 17.1% (12/70) in surgically curable breast cancer patients. Possibility of bone marrow micrometastases tend to be increasing with an association of the presence of axillary lymph node invasion (P=0.03). High tumoric angiogenesis is associated with a high risk of bone marrow micrometastases (P=0.039).
CONCLUSION
High tumoric angiogenesis is necessary for bone marrow micrometastases but, not sufficient by itself. A further study may need to reveal other factors contributing the bone marrow spread of cancer cells, assoiciated with angiogenesis.

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Skin - sparing Mastectomy with Circumareolar Incision and Immediate TRAM & One - stage Star Flap Nipple - areolar Complex Reconstruction: S H Ahn, P C Lee, B H Son, S H Han; J Korean Cancer Assoc. 2000;32(2):261-269.

Abstract PDF: PURPOSE
Breast reconstruction after a mastectomy is being performed using a tissue expander or a TRAM flap. However, a conventional mastectomy leaves a long linear scar after reconstruction. A skin-sparing mastectomy (SSM) with immediate TRAM flap and one-stage star flap nipple-areolar complex reconstruction makes minimal scar tissue and is becoming virtually imperceptible. The purpose of this study is to identify the clinical indications, to evaluate the clinical results, and to encourage the application of this method for the indicated patients. Meterial and Methods: From Apr. 1996 to Mar. 1999, there were 1,027 breast-cancer surgeries. Among them, there were 61 reconstruction cases and a skin-sparing mastectomy (SSM) with immediate reconstruction was performed on 29 cases. Of these patients, 15 underwent SSM and TRAM flap and one-stage star flap nipple-areolar complex reconstruction. Our selection criteria of SSM were as follows; diffuse DCIS that is not candidates for breast conserving surgery, Paget's disease of the nipple, clinically early breast cancer without skin involvement, and the centrally located cancer that would require removal of the nipple-areolar complex.
RESULTS
All of the TRAM flap and star flap were alive. The cosmetic results were fairly acceptable to the patients. The main drawback was bleeding and wound seroma which was managed by conservative management.
CONCLUSION
Skin-sparing mastectomy with immediate TRAM and star flap reconstruction gives markedly improved results by reducing the scars on the reconstructed breast, providing a supple breast with a natural ptotic shape, and aesthetically satisfied.

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Phorbol Ester Induced - Apoptosis Mediated by Activating Serine Protease ( s ) and Caspase - 3 / CPP32 in SNU - 16 Human Gastric Cancer Cell Line: I C Park, M J Park, T B Choe, J J Jang, S I Hong, S H Lee; J Korean Cancer Assoc. 2000;32(2):270-278.

Abstract PDF: PURPOSE
Protein kinase C (PKC) is a family of phospholipid dependent serine/threonine protein kinases that have important role in differentiation, development and tumor promotion. PKC also has been reported to be implicated in the induction of apoptosis in a number of studies, but the efforts to define a role for PKC in the induction of apoptosis have been complicated by conflicting reports.
MATERIALS AND METHODS
To determine the effect of phorbol 12-myristate 13-acetate (PMA) on the induction of apoptosis, DNA fragmentation was detected by agarose gel electrophoresis and morphological changes of apoptotic cells were detected by Hoechst 33258 staining. For the detection of caspase-3/CPP32 activity, we used the enzyme substrate Ac-DEVD-pNa and anti- D4-GDI antibody.
RESULTS
In the present study, PMA, a PKC activator, induced apoptosis in SNU-16 human gastric cancer cell line, whose apoptosis was significantly inhibited by the PKC inhibitor, chelerythrine chloride. The caspase-3/CPP32 protease activity was increased in PMA-induced apoptosis. Furthermore, 4-(2-aminoethyl) benzenesulfonyl fluoride (AEBSF), a serine profease inhibitor, also significantly suppressed PMA-induced cell death in an upstream of caspase-3/CPP32.
CONCLUSION
These findings indicate that PMA induces apoptotic cell death in the SNU-16 adenocarcinoma cells through PKC activation, which activates AEBSF-sensitive serine proteases and caspase-3/CPP32. Therefore, our results suggest that PKC would be a potential target for induction of apoptosis.

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Expression of Cell Cycle Control Genes in Korean Gastric Cancer Cell Lines: C C Lim, I H Kim, J W Cho, W K Baek, S I Suh, M H Suh, J W Park, J S Kang, S S Sohn; J Korean Cancer Assoc. 2000;32(2):279-287.

Abstract PDF: PURPOSE
In order to elucidate the roles of the cell cycle control genes in the carcinogenesis of Korean gastric cancer, the expressions of cyclin A, Dl, E, p16INK4a and Rb in Korean gastric cancer cells were investigated in this study.
MATERIALS AND METHODS
The expression patterns of major cell cycle control genes in Korean gastric cancer cells (SNU1, 5, 216, 484, 601, 620, 638, 668, 710) were analysed by using western blot and reverse transcription-polymerase chain reaction (RT-PCR).
RESULTS
In most of the gastric cancer cells investigated, the overexpressions of cyclin A and hyperphosphorylated Rb, and markedly decreased expression of p16INK4a were observed. Over-expression of cyclin E was also observed in SNU1, 484, 601 and 638 gastric cancer cells.
CONCLUSION
Considering all these findings, the following model of the gastric catcinogenesis caused by the altered expressions of the cell cycle control genes can be postulated: over-expressions of cyclin A and E cause acceleration of Rb phosphorylation, inactivation of Rb functions and acceleration of Gl/S transition of the cells; decreased expression of pl6INK4a causes inadequate inhibition of cyclin-CDK and further acceleration of Rb phosphorylation; consequently, Rb inactivation, Gl shortening, inappropriate cell division and decreased function of the maintenance of genomic stability occurs. All these abnormalities should contribute to the carcinogenesis of Korean gastric cancer cells.

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A Study of Relationship between the Progression and Subtypes of Gastric Adenocarcinoma and Fas - L / sFas - L: S C Lim, Y D Min; J Korean Cancer Assoc. 2000;32(2):288-296.

Abstract PDF: PURPOSE
The purpose of this study is to determine whether human gastric adenocarcinoma expresses Fas-L, whether serum sFas-L level is changed in patients before and after gastrectomy, and whether Fas-L or sFas-L is concerned in tumor stage and histologic type.
MATERIALS AND METHODS
The authors analysed 38 cases of early gastric carcinoma (EGC) and 61 cases of advanced gastric carcinoma (AGC) who received gastric resection from 1997 to 1998, in whom the number of diffuse type is 38 cases and the number of intestinal type is 61 cases. The authors used immunohistochemical staining for tumoral Fas-L detection and sFas ligand ELISA kit for serum sFas-L detection.
RESULTS
Fas-L was localized to neoplastic cells in 61% (23/38) cases of EGC group and 66% (40/61) cases of AGC group. The extent of Fas-L expression was variable, with both FasL- positive and -negative neoplastic region occuring within tumors. The mean serum sFas-L level was highly significantly higher in patients before treatment compared with controls, whereas in patients in post-gastrectomy was significantly lower as the level of controls. Some patients whose preoperative serum sFas-L levels were within normal limits expressed no tumoral Fas-L. In addition, factors such as tumor stage, histologic subtype and other prognostic factors were not concerned in Fas-L expression and serum sFas-L level.
CONCLUSION
The authors demonstrate a statistically significant expression of tumoral Fas-L with concomitant increment of serum sFas-L in gastric adenocarcinoma. This finding suggests Fas-mediated apoptosis in response to Fas-L expression by gastric adenocarcinoma, and provide the evidence to support the Fas counterattack and indicate that the serum sFas-L level is a useful indicator in evaluating preoperative diagnosis and postoperative follow-up of gastric adeno- carcinoma. In addition, every clinical stages of gastric adenocarcinoma of the intestinal and the diffuse type not differ in their expression of the Fas and sFas-L.

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Relationship between Disease Progression and Angiogenic Cytokine Vascular Endothelial Growth Factor in Patients with Stomach Cancer: S H Baick, D T Lee, S G Park, J H Won, D S Hong, H S Park; J Korean Cancer Assoc. 2000;32(2):297-303.

Abstract PDF: PURPOSE
Angiogenesis is required for tumor growth and metastasi. Vascular endothelial growth factor (VEGF) is one of the most important angiogenic cytokines. VEGF was expressed by several human solid tumors and serum VEGF levels have previously been shown to be raised in patients with breast, gastrointestinal tract, renal, ovarian cancer and melanoma. Tumor-derived VEGF plays a pivotal role in malignant ascites formation likely by increasing vascular permeability. In present study, amount of VEGF in plasmas and tumor tissues and cytology-proven malignant ascites were tested and compared with their normal counterparts and tumor stage to know relationship between the disease progression and VEGF quantitation in patients with stomach cancer. Also change of plasma VEGF level after tumor resection was performed.
MATERIALS AND METHODS
VEGF level was measured by ELISA in plasmas from 81 patients and tumors and peritumoral mucosas (5 cm from the tumor) from 43 patients and malignant ascites from 14 patients with gastric carcinoma. Also level of plasma VEGF from 48 patients was measured after tumor resection.
RESULTS
VEGF levels were significantly higher in plasma and in tumor tissues than in normal controls and in peritumoral mucosas. The levels of VEGF in plasma and tumor tissue were significantly correlated with the stage of disease. Moreover Tl showed significantly elevation of plasma VEGF level than those of controls. A significant correlation was found between plasma VEGF and tumor VEGF levels in stomach cancer patients. VEGF levels in fluid of cytology- proven malignant ascites were higher than in ascitic fluid with benign diseases. Plasma VEGF level fell after tumor resection, CONCLUSION: VEGF could act in a supporting tumor progression and may be useful for predicting prognosis of patients with gastric carcinoma.

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Detection of Circulating Tumor Cells in Peripheral Blood by Reverse Transcriptase - polymerase Chain Reaction in Gastric Cancer Patients: H Kim, Y Y Lee, T J Jeong, I Y Choi, I S Kim, D S Han, Y C Jeon, J H Sohn, W G Park, H G Paik, H G Lee, Y S Nam, M J Ahn; J Korean Cancer Assoc. 2000;32(2):304-311.

Abstract PDF: PURPOSE
Cancer cells can be detected in bloods, lymph nodes or bone marrows by using reverse transcriptase-polymerase chain reaction (RT-PCR). We investigated to detect carcinoembryonic antigen (CEA) mRNA in peripheral blood by RT-PCR as a circulating tumor cell maker of gastric cancer patients.
MATERIALS AND METHODS
Gastric cancer patients were early gastric cancer with curative surgery (Group A, n=9), advanced gastric cancer with curative surgery (Group B, n 18) and relapsed or metastatic gastric cancer (Group C, n=13). RT-PCR was performed to detect CEA mRNA expression in the peripheral blood mononuclear cells and we used Colo 201 cells as a positive control.
RESULTS
Seventeen patients (42.5%) were positive for CEA mRNA, whereas all the nine normal subjects were negative. There were significant differences between group A and C (p=0.041), group B and C (p=0.001) and between patients underwent curative surgery and metastatic gastric cancer patients (p 0.001) but not between A and B (p 0.326) for the positive rate of CEA mRNA.
CONCLUSION
Large number of gastric cancer patients showed positive CEA mRNA in peripheral blood suggesting that gastric cancer cells can metastasize into blood at early stage.

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Clinicopathological Analysis for Recurrence after Surgery for Early Gastric Cancer: K W Chung, S J Cho, H K Yang, W H Kim, K U Lee, K J Choe, Y I Kim, J P Kim; J Korean Cancer Assoc. 2000;32(2):312-320.

Abstract PDF: PURPOSE
The incidence of early gastric cancer (EGC) is increasing in Korea. The prognosis of EGC is excellent but a small portion of patients experience recurrence after curative resection. We aimed to study recurrence rate of EGC, recurrence pattern of EGC and to find predicting factors for recurrence. We analyzed treatment results after recurrence in EGC.
MATERIALS AND METHODS
One thousand four hundred fifty eight patients with EGC at Department of Surgery, Seoul National University Hospital (1986~1995) were reviewed for recurrence retrospectively.
RESULTS
Twenty-six patients had recurrence after curative resection (1.79%). Thirteen cases (50%) recurred within 24 months (early recurrence) and late recurrence after 60 months occured in 4 cases (15%). The common modes of recurrence were locoregional (9, 34.6%) and distant metastasis (9, 34.6%). Submucosal invasion was in 19 cases and lymph node metastasis was positive in 14 cases. Median survival after recurrence was 5.6 months. Median survival after recurrence was 3.1 months after conservative management, 5.8 months after chemotherapy, and 46.8 months after resection. Recurrence rate was significantly higher in submucosal invasion group than mucosal invasion group (2.6% vs. 1.0%, p<0.05) and lymph node metastasis positive group than negative group (7.4% vs. 1.0%, p <0.001) by univariate analysis. Multivariate analysis revealed significantly high correlation between positive lymph node metastasis and recurrence (p < 0.001).
CONCLUSION
Lymph node metastasis is the most significant predictor of recurrence. Resection for locoregional recurrence can be beneficial.

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Diagnostic Value of MRI in the T Staging of Colorectal Carcinoma: B C Kang, S W Lee, S Y Baek, H Y Choi, S Lee; J Korean Cancer Assoc. 2000;32(2):321-330.

Abstract PDF: PURPOSE
We studied to determine the usefulness of magnetic resonance imaging (MRI) in the preoperative T-staging of colorectal cancer.
MATERIALS AND METHODS
Twenty patients with colon cancer and S patients with rectosigmoid neoplasm, who were diagnosed between October 1997 and June 1998 by barium enema, colono-scopic biopsy were evaluated. Patients consisted of 16 men and 12 women, with ages ranging from 46 to 68 years (mean 61 years). Preoperative staging was done with MRI. We used 2D-FLASH (Fast Low-Angle Shot), FISP (Fast-Imaging Shot-angle Precession), and Turbo-SE (Spin-Echo) sequences. Acquisition time of these MR techniques was 13~15 sec. 2D-FLASH MRI after intravenous injection of 0.1 mmol/kg Gd-DTPA were obtained for the dynamic and delayed enhanced MR images. Preoperative stages of MRI were decided with a consensus by two radiologists. Pathologic stages were done by TNM classification.
RESULTS
T-stages determined by enhanced 2D-FLASH MR images of colorectal cancer were correlated with histopathologic findings in 2 of 3 pT2 (pathologic T2) tumor (67%), 17 of 21 pT3 (81%), and 4 of 4 pT4 tumors (100%). T-stages determined by FISP were correlated with histopathologic findings in 2 of 3 pT2 tumor (67%), 16 of 21 pT3 (76%), and 3 of 4 pT4 tumors (75%), and T-stages by Turbo-SE were correlated in 2 of 3 pT2 tumor (67%), 18 of 21 pT3 (86%), and 3 of 4 pT4 tumors (75%). MRI correctly diagnosed tumor deposits of involved lymph nodes in 16 patients, overall accuracy was 57% (16/28%). Signal intensity between the cancerous and normal wall was not significantly different on MRI using FISP (P>0.05). But, that was significantly different on the MRI using Turbo-SE (p<0.05), CONCLUSION: Fast MR sequences has a role for the preoperative T-staging of colorectal neoplasm.

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Prognostic Factors and Survival Analysis for Patients with Colorectal Carcinomas: S H Kim, Byung Kwon Ahn, S U Baek; J Korean Cancer Assoc. 2000;32(2):331-338.

Abstract PDF: PURPOSE
Colorectal carcinomas are one of the most common malignant tumors in western countries. In Korea, it is the fourth common malignancy and the incidence has been rising over the past 10 years. We studied respectively to analyse prognostic factors in patients with colorectal cancer.
MATERIALS AND METHODS
893 patients with primary colorectal carcinomas who were operated at our hospital between 1989 and 1997 were reviewed. We examined possible prognostic factors such as, age and sex of patients, size and location of tumors, preoperative serum CEA and CA19-9 level, modified Dukes stage, operative methods, and lymph node metastases.
RESULTS
Overall 5-year survival rate was 61.8%. The 5-year survival rates in modified Dukes stage A, Bl, B2, Cl, C2 and D were 100%, 89.4%, 72.5%, 63.3%, 55.1% and 21.5%, respectively. Univariate analysis showed that age, modified Dukes stage, preoperative serum CEA and CA19-9 level, and lymphatic metastases were significant factors. The size of tumor was a significant factor in rectal carcinomas but not in colon carcinomas. In extraperitoneal rectal carcinomas, there were no survival differences between low anterior resection and abdominoperineal resection groups. Preoperative serum CEA level and modified Dukes' stage were significant in multivariate analysis, CONCLUSION: Modified Dukes stage, preoperative serum CEA were independent prognostic factors for patients with colorectal cancer.

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Induced Apoptosis of Cancer Cells by Antisense ATM Gene Therapy: H K Yi, S H Chang, D Y Lee, J S Kim, R H Hwang; J Korean Cancer Assoc. 2000;32(2):339-349.

Abstract PDF: PURPOSE
Recently cloned AT gene mutated (ATM) in ataxia telangiectasia is involved in DNA damage response at different cell cycle checkpoints and also appears to have a wide role in signal transduction. ATM phenotype cells increased sensitivity to ionizing radiation and chemother- apeutic agents, and are defective Gl/S checkpoints in response to DNA damage. We have trying to focus on the possible role of hypersensitivity to DNA damage-induced apoptosis in the ATM cells. We hypothesized that cancers could be made more sensitive to therapeutic x-rays and agents by disabling the AT gene in tumor cells using ATM antisense strategy. Therefore, we investigated whether antisense ATM transduced cancer cells show ATM phenotype cells and undergo apoptotic death after exposure to low concentration of chemotherapeutic agents or irradiation doses that do not induce appreciable apoptosis in control cells.
MATERIALS AND METHODS
NH2-terminal portion of AT gene was recloned and ligated in reverse orientation in pcDNA3. This antisense ATM expression vector transfected to MCF-7 cells, and Ve3 cells by calcium phosphate method. The transformed cells were selected in the presence of G418 and confirmed AT protein expression by immunohistochemistry. We have analyzed the induction of apoptosis of antisense ATM transduced MCF-7 and Ve3 cells after treatment of chemotherapeutic agents or irradiation using DNA fragmentation, MTT assay and FACScan.
RESULTS
Antisense ATM transduced Ve3 and MCF-7 cells were showed the inhibition of ATM protein expression. Its expression was predominantly detected in the nucleus. The antisense ATM transduced Ve3 and MCF-7 cells showed increased progress of DNA fragmentaion induced by etoposide treatment, increased radiosensitization and induced apototic cells (Ao phase) of FACScan after irradiation, and increased susceptibility of apoptosis induced by treatment with low concentration of chemotherapeutic agents.
CONCLUSIONS
ATM playing in cell cycle progression and cell death in response to DNA damage may help identify potential targets for improved cancer therapies, and ATM antisense gene therapy can be a useful therapeutic tool to combat various cancers.

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Study on the Expression of Prostate Specific Antigen ( PSA ) and Effects of Androgen on Induction of Apoptosis in Human Prostate Cell Lines: M S Lee, E J Kwon; J Korean Cancer Assoc. 2000;32(2):350-359.

Abstract PDF: PURPOSE
Prostate specific antigen (PSA) is expressed exclusively in human prostatic epithelial cells. PSA protein has been an important biological marker for prostate cancer. Until now, very little was known about the regulation of PSA expression in prostatic cells. In this study, we were used human prostate cell lines (pRNS-1-1 and LNCaP) as in vitro model system to investigate the induction of apoptosis and the changes of expression of prostate specific antigen (PSA) in response to androgen (5 a-dihydrotestosterone: DHT) and/or 12-tetradecanoyl phorbol 13-acetate (TPA).
MATERIALS AND METHODS
DNA gel electrophoresis, flow cytometry, and microscopic analysis for the induction of apoptosis, and western blot analysis for PSA expression were used to characterize DHT and/or TPA response in human prostate cells.
RESULTS
TPA induced LNCaP Cell death. Cells exhibited morphological and ultrastructural features indication of apoptosis, cytoplasmic contraction, condensation of nuclear chromatin, and formation of membrane-bound apoptotic bodies were observed. The characteristic endonuclease- generated DNA ladder, commonly associated with apoptosis, were observed in TPA-treated and accumulation of cells in Ao (apoptotic region) LNCaP cells. But pRNS-1-1 cells showed no DNA fragmentation, no apoptotic bodies, and accumulation of cells in Ao was not observed. TPA resulted in dose-dependent inhibition of PSA expression. In contrast, DHT induced increase in PSA expression and decrease on degradation of DNA into oligonucleosomal size DNA fragment.
CONCLUSION
The data presented here suggest that DHT protects against TPA-induced apoptosis in cycling LNCaP cells and PSA expression is up-regulated predominantly by androgen, down-regulated in a dose dependent fashion by TPA.

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Change of Bone Mineral Density after 1,25(OH)2VitD Therapy In Newly Diagnosed Prostate Cancer Patients Treated with Total Androgen Blockade: The Prospective Study: P B Jung, D G Moon, D S Lee, J J Kim, S K Koh, J Cheon; J Korean Cancer Assoc. 2000;32(2):360-366.

Abstract PDF: No abstract available.

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Results of Additional BCG Therapy for Recurrent Transitional Cell Carcinoma after Complete Response to Initial BCG Therapy: H S Ha, C H Park, C I Kim; J Korean Cancer Assoc. 2000;32(2):367-373.

Abstract PDF: PURPOSE
The effect of repeated 6 week courses of intravesical BCG therapy after early failure of the first induction course is well known, but few studies have evaluated the effect of repeat BCG therapy for transitional cell carcinoma (TCC) achieving a complete response (CR) with initial BCG therapy. We evaluated the results of additional BCG therapy for TCC recurring after a CR to the initial treatment course of BCG.
MATERIALS AND METHODS
All of 129 patients treated with BCO with minimum follow-up of 2 years were reviewed to identify complete responders who subsequently recurred and received additional BCG therapy. The duration of initial response and the incidence and duration of a secondary CR were recorded.
RESULTS
Of 129 patients treated with BCG, 82 patients had a CR to the initial treatment of BCG. Sixteen of the 82 patients who had a CR to the initial treatment of BCG and had recurred were subsequently retreated with BCG. Ten of 16 patients receiving a second course of BCG achieved a second CR. Of 6 patients who had a second recurrence after second course of BCG, 2 received third course of BCG and 4 intravesical mitomycin-C therapy. One of 2 patients receiving a third course of BCG had a third CR and 1 proceeded to cystectomy for disease progression. Two of 4 patients receiving intravesical mitomycin-C therapy had a CR and 2 had a third recurrence. One of 2 patients who had a third recurrence received intravesical mitomycin-C therapy and 1 third course of BCG, then they achieved CR after therapy.
CONCLUSIONS
A repeat course of BCG is a reasonable option of therapy for transitional cell carcinoma that has recurred after a CR to a prior course of BCG. But careful monitoring by cytology, cystoscopy and biopsy is mandatory to continue disease free status after additional BCG.

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Initial Experience of Fractionated Stereotactic Radiotherapy for Metastatic Brain Tumors: Moon June Cho, Ki Hwan Kim, Ji Young Jang, Jun Sang Kim, Seong Ho Kim, Chang Joon Song, Jae Sung Kim; J Korean Cancer Assoc. 2000;32(2):374-381.

Abstract PDF: PURPOSE
This study aimed to evaluate the preliminary treatment results of fractionated stereotactic radiotherapy (FSRT) for metastatic brain tumors.
MATERIALS AND METHODS
Between August 1997 and December 1998, frameless FSRT was performed in 11 patients with metastatic brain tumor (1S lesions). Primary sites were lung in 7 patients, breast in 2, stomach in 1, and malignant melanoma in 1, All patients received 30-36 Gy/10-20 fx external beam irradiation to whole brain. Eight patients received FSRT for 1 lesion, one for 2 lesions, and two for 4 lesions. Fractionation schedule was 25 Gy/5 fx in 11 lesions, 18 Gy(1 fx in 3, 30 Gy/5 fx in 2, 15 Gy/5 fx in 1. Mean tumor volume was 7.0 cc (0.39~55.23 cc). Multiple-arc FSRT was delivered to 16 lesions and conformal FSRT through irregular ports shaped to tumor profile to 2 lesions.
RESULTS
No patient experienced any acute side reaction from FSRT. Follow-up radiologic evaluation was available in 9 patients. Six of nine patients achieved the complete response, but two showed the partial response and one showed no response on follow-up radiologic studies. Among six patients with complete response, 5 patients survived from 5 to 15 months and showed no evidence of metastatic brain d#isease clinically and/or radiologically at last follow-up. Among two patients who did not have radiologic evaluation, one showed clinically complete response until death and the other died just after FSRT caused by intercurrent disease. One patient with no response radiologically survived 7 months and showed nearly complete disappearance of clinical symptom with stable status radiologically, CONCLUSION: Initial experience in this study suggests that the external beam irradiation to whole brain with 30 Gy/10 fx followed by FSRT with 20~30 Gy/5~6 fx could be the good treatment option to the patients with metastatic brain tumor. This study suggests that the fractionation schedule for FSRT should be determined in consideration of performance status, number of metastasis, tumor volume, location, presence of extracranial disease, and age.

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p27Kipl, K-67 and Bcl-2 Expression in Adenoid Cystic Carcinoma of Head and Neck: C S Choi, G Choi, J J Song, K S Hwang, K Y Jung, J O Choi; J Korean Cancer Assoc. 2000;32(2):382-389.

Abstract PDF: PURPOSE
p27Kip1 negatively regulates cell proliferation by mediating cell cycle arrest in Gl and Ki-67 is a reliable cellular proliferative index. Also Bcl-2, an inhibitor of apoptosis, has potential activity toward cell survival. The present study investigated p27Kip1, Ki-67 and Bcl-2 expression in adenoid cystic carcinoma for their usefulness of indicator in tumor progression and aggressiveness.
MATERIALS AND METHODS
Formalin-fixed paraffin-embedded surgical specimens were obtained from seventeen patients with adenoid cystic carcinoma. We performed immunohistochemical staining with p27Kip1, Ki-67 and Bcl-2 monoclonal antibodies and compared with patients clinicopathologic features.
RESULTS
There were significant correlation between low p27Kip1 expression and high grade and T classification, positive nodal status and perineural invasion and high stages. However, Ki-67 and Bcl-2 expression had no significant differences in clinicopathologic features and p27Kip1 expression.
CONCLUSION
p27Kip1 is a good reliable marker of tumor progression and aggressiveness in adenoid cystic carcinomas.

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Correlation between p53 and p27kip1 Expression and Clinicopathologic Features in Hepatocellular Carcinoma: P L Lee, J S Kim, H C Yeon, Y C Lee, S U Lee, D W Kim, S T Kim; J Korean Cancer Assoc. 2000;32(2):390-397.

Abstract PDF: PURPOSE
The aim of this study was to evaluate the expression of p53 and p27Kip1 and its association with numerous prognostic indicators of hepatocellular carcinoma (HCC).
MATERIALS AND METHODS
We reviewd the clinicopathologic features of 59 patients with HCC between 1993 and 1998. p53 and p27Kip1 expression were evaluated for relation with level of AFP, presence of HBsAg and microscopic findings such as Edmonson grade, grade of mitosis, cirrhotic background, tumor margin and Ki67 labeling index.
RESULTS
The expression rate of p53 was positively correlated with with Edmonson grade, high mitosis, infiltrative tumor margin and level of serum AFP. The expression rate of p27Kip1 was correlated inversely with Edmonson grade and presence of cirrhotic background. Ki67 labeling index was well correlated with Edmonson grade and mitotic activity. There was no correalation between p53 and p27Kip1 expression.
CONCLUSION
The aberrant expression of p53 and p27Kip1 is well associated with various prognostic factors of HCC.

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Expressions of Phospholipase D, MMP-2, and TIMP-2 in Adenocarcinomas of the Lung: J H Park, K M Lee, J K Shin, S K Park, H K Kim, S S Kim, S D Lim, J R Huh, J Y Roh, P G Suh, S H Ryu; J Korean Cancer Assoc. 2000;32(2):398-406.

Abstract PDF: PURPOSE
Metastatic spread depends critically upon the invasiveness of tumor cells, i.e. their ability to breach basement membranes by elaborating and secreting specific proteolytic enzymes such as gelatinase A (MMP-2). Phospholipase D (PLD) is believed to play an important role in cell proliferation and tumorigenesis. Also several studies suggested that activation of PLD and consequent generation of phosphatidic acid are involved in signal propagation pathway leading to induction of MMP-2. However, the relation between PLD and MMP-2 is not fully studied in lung cancer tissue, yet.
MATERIALS AND METHODS
Adenocarcinomas of the lung from 20 patients were studied for immunohistochemical expressions of PLD, MMP-2 and TIMP-2 to assess their diagnostic and prognostic importance in lung tumors.
RESULTS
With decreasing tumor differentiation, there was a progressive increase of MMP-2 and PLD and TIMP-2 expression decreased. Type IV collagenase expression was significantly associated with the presence of lymph node metastases, with moderate to strong expression, presented in 60% node positive tumors compared with none of the node negative tumors (p < 0.05). PLD was increased in tumor (strong: 60%) with nodal metastases compared with those without nodal metastases (p < 0.05), Increase of MMP-2 and PLD expression was associated with loss of TIMP-2 expression.
CONCLUSION
In correlation expression of the immunohistochemical markers and invasion, PLD as well as type IV collagenase and TIMP2 expressions was found to be a predictor of invasiveness. Measurable alterations in MMP-2 and TIMP-2 and in particular, expression of PLD may be an important factor to assess invasiveness in resectable adenocarcinoma of the lung.

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Transcriptional Regulation of H2B Histone Gene Expression by Nocodazole in HL-60 Cells: Kyu Lim, Ye Gi Hong, Myung Sun Lee, Mee Young Son, Kyung Ah Yun, Jong Il Park, Wan Hee Yoon, Sung Kiel Park, Byung Doo Hwang; J Korean Cancer Assoc. 2000;32(2):407-416.

Abstract PDF: PURPOSE
Nocodazole, a microtubule disrupting reagent, is known to arrest cells in the M phase, To gain insight on the regulatory mechanism of H2B histone gene expression by nocodazole in HL-60 cell, the binding pattern of nuclear proteins to cis element in the human H2B histone gene promoter has been investigated with DNase I footprinting and DNA mobility shift assay.
MATERIALS AND METHODS
Northern blot hybridization was performed by the method of Virca et al. A Hinc II-Sac I fragment of pSPH28 was used as probe for Northern blot analysis of H2B histone mRNA. DNase I footprinting and DNA mobility shift assay were performed by the method of Lim et al. End labeled DNA oligomer (upper strand, 5'-CTTCACCTTATTTGCATAA GCGATTC-3') for octamer binding activity was mixed with nuclear extracts in a 20 ul reaction volume containing 60 mM KC1, 12 mM HEPES, pH 7.9, 5 mM MgCl2, 0.2 mM EDTA, 0.2 mM DTT, 12% glycerol, and 2 ug of poly [dI-dC].
RESULTS
The level of H2B histone mRNA rapidly was reduced at 24 hours in nocodazole-treated HL-60 cells and the mRNA was repressed in proportion to the concentration of nocodazole. Nocodazole-dependent repression of H2B histone gene was restored by replacement with nocodazole-free media. In DNase I footprinting analysis, one nuclear factor bound at 42 bp site (octamer motif) in the absence of nocodazole. In the presence of nocodazole, the binding of nuclear factor on octamer motif partially vanished. In DNA mobility shift assay, one DNA-protein complex (Octl) was formed when octamer motif was incubated with nuclear extract of HL-60 cell. After nocodazole treatment, Octl binding activity was reduced by time dependent manner.
CONCLUSION
These results suggest that nocodazole-dependent repression of H2B histone gene is correlated with reduction of Octl binding activity in HL-60 cell.

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Proteolytic Regulation of Retinoblastoma Family Protein p107 by Ubiquitin - proteasome Pathway: J S Jang, B K Park, S G Hwang; J Korean Cancer Assoc. 2000;32(2):417-421.

Abstract PDF: PURPOSE
Proteolysis is an important way to regulate cell cycle regulatory proteins. Ubiquitin- proteasome pathway regards as highly selective proteolytic machinary mostly in physiological state. We investigated the role of ubiquitin-proteasome pathway in p107 protein degradation.
MATERIALS AND METHODS
p107 protein level was determined by western blot analysis in Ewings sarcoma cell line incubated with HMG-CoA inhibitor lovastatin. Recovery of p107 protein was determined with inhibitors of proteasome, serine protease or caspase. Ubiquitination of p107 protein was assessed by ubiquitin western analysis.
RESULTS
pl07 protein level was decreased with lovastin and its proteolytic effect was counteracted with proteasome inhibitors. Ubiquitin western analysis showed p107 protein fragments were tagged with ubiquitin and it was more evident with specific proteasome inhibitor lactacystin.
CONCLUSION
Lovastatin drives p107 protein to be degraded. In a certain circumstance proteolysis of p107 protein was executed by ubiquitin-proteasome pathway.

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Effects of Integrin avB5 and av B53 on the Adenovirus - Mediated Gene Transduction: J Y Park, S Y Joo, H S Jeon, H J Chang, S Kam, I S Kim; J Korean Cancer Assoc. 2000;32(2):422-430.

Abstract PDF: PURPOSE
Human adenovirus, commonly used as a vector for gene therapy, enters host cells by receptor mediated endocytosis. Since integrin av B5 of cell surface promotes endocytosis of adenovirus and subsequent disruption of endosome, we hypothesized that the level of integrin av B5 of target cells may determine the efficiency of adenovirus- mediated gene transfer and its therapeutic effects.
MATERIALS AND METHODS
We transduced lacZ gene or herpes simplex virus thymidine kinase (HSVtk) gene, using adenoviral vector, into human lung cancer cell lines (H1299, H157, and H322). Then we evaluated the relationship between the level of integrin av B5 and av 53 of target cells, and adenovirus-mediated gene transduction efficiency.
RESULTS
The trasduction efficiency, observed by X-gal stain and B-gal activity after infection of recombinant-adenovirus encoding lacZ gene, was correlated with the level of integrin av B5, assessed by Western blotting. The bystander mediated cell killing, after transduction of HSVtk gene, was also correlated with the level of integrin av B5 of cell lines.
CONCLUSION
These results suggest that quantitative measurement of the level of integrin av B5 of target cells may be a useful predictor of the efficiency and effectiveness of gene transfer by means of an adenoviral vector.

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Analysis of Clinical Trials in the Journal of Korean Cancer Association for the Last Ten Years: Y S Park; J Korean Cancer Assoc. 2000;32(2):431-438.

Abstract PDF: PURPOSE
In Korea, many clinical trials have been published in medical journals. However, there has yet to be a study focusing on the scientific competence of the planning, execution and result interpretation of these reports. Therefore, this paper analyzed the clinical trials in the Journal of Korean Cancer Association for the last 10 years.
MATERIALS AND METHODS
All the clinical trials were analyzed according to the characteristics of clinical trial, disease, types and goals of treatment, The prospective studies were analyzed according to the competence of objectives, methods, results, and conclusion section. Clinical trials of surgical treatment were excluded from this study.
RESULTS
A total 223 (20.6%) out of 1,0S2 papers were reports of clinical trials. Of all the elinical trials, phase II, prospective, and single center studies were most common. Among 157 studies (70.4%) that were prospective, 29 studies (18.5%) did not clearly define eligibility criteria. The most common defect in the results was the lack of patients for the analysis (68 trials, 43.3%), and the median size of the trial was 30 patients. Statistical errors were found in 38 trials (24.3%).
CONCLUSION
A lot of clinical trials reported in the Journal of Korean Cancer Association need to be improved in tenns of quality. Also, the editors should review the submitted reports more thoroughly.

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Primary Non - Hodgkin's Lymphomas of the Uterine Corpus: Report of two cases: S Y Han, N H Park, Y B Kim, J W Kim, Y S Song, I A Park, S B Kang, H P Lee; J Korean Cancer Assoc. 2000;32(2):439-446.

Abstract PDF: Primary non-Hodgkins malignant lymphomas of the uterine corpus are very rare lesions, although lymphomas and leukemias frequently involve the female genital tract in advanced cases of disease. Because of this rarity, the etiology, standard treatment, and prognosis have not been defined. Here, we report two cases of primary uterine corpus lymphomas. In one patient, a non-Hodgkins lymphoma, especially, diffuse large B-cell lymphoma stage IE was diagnosed and treatment consisted of debulking surgery and radiation due to poor performance status and old age. In the other patient, a non-Hodgkins lymphoma stage IVE was diagnosed and although she was older than the first case, she was treated with combination chemotherapy. The former shows progressive disease, despite of early stage and adjuvant radiation therapy, the latter shows complete response at 3 months of follow up after chemotherapy.

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