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Arsenic Trioxide Induces Apoptosis of HL-60 Cells via Activation of Intrinsic Caspase Protease with Mitochondrial Dysfunction.

Byung Hak JUNG ; Channy PARK ; Hak Ryul KIM ; Moo Rim PARK

Cancer Research and Treatment.2002;34(4):308-315.

Arsenic trioxide (As2O3) was introduced into the treatment of refractory or relapsed acute promyelocytic leukemia and showed a striking effectiveness in China and United States multicenter study. However, the mechanistic basis for the carcinogenic or therapeutic effects of arsenics is still poorly understood. So, this study is performed to determine whether As2O3 induces apoptosis through intrinsic caspase cascades in acute promyelocytic leukemia HL-60 cells. MATERIALS AND METHODS: HL-60 cells were treated with As2O3 to investigate apoptosis through signaling of caspase cascades and mitochondrial dysfunction. RESULTS: As2O3 (>0.5 uM) decreased the viability of HL-60 cells in a dose-dependent manner, which was revealed as apoptosis shown chromatin condensation and ladder pattern DNA fragmentation. As2O3 increased the catalytic activity of caspase family cysteine proteases including caspase-3 and -9 proteases. Consistently, PARP, an intracellular biosubstrate of caspase-3 protease, was cleaved from 116 kDa to 85 kDa fragments. It also induced the change of mitochondrial membrane potential. Morever, As2O3 resulted in the increase of Bak. CONCLUSION: These data suggest that As2O3 induces apoptosis of HL-60 cells through activation of intrinsic caspase protease with mitochondrial dysfunction.
Apoptosis* ; Arsenic* ; Caspase 3 ; China ; Chromatin ; Cysteine Proteases ; DNA Fragmentation ; HL-60 Cells* ; Humans ; Leukemia, Promyelocytic, Acute ; Membrane Potential, Mitochondrial ; Peptide Hydrolases ; Strikes, Employee ; United States

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Suppression of Peritoneal Metastases by Expression of Murine Endostatin cDNA.

Seung Ho CHOI ; Jae Hoon LEE ; Sung Hee HONG ; Woo Jin HYUNG ; Sung Hoon NOH ; Hyun Cheol CHUNG ; Jae Kyung ROH ; Jin Sik MIN

Cancer Research and Treatment.2002;34(4):302-307.

Peritoneal seeding is one of problems to be solved in gastrointestinal and ovarian cancers. Angiogenesis is the critical step for a dormancy tumor cluster to be an overt metastatic nodule. However, whether an anti-angiogenesis strategy is effective in the control of peritoneal metastases is still obscure. In this study, we evaluated whether endostatin, an endogenous angiogenesis inhibitor, suppresses peritoneal metastases. MATERIALS AND METHODS: We transduced a human gastric cancer cell line, AGS and a murine renal cancer cell line, Renca, with the plasmid pEndoSTHB, which encodes a secretable form of murine endostatin. Endostatin expression was tested with western blotting, and the biological activity of the secreted endostatin was confirmed with in vitro endothelial cell growth inhibition. In the animal experiments, stable transfectants were injected intraperitoneally. RESULTS: We demonstrated secretion of endostatin from two cell lines transduced with the plasmid pEndoSTHB. Conditioned media secreted from pEndoSTSB-transduced mammalian cells were shown to potently inhibit endothelial cell growth in vitro. We selected stable transfectants with similar in vitro growth rates of their parental cell lines. Significant tumor growth inhibition was observed in the endostatin-expressing Renca cells intraperitoneal injection group at days of 28, compared to the null transfectants intraperitoneal injection control group. CONCLUSION: These results support that peritoneal seeding is angiogenesis-dependant and an anti-angiogenesis strategy is a good way to control peritoneal metastases.
Animal Experimentation ; Blotting, Western ; Cell Line ; Culture Media, Conditioned ; DNA, Complementary* ; Endostatins* ; Endothelial Cells ; Humans ; Injections, Intraperitoneal ; Kidney Neoplasms ; Neoplasm Metastasis* ; Ovarian Neoplasms ; Parents ; Plasmids ; Stomach Neoplasms

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5-Fluorouracil and Cisplatin (FP) with Concurrent Radiotherapy for Locally Advanced Head and Neck Cancer.

Hyoung Sam KIM ; Ki Seok KIM ; Sang Seok BEA ; Seok Jin OH ; Ki Hyeong LEE ; Won Dong KIM ; Woo Yoon PARK ; Seung Taik KIM

Cancer Research and Treatment.2002;34(4):296-301.

The combination of chemotherapy and radiotherapy is emerging as the new standard modality for the treatment of locally advanced head and neck cancer, due to the inherent functional and cosmetic sequelae associated with its surgical management. Combination chemotherapy with 5-fluorouracil and cisplatin (FP) is one of the most active regimens for the head and neck cancer. Furthermore, both agents are known to act as radiosensitizer. This study was conducted to determine the efficacy, feasibility, and the toxicities of concurrent FP chemotherapy with radiotherapy. MATERIALS AND METHODS: Patients with histologically proven locally advanced head and neck cancer (T3-4 or node positive) were enrolled in the study. Patients received 5-fluorouracil, 1,000 mg/m2/day, continuously for 4 days, and cisplatin, 75 mg/m2, on day 1. This regimen was given every four weeks. The radiotherapy (45 Gy) was started on day 1 of the first cycle, and administered in 25 fractions. Following a three-week interval, the radiotherapy was resumed on day 1 of the third cycle of chemotherapy, and administered in 15 fractions (27 Gy). RESULTS: Of the 31 eligible patients included, 28 were able to be evaluated for the tumor response. The response rate for the 28 patients was 93% (16 complete responses, 10 partial responses). Disease free survival for the 16 complete responders was 37 months (median, 1 ~41 months), with a median follow-up time of 31 months. The 1-, 2-, and 3-year survival rates were 82%, 69%, and 63%, respectively. Regarding the feasibility of this treatments, only nineteen patients (61%) received the complete courses of scheduled treatments. The median duration of admission for all patients was 39 days. Grade 3 or 4 stomatitis were observed in 25 patients (83%) and appeared as the dose limiting toxicity of this regimen CONCLUSION: Although FP chemotherapy with concurrent radiotherapy is toxic, it is an effective and relatively feasible treatment for locally advanced head and neck cancer. The majority of patients experienced severe stomatitis, which appeared as the dose limiting toxicity of this regimen.
Chemoradiotherapy ; Cisplatin* ; Disease-Free Survival ; Drug Therapy ; Drug Therapy, Combination ; Fluorouracil* ; Follow-Up Studies ; Head and Neck Neoplasms* ; Head* ; Humans ; Radiotherapy* ; Stomatitis ; Survival Rate

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The Outcome of Philadelphia Chromosome-Positive Adult ALL: Characteristics and Prognosis.

Hun Ho SONG ; Je Hwan LEE ; Byung Min JEON ; Jung Hee LEE ; Eul Ju SEO ; Chan Jeoung PARK ; Hyun Sook CHI ; Jung Shin LEE ; Woo Kun KIM ; Kyoo Hyung LEE

Cancer Research and Treatment.2002;34(4):289-295.

The Philadelphia (Ph) chromosome is a well- known chromosome abnormality in adults with B-lineage ALL, and is associated with a poor prognosis. This study compared the clinical manifestations and prognosis in adult Ph-positive and Ph-negative ALL patients. MATERIALS AND METHODS: We retrospectively analyzed the clinical records of adult patients newly diagnosed as B-lineage ALL, between January 1995 and February 2001. Fifty five patients were included in this study. We divided the patients into Ph-positive and Ph-negative groups. RESULTS: Eighteen of the 55 patients (32.7%) were found to have the Ph chromosome. At initial diagnosis, the Ph-positive patients had higher circulating leukocyte counts, lower platelet counts and had a greater tendency to bleed, than the Ph-negative group. The complete remission rates were 83.3% and 83.8% for the Ph-positive and the Ph-negative groups, respectively. Four of the Ph-positive, and 13 of the Ph-negative, patients underwent allogenic bone marrow transplantation. The median follow-up for the surviving patients was 39.3 months. The three-year survival rates were 10.4% and 51.8% for the Ph-positive and the Ph-negative groups, respectively. The median disease-free survival was 7.7 months for the Ph-positive group, but did not reach the median value in the Ph-negative group. Among the Ph-positive patients, age was the only factor that had an impact on the disease outcome. CONCLUSION: In adult B-lineage ALL, the Ph-positive patients had similar complete remission rates to other patients; however, the remission was of shorter duration, with a higher relapse rate in the Ph-positive patients. More effective treatments are needed to improve the survival of the Ph-positive patients.
Adult* ; Bone Marrow Transplantation ; Chromosome Aberrations ; Diagnosis ; Disease-Free Survival ; Follow-Up Studies ; Humans ; Hydrogen-Ion Concentration ; Leukocyte Count ; Philadelphia Chromosome ; Platelet Count ; Prognosis* ; Recurrence ; Retrospective Studies ; Survival Rate

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Treatment Outcome of Brain Metastasis after the Cranial Radiotherapy Followed by Fractionated Stereotactic Radiotherapy and Its Prognostic Factors.

Hak Jae KIM ; Semie HONG ; Suzy KIM ; Jin Ho KIM ; Il Han KIM ; Charn Il PARK ; Sung Whan HA ; Hong Gyun WU ; Wee Saing KANG

Cancer Research and Treatment.2002;34(4):284-288.

To evaluate the effectiveness of whole brain radiotherapy followed by stereotactic radiotherapy for newly diagnosed brain metastasis. MATERIALS AND METHODS: Thirty-three metastatic brain tumors received radiotherapy to the whole brain and stereotactic radiotherapy in 25 patients. Lung carcinomas were the most common (17/25) primary tumor. The radiation dose was 30 to 40 Gy for the whole brain, with a 12 to 40 Gy boost to the metastatic foci. Survival and local control rates were determined, and the prognostic factors for survival were evaluated. RESULTS: The overall median survival was 15 months and the actuarial survivals at 1- and 2-year were 67% and 31%, respectively. The local tumor control rate was 79%, with a median follow-up period of 9 months (2~36 months). The prognostic factors associated with survival were age, tumor size and the existence of active extracranial metastasis, with the performance status showing marginal significance. No acute or chronic complications were observed in the patients. CONCLUSION: From our data, cranial radiotherapy followed by stereotactic radiotherapy was useful in the local control of metastatic tumors, and in the survival of patients with tumor factors, such as small size or the absence of extracranial tumor activity, and host factors, such as young age or good performance status.
Brain Neoplasms ; Brain* ; Follow-Up Studies ; Humans ; Lung ; Neoplasm Metastasis* ; Radiotherapy* ; Treatment Outcome*

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Pirarubicin, UFT, Leucovorin Chemotherapy in Non-embolizable and Transcatheter Arterial Chemoembolization-Failed Hepatocellular Carcinoma Patients; A Phase II Clinical Study.

Kyong Hwa PARK ; So Young YOON ; Sang Cheul OH ; Jae Hong SEO ; Chul Won CHOI ; Jong Eun YEON ; Byung Soo KIM ; Sang Won SHIN ; Yeul Hong KIM ; Kwan Soo BYUN ; Jun Suk KIM ; Chang Hong LEE

Cancer Research and Treatment.2002;34(4):280-283.

Hepatocellular carcinomas are one of the most common malignancies in the world. However, no effective therapeutic modality has been proven to prolong the survival of patients in an inoperable stage. The purpose of this study was to determine the response rate and the toxicities of a combination of pirarubicin, UFT and leucovorin in patients with non-embolizable hepatocellular carcinomas, or who had progressed during their transcatheter arterial chemoembolization treatment. MATERIALS AND METHODS: Of 23 patients with a hepatocellular carcinoma, 11 had progressed during a transcatheter arterial chemoembolization, with the other 12 being transcatheter arterial chemoembolization-naive. All the patients were treated with pirarubicin (70 mg/m2 i.v., day 1), UFT (350 mg/m2 P.O., day 1~21), and leucovorin (25 mg/m2 P.O., day 1~21). RESULTS: Twenty patients were able to be evaluated, with a partial response being achieved in four, giving an overall response rate of 20% (95% confidence interval, 7~44%). The median overall survival time was 6 months, and the median survival time of the transcatheter arterial chemoembolization-naive patients was significantly longer than that of those treated by transcatheter arterial chemoembolization (p=0.012). The most significant dose-limiting toxicity was leucopenia and thrombocytopenia. CONCLUSION: The combination of pirarubicin, UFT and leucovorin therapies showed marginal antitumor activity and significant toxicity in patients with non-embolizable or failed transcatheter arterial chemoembolization hepatocellular carcinomas.
Carcinoma, Hepatocellular* ; Drug Therapy* ; Humans ; Leucovorin* ; Thrombocytopenia

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A Phase II Study of Gemcitabine Monotherapy in Breast Cancer Patients Refractory to Anthracycline and Taxane.

Jun Yong PARK ; Chul KIM ; Joo Hyuk SOHN ; Yong Tae KIM ; Sun Young RHA ; Woo Ick JANG ; Gwi Eon KIM ; Hyun Cheol CHUNG

Cancer Research and Treatment.2002;34(4):274-279.

We performed a phase II trial to evaluate the efficacy and the safety of gemcitabine monotherapy, a pyrimidine antimetabolite, in patients, who had previously failed anthracycline and taxane-based chemotherapy for the treatment of metastatic breast cancer. MATERIALS AND METHODS: Twenty-one patients with metastatic breast cancer, which was unresponsive to previous chemotherapy, were entered into this study. Gemcitabine was administered at 850 mg/m2, as a 60- minute intravenous infusion on days 1, 8 and 15. This regimen was repeated every 28 days with G-CSF support, but without dose reduction. RESULTS: Objective responses were seen in 6 of the 20 patients who were able to be evaluated (1 complete response and 5 partial responses), with an objective response rate of 30%. The median time to progression was 5 (1~20) months, and the median overall survival duration was 11 (2~21) months. The actual dose intensity was 566.7 mg/m2/wk (range; 340~637.5 mg/m2/wk) and the relative dose intensity was 0.89 (range; 0.40~1.00). Toxicity was mainly hematological. Toxicities included: grade 3 neutropenia in 20% and anemia in 5%. Grades 3 and 4 thrombocytopenia occurred in 15% of the patients. CONCLUSION: Gemcitabine monotherapy is an effective and safe treatment for refractory breast cancer patients heavily treated with the anthracycline and taxane- based regimen.
Anemia ; Breast Neoplasms* ; Breast* ; Drug Therapy ; Granulocyte Colony-Stimulating Factor ; Humans ; Infusions, Intravenous ; Neutropenia ; Thrombocytopenia

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Expression of G1/S Phase Checkpoint Proteins in Breast Carcinoma: Relationship to Clinicopathologic Factors andSurvival Rate.

Mi Ja LEE

Cancer Research and Treatment.2002;34(4):268-273.

The retinoblastoma protein (pRb)/cyclin D1/ p16 pathway plays a critical role in controlling the progression from G1 to S phase of the cell cycle. Abnormal expression of the individual components of the pathway has been reported in many human cancers, including the breast. Our aim was to investigate the role of this pathway in tumorigenesis and tumor progression, and to evaluate the value of these oncoproteins as potential prognostic factors in breast cancer. MATERIALS AND METHODS: We examined the significance of the p16, pRb, and cyclin D1 expression in 128 cases of invasive breast carcinomas using immunohistochemistry on formalin fixed, paraffin sections. The results correlated with the survival rate and clinicopathologic variables, including age, histologic grade, lymph node status, tumor size, estrogen receptor (ER) and progesterone receptor (PR) content. The negative finding for nuclear staining for pRb and p16 were defined as abnormal. RESULTS: Abnormal expression of the p16 and pRb were seen in 21% and 43% of tumors, respectively. There was a significant inverse relationship between the p16 and pRb expressions. There was no association between the p16 staining and any other parameters, including survival rate, cyclin D1, or clinicopathologic variables. Surprisingly, there was a trend for pRb positive tumors to be grade III ductal carcinomas. Cyclin D1 positivity was noted in 46% of cases. The expression of cyclin D1 protein was significantly higher in lower histologic grades, and with higher ER and PR expressions. CONCLUSION: These findings suggest the p16 may be negatively regulated by the pRb, and that cyclin D1 is involved in the tumor progression in well-differentiated tumors and could be an ER and PR related protein. In a Cox multivariate analysis, the p16, pRb, and cyclin D1 were not independent predictors of patient outcome.
Breast Neoplasms* ; Breast* ; Carcinogenesis ; Carcinoma, Ductal ; Cell Cycle ; Cyclin D1 ; Estrogens ; Formaldehyde ; Humans ; Immunohistochemistry ; Lymph Nodes ; Multivariate Analysis ; Oncogene Proteins ; Paraffin ; Receptors, Progesterone ; Retinoblastoma Protein ; S Phase ; Survival Rate

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The Effects of Irradiation on Lung Function in Patients with Lung Cancer.

Kyung Hee GANG ; Jae Yong PARK ; Kyung Rok KIM ; Po Hee CHAE ; Nack Cheon BAE ; Seung Ick CHA ; Chang Ho KIM ; Tae Hoon JUNG

Cancer Research and Treatment.2002;34(4):264-267.

This study was performed to assist in the prediction of the clinical tolerance of patients with lung cancer to irradiation. MATERIALS AND METHODS: The changes in lung function of 26 patients with lung carcinomas, who had received radiation with curative intent, or postoperative adjuvant radiotherapy, were prospectively studied. Their pulmonary function tests were conducted at presentation, and then at 2 weeks, 2 months, and 6 months, following radiotherapy. RESULTS: When the parameters of postirradiation pulmonary functions (2 weeks, 2 months and 6 months) were compared with the preirradiation baseline data, there was a statistically significant decrease in FEF25~75% at 2 months, but the rest of the parameters showed no significant change following irradiation. However, when the baseline lung function was compared with the lung function at the lowest FVC, in patients with curative radiotherapy, there was a statistically significant decrease of about 10% in the FEV1 and DLCO. CONCLUSION: Preirradiation assessment of pulmonary functions, particularly the FEV1 and DLCO will be useful for the prediction of the clinical tolerance to irradiation.
Humans ; Lung Neoplasms* ; Lung* ; Prospective Studies ; Radiotherapy ; Radiotherapy, Adjuvant ; Respiratory Function Tests

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Altered Retinoblastoma Protein Expression and Proliferative Activity in Urethane Induced Mouse Lung Tumorigenesis.

Jin Haeng CHUNG ; Ja June JANG ; Min Jae LEE ; Eul Keun HAM

Cancer Research and Treatment.2002;34(4):258-263.

Lung cancer develops through a multistage process involving the accumulation of diverse genetic alterations. To gain an understanding of the roles played by tumor suppressor gene proteins and proliferating cell nuclear antigen (PCNA) in chemical carcinogen-induced mouse lung tumorigenesis, we examined the expression of retinoblastoma protein (Rb), p53, and PCNA in normal lung tissues and urethane-induced mouse lung tumors. MATERIALS AND METHODS: ICR mice were given urethane by intra-peritoneal injection, and sacrificed at 5, 13, 21, 31, and 37 weeks following treatment. Sequential morphological changes and the immunohistochemical expression of Rb protein, p53, and (PCNA), during mouse lung tumorigenesis, were examined. RESULTS: During the carcinogenesis, sequential histological changes from hyperplasia of type II pneumocytes, to adenomas, and ultimately to overt adenocarcinomas were noted. Intense nuclear staining of the Rb protein was observed in normal and hyperplastic alveolar epithelial cells and adenomas. In adenocarcinomas, the Rb protein expression was significantly diminished. The p53 mutant protein was not detected in any lesion. The PCNA labeling index increased along with the advance in the histological grade. CONCLUSION: The above results indicate that mouse pulmonary adenocarcinomas develop through premalignant lesions, and down-regulation of the Rb protein expression may be implicated in the urethane-induced mouse lung tumorigenesis. In addition, the PCNA labeling index may reflect the malignant potential during the tumor progression.
Adenocarcinoma ; Adenoma ; Animals ; Carcinogenesis* ; Down-Regulation ; Epithelial Cells ; Genes, Tumor Suppressor ; Hyperplasia ; Lung Neoplasms ; Lung* ; Mice* ; Mice, Inbred ICR ; Mutant Proteins ; Pneumocytes ; Proliferating Cell Nuclear Antigen ; Retinoblastoma Protein* ; Retinoblastoma* ; Urethane*

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