BACKGROUND: To study the prognosis of patients with lung cancer, many investigators have reported the methods to detect cell proliferation in tissues including PCNA, thymidine autoradiography, flow cytometry and Ki-67. PCNA, also known as cyclin, is a cell related nuclear protein with 36KD intranuclear polypeptide that is maximally elevated in S phase of proliferating cells. In this study, PCNA was identified by paraffin-embedding tissue using immunohistochemistry which has an advantage of simplicity and maintenance of tissue architecture. The variation of PCNA expression is known to be related with proliferating fraction, histologic type, anatomic(TNM) stage, degree of cell differentiation, S-phase fraction and survival rate. We analyzed the correlation between PCNA expression and S-phase fraction, survival. METHODS: To investigate expression of PCNA in primary lung cancer, we used immunohistochemical stain to paraffin-embedded sections of 57 resected primary non-small cell lung cancer specimen and the results were analyzed according to the cell type, cell differentiation, TNM stage, S-phase fraction and survival. RESULTS: PCNA expression was dMded into five group according to degree of staging(-, +, ++, +++,++++). Squamous cell type showed high positivity than in adenocarcinoma. Nonsignificant difference related to TNM stage was noticed. Nonsignificant difference related to degree of cell differentiation was noticed. S-phase fraction was increased wit advance of PCNA positivity, but t could not reach the statistic significance. The 2 year survival rate and median survival time were -50% 13 months, +75% 41.3 months, ++73% 33.6 months, +++67% 29.0 months, ++++25% 9 months with statistic significance (P<0.05, Kaplan-Meier, generalized Wilcox). CONCLUSION: From this study. PCNA expression was high positive n squamous cell cancer. And, there was no relationship between PCNA positivity and TNM stage, cellular differentiation or S-phase fraction. But, the patients with high positive PCNA staining showed poor survival rate than the patients with lower positive PCNA. It was concluded that PCNA immunostaining is a simple and useful method for survival prediction in paraffin embedded tissue of non-small cell lung cancer.
Adenocarcinoma ; Autoradiography ; Carcinoma, Non-Small-Cell Lung* ; Cell Differentiation ; Cell Proliferation ; Cyclins ; Flow Cytometry ; Humans ; Immunohistochemistry ; Lung Neoplasms ; Neoplasms, Squamous Cell ; Nuclear Proteins ; Paraffin ; Prognosis ; Proliferating Cell Nuclear Antigen* ; Research Personnel ; S Phase ; Survival Rate* ; Thymidine

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

Surgery represents a noxious stimulus to the body, which responds to the injury in the form of an endocrine metabolic reaction. This stress responsehas usually been considered to be a homeostatic defence mechanism by which the body protects itself against injury. This study was primarily undertaken to observe the modulation of stress response to the surgical stimuli under the effects of general and spinal anesthesia by measuring endogenous catecholamines. Fifteen pateints scheuled for elective surgical procedures on the lower half of the body were divided into two group: general and spinal anesthesia groups. No premedication was given to any patient. After the patient was laid down the surgical table, intravenous line was placed and secured in an antecuhital vein for maintenance of fluid and obtaining blood samples. After the intravenous cathether was inserted and a 10-minute rest period was allowed for reassurance, the first baseline sample was obtained for measurement of catecholamines and then anesthesia was induced. .General anesthesia group: Anesthesia in five patients was induced with sodium thiopental (5 mg/ kg), succinylcholine (1 mg/kg) followed by endotracheal intubation and was maintained with halothane, N2O and muscle relaxation using pancuronium. Spinal anesthesia group: Spinal anesthesia in ten patients was performed in a sitting position at L3-L4 intervertebral space using lidocaine 50-150 mg. The anesthesia level was determined by a pinprick test. Subsequent samples were obtained at 30 minutes after the surgical incision and in the recovery room at least 60 minutes after the discontiuation of inhalational anesthesia or after recovery of senastion and motor function of the lower extremites. Mean arterial pressure was measurd by a noninvasive automatic blood pressure monitor. Plasma epinephrine and norepinephrine were measured by Peuler and Johnson radioenzymatic method. The results are summerized as follows: Inhalation anesthesia group: Plasma norepinephrine was increased during surgery and epinephrine was increased during the postoperative recovery period. Spinal anesthesia group: Plasma norepinephrine and epinephrine were not increased during the intra and postoperative periods. High spinal anesthesia resulted in a suppression of both plasma norepinephrine, epinephrine with a fall of mean arterial pressure but no changes of norepinephrine, epinephrine, or mean arterial pressure were observed in the patients receiving low spinal anesthesia. There was a relationship between the sensory dermatome anesthesia level and changes of both plasma norepinephrine (r=0.748, P<0.01)and epinephrine (r=0.667, P<0.05). There is a relationship between changes of blood pressure and plasma norepinephrine levels during spinal anesthesia and inhalational anesthesia (r=0.827, p<0.01). The effect of spinal anesthesia on adrenergic tone depends on the level of anesthesia. The catecholamine responses to surgical stress were prevented by low spinal anesthesia which had no supression of efferent adrenergic tone. Therefore, low spinal anesthesia maybe useful to prevent adrenergic responses to surgical stress in high-risk patients scheduled for surgery on the lower half of the body.
Anesthesia* ; Anesthesia, General ; Anesthesia, Inhalation ; Anesthesia, Spinal ; Arterial Pressure ; Blood Pressure ; Blood Pressure Monitors ; Catecholamines ; Epinephrine ; Halothane ; Humans ; Intubation, Intratracheal ; Lidocaine ; Muscle Relaxation ; Norepinephrine ; Pancuronium ; Plasma* ; Postoperative Period ; Premedication ; Recovery Room ; Sodium ; Succinylcholine ; Surgical Procedures, Elective ; Thiopental ; Veins

BACKGROUND: EGFR is one of the initial step in signal transduction pathway about multistep carcinogenesis. It is homologous to oncogene erbB-2 and is the receptor for EGF and TGF alpha. EGFR has important role in the growth and differentiation of tumor cells. So, EGFR in non-small cell lung cancer was examined to search for possible evidence as clinical prognostic factor. METHODS: To investigate the role of EGFR in lung cancer, the author performed immunohistochemical stain of EGFR on 57 resected primary non-small cell lung cancer specimens. And the author analyzed the correlation between EGFR expression, clinical parameters, S and G1 phase fraction and survival. RESULTS: 1) EGFR were detected in 56% of total 57 patients (according to histologic type, squamous cancer 50%, adenocarcinoma 63%, large cell cancer 75%) (according to TNM stage, stage I 64%, stage II 38%, stage III 55%) (according to cellular differentiation, well 50%, moderately 52%, poorly 65%). All differences were insignificant. 2) Using the flow cytometric analysis, mean S-phase fraction of EGFR (+) and (-) group were 22.3(+/-10.5)%. 18.0(+/-10.9)% (p>0.05), mean G1-phase fraction of EGFR (+) and (-) group were 68.4(+/-11.6)%, 71.1(+/-12.8)%, (p>0.05) 3) Two-year survival rate of EGFR (+) and (-) group were 53%, 84%, median survival time of EGFR (+) and (-) group were 26, 53 months. (p<0.05, Kaplan-Meier, generalized Wilcox) CONCLUISON: EGFR immunostaining may be a simple and useful method for survival prediction in non-small cell lung cancer.
Adenocarcinoma ; Carcinogenesis ; Carcinoma, Non-Small-Cell Lung* ; Epidermal Growth Factor ; G1 Phase ; Humans ; Lung Neoplasms ; Oncogenes ; Signal Transduction ; Survival Rate

BACKGROUND: Matrix metalloproteinases (MMPs) are a large family of proteolytic enzymes, which are in volved in the degradation of many different components of the extracellular matrix. There is increasing evidence indicating that individual MMPs have important roles in tumor invasion and metastasis. A tissue inhibitor of metalloproteinase(TIMPs) has been reported to inhibit tumor invasion by inactivating the MMPs. In this study, the correlation between MMPs and TIMPs expression, and the clinical outcome was investigated. METHODS: Immunohistochemical staining of MMP-2,9 and TIMP-1,2 were performed on paraffin-embedded tumor sections from 74 resected primary non-small cell lung cancers. RESULTS: In 74 patients, MMP-2, MMP-9, TIMP-1, and TIMP-2 immunoreactivity was demonstrated in 24 (34%), 19(26%), 27(36%) and 32(43%) of the paraffin-embedded tumors, respectively. The median survival of the MMP-2 positive cases was significantly shorter than that of the negative cases(20 vs 34 months). The median survival of the TIMP-2 positive cases was also was significantly longer than that of negative case (34 vs 18 months). The MMP-2, and MMP-9 expression level had a positively correlation with a more advanced stage and lymph node metastasis. There was inverse correlation between TIMP-2 expression and tumor invasion. The median survival of the MMP-2 negative/TIMP-2 positive cases was higher than that of the other cases. CONCLUSION: These results suggest that tumor invasion and lymph node metastasis are closely related to MMP-2 and MMP-9 expression. There was an inverse correlation between TIMP-2 MMP-9 expression, and tumor invasion.
Carcinoma, Non-Small-Cell Lung* ; Extracellular Matrix ; Humans ; Lung Neoplasms ; Lymph Nodes ; Matrix Metalloproteinases ; Neoplasm Metastasis ; Peptide Hydrolases ; Tissue Inhibitor of Metalloproteinase-1 ; Tissue Inhibitor of Metalloproteinase-2

Extraosseous pulmonary chondrosarcoma is a rare neoplasm, which is characterized into two groups. One is termed a primary chondrosarcoma, and arise de novo (bronchial cartilage), the other is termed a secondary chondrosarcoma, and is superimposed on preexisting benign cartilagenous neoplasms, such as a chondroma or hamartoma. The preferred treatment is surgical resection. We recently experienced a secondary chondrosarcoma changed from a hamartoma.A 54-year-old woman was referred to our hospital becaused of an abnormal chest X-ray with mild dyspnea. We performed a percutaneous transthoracic needle biopsy and sputum examination. The abnormal mass had been diagnosed as a chondromatous hamortoma wit active pulmonary tuberculosis, which had been treated with anti-tuberculosis regimens. Despite her medication, and abnormal mass had grown. Therefore, we undertook a pneumonectomy with chest wall reconstruction.Histopathologically, the mass was grade II, dedifferenciated chondrosarcoma, with chronic granulomatous inflammation and necrosis.We suggest this case had changed from a chondromatous hamartoma to a dedifferentiated chondrosarcoma, with associated pulmonary tuberculosis. We report this case with a brief literature review.
Biopsy, Needle ; Chondroma ; Chondrosarcoma ; Dyspnea ; Female ; Hamartoma* ; Humans ; Inflammation ; Middle Aged ; Pneumonectomy ; Sputum ; Thoracic Wall ; Thorax ; Tuberculosis, Pulmonary

Arsenic trioxide(As2O3) was introduced into the treatment of refractory or relapsed acute promyelocytic leukemia. Some investigators have reported that arsenic trioxide had induced apoptosis in a variety of solid human tumor cell lines, including non-small cell lung cancer. Non-steroidal anti-inflammatory drugs(NSAIDs) are powerful chemopreventive agents for gastrointestinal cancers and the growth of established tumors are reduced by inducing apoptosis. It's also reported that NSAIDs enhanced tumor response to chemotherapeutic drugs or radiation. In this study, we aimed to determine whether combination of arsenic trioxide with sulindac augmented its apoptotic potential in NCI-H157 human lung cancer cells. The human lung cancer cell line NCI-H157 was treated with arsenic trioxide and sulindac. Cell viability was measured by the MTT assay. Apoptosis was measured by nuclear staining and flow cytometric analysis. The catalytic activity of the caspase families were measured by the fluorogenic cleavage of biosubstrates. The western blotting were also performed to define the mechanical basis of apoptosis. Combination treatment of arsenic trioxide and sulindac decreased the viability of NCI-H157 human lung cancer cells in a dose-dependent manner. The catalytic activity of caspase-3, 8 and 9 proteases were increased after combination treatment. Consistently PARP was cleaved from 116kDa to 85kDa fragments, and the expression of ICAD was decreased by time-dependent manner. Also combination treatment increased the expression of Fas and Fas/L. Combination therapy of arsenic trioxide with sulindac augments cell death and induces apoptosis via the activation of caspase cascade in NCI-H157 human lung carcinoma cells.
Anti-Inflammatory Agents, Non-Steroidal ; Apoptosis* ; Arsenic* ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung ; Caspase 3 ; Cell Death ; Cell Line ; Cell Line, Tumor ; Cell Survival ; Gastrointestinal Neoplasms ; Humans* ; Leukemia, Promyelocytic, Acute ; Lung Neoplasms ; Lung* ; Peptide Hydrolases ; Research Personnel ; Sulindac*

BACKGROUND: Non-steroidal anti-inflammatory drugs (NSAID) are useful in chemoprevention of colorectal cancers. Continuous NSAID administation causes 40% to 50% reduction in relative risk for colorectal cancer. Sulindac possesses an antiproliferative effect and induces apoptosis and tumor regression on colon cancer and other types of cancers. We intended to analyze the effects of sulindac in three non-small cell lung cancer cell lines. MATERIALS AND METHODS: The human lung cancer cell lines, A549, NCI-H157 and NCI-H460 were used for this study. Viability was tested by MTT assay, and cell death rate was measured by lactate dehydrogenase(LDH) release. Apoptosis was estimated by flow cytometric analysis and nuclear staining. RESULTS: Sulindac was able to decrease the viability of non-small cell lung cancer cells in a dose- and time- dependent manner. In a parallel effect of sulindac on cell death rate, LDH release was increased in sulindac-treated lung cancer cells. Sulindac significantly increased apoptosis characterized by an increase of sub-G0/G1 fraction and morphological change of nuclei. The rate of apoptotic cells after sulindac treatment in lung cancer cells increased in a time- and dose- dependent manner in flow cytometric analysis. Apoptotic cells were defined as nuclear shrinkage, chromatin condensation and nuclear fragmentation of cells. CONCLUSION: Sulindac decreases viability and induces the apoptosis of lung cancer cells. Further studies will be needed to elucidate the potential mechanism of sulindac-induced apoptosis in lung cancer cells.
Apoptosis* ; Carcinoma, Non-Small-Cell Lung ; Cell Death ; Cell Line ; Chemoprevention ; Chromatin ; Colonic Neoplasms ; Colorectal Neoplasms ; Humans* ; Lactic Acid ; Lung Neoplasms* ; Lung* ; Sulindac*

BACKGROUND: The majority of chemotherapy-treated small cell lung cancers(SCLC) patients eventually recur. Although many patients are in excellent physical condition at the time of recurrence, few drugs or drug comb inations are capable of effecting a tumor regression in this setting. Topotecan, a topoisomerase I inhibitor, is one of the more widely studied single agents in SCLC. The aim of theis study was to determine the response rate survival and toxicity of topotecan as a second line treatment in SCLS. METHODS: 19 patients with measurable SCLC, progressive during the first line chemotherapy (9 cases) or recurrent after the first line chemotherpy(10 cases), were enrolled in this study. Topotecan was administered as a 30-minute daily infusion at a dose of 1.5mg/m2 for 5 consecutive days, every 3 week. RESULTS: The overall response rate was 26.3%(5/19, CR 2, PR 3, SD3, PD 11). The median survival was 24 weeks. The response rate and survival were poor in the nonresponders during first chemotherapy, those who were refractory to the first chemotherapy (recurrent within 3 months after complection of first chemotherapy and extensive disease, but the results were not statistically significant. The toxicities were mainly hematologic and anemia grade III 1/90, leukopenia grade III 6/90 IV 4/90, thrombocytopenia grade III 1/90 IV 1/90, vomiting grade III 1/90 of cycles were occurred. There was no treatment-related deaths due to severe myelosuppression. CONCLUSION: Topotecan can be an active second line chemotherpeutic agent for treating SCLC.
Anemia ; Animals ; Comb and Wattles ; DNA Topoisomerases, Type I ; Drug Therapy ; Humans ; Leukopenia ; Lung ; Recurrence ; Small Cell Lung Carcinoma* ; Thrombocytopenia ; Topotecan* ; Vomiting

BACKGROUND: Arsenic trioxide (As2O3) has been used to treat acute promyelocytic leukemia, and it induces apoptosis in a variety of solid tumor cell lines including non-small cell lung cancer cells. However, nonsteroidal anti- inflammatory drugs (NSAID) can enhance tumor response to chemotherapeutic drugs or radiation. It was previously demonstrated that a combination treatment with As2O3 and sulindac induces the apoptosis of NCI-H157 human lung carcinoma cells by activating the caspase cascade. This study aimed to determine if a combination treatment augmented its apoptotic potential through other pathways except for the activation of the caspase cascade. MATERIAL AND METHODS: The NCI-H157 cells were treated with As2O3, sulindac and antioxidants such as glutathione (GSH) and N-acetylcysteine (NAC). The cell viability was measured by a MTT assay, and the level of intracellular hydrogen peroxide (H2O2) generation was monitored fluorimetrically using a scopoletin-horse radish peroxidase (HRP) assay. Western blotting and mitochondrial membrane potential transition analysis were performed in order to define the mechanical basis of apoptosis. RESULTS: The viability of the cells was decreased by a combination treatment of As2O3 and sulindac, and the cells were protected using antioxidants in a dose-dependent manner. The increased H2O2 generation by the combination treatment was inhibited by antioxidants. The combination treatment induced changes in the mitochondrial tran-smembrane potential as well as the expression of the Bcl-2 family proteins, and increased cytochrome c release into the cytosol. However, the antioxidants inhibited the effects of the combination treatment. CONCLUSION: Combination treatment with As2O3 and sulindac induces apoptosis in NCI-H157 human lung carcinoma cells via ROS generation with a mitochondrial dysfunction.
Acetylcysteine ; Antioxidants ; Apoptosis* ; Arsenic* ; Blotting, Western ; Carcinoma, Non-Small-Cell Lung ; Cell Line, Tumor ; Cell Survival ; Cytochromes c ; Cytosol ; Glutathione ; Humans* ; Hydrogen Peroxide ; Leukemia, Promyelocytic, Acute ; Lung* ; Membrane Potential, Mitochondrial ; Peroxidase ; Raphanus ; Sulindac*