Hypoxia plays a major role in the induction of angiogenesis during tumor development. One mechanism by which tumor cells respond to a reduced oxygen level is via the activation of hypoxia-inducible factor-1 (HIF-1). HIF-1 is an oxygen-dependent transcriptional activator that plays crucial roles in the angiogenesis of tumors and mammalian development. HIF-1 consists of a constitutively expressed HIF-1beta subunit and the highly regulated HIF-1 alpha subunits. The stability and activity of HIF-1alpha are regulated by various post-translational modifications, hydroxylation, acetylation, phosphorylation and sumoyaltion. Therefore, HIF-1alpha interacts with several protein factors including PHD, pVHL, ARD-1, SUMO and p300/ CBP. Under normoxia, the HIF-1alpha subunit is rapidly degraded via the von Hippel-Lindau tumor suppressor gene product (pVHL)-mediated ubiquitin/proteasome pathway. The association of pVHL and HIF-1alpha under normoxic conditions is triggered by the hydroxylation of prolines and the acetylation of lysine within a polypeptide segment known as the oxygen-dependent degradation (ODD) domain. On the contrary, under the hypoxia condition, the HIF-1alpha subunit becomes stable and interacts with coactivators such as p300/CBP to modulate its transcriptional activity. Under hypoxic conditions, HIF-1 eventually acts as a master regulator of numerous hypoxia-inducible genes. The target genes of HIF-1 are especially related to angiogenesis, cell proliferation and survival, and to glucose and iron metabolism. Moreover, it was reported that the activation of HIF-1alpha is closely associated with a variety of tumors and oncogenic pathways. Hence, the blocking of HIF-1alpha itself or the blocking of HIF-1alpha interacting proteins inhibits tumor growth. Based on these findings, HIF-1 can be a prime target for anticancer therapies. Therefore, this review summarizes the molecular mechanism of HIF-1alpha stability, the biological functions of HIF-1 and its potential applications for cancer therapies.
Acetylation ; Anoxia ; Cell Proliferation ; Genes, Tumor Suppressor ; Glucose ; Hydroxylation ; Iron ; Lysine ; Metabolism ; Oxygen ; Phosphorylation ; Protein Processing, Post-Translational ; Transcription Factors

No abstract available.
Chemoradiotherapy* ; Rectal Neoplasms*

FA (Fanconi's Anemia) is an autosomal recessive disorder that is characterized by pancytopenia with bone marrow hypoplasia, diverse congenital abnormalities and an increased predisposition towards malignancy. The mainstay of the treatment for these cancers has been surgery, because of the hypersensitive reactions of FA patients to DNA cross- linking agents or radiation. Therefore, there has been no effective therapy for advanced squa mous cell carcinoma. We report here on a patient suffering from advanced multiple squamous cell carcinoma and hepatocellular carcinoma along with an FA, and this patient was treated with gefitinib.
Bone Marrow ; Carcinoma, Hepatocellular* ; Carcinoma, Squamous Cell* ; Congenital Abnormalities ; DNA ; Fanconi Anemia* ; Humans ; Pancytopenia

We have experienced three cases of extramammary Paget's disease (EMPD) of the vulva that received radiation therapy (RT). Here, we analyze the efficacy of RT and include a literature survey. Three patients with EMPD of the vulva were treated with curative RT between 1993 and 1998. One of the patients had associated underlying adenocarcinoma of the vulva. The total doses of radiation administered were 54~78 Gy/6~8 weeks. Radiation fields encompassed 2 to 3 cm outer margins free from all visible disease including or not including the inguinal area using a 9 MeV electron or a 6 MV photon beam. Follow-up durations after radiotherapy were 0.6~11 years. Complete response was obtained in all three patients. Marginal failure occurred in one patient, and another patient with underlying adenocarcinoma treated by vulvectomy with bilateral inguinal lymph node dissection followed by external RT showed no relapse. Radiation induced side effects were transient acute confluent wet desquamation in the treated area resulting in mild late atrophic skin changes. Although surgery is currently considered the preferred primary treatment for EMPD, it has a high relapse rate due to the multifocal nature of the disease. We conclude that RT is of benefit in some selected cases of EMPD.
Adenocarcinoma ; Follow-Up Studies ; Humans ; Lymph Node Excision ; Paget Disease, Extramammary* ; Radiotherapy ; Recurrence ; Skin ; Vulva*

PURPOSE: The metastatic tumor antigen (MTA) gene is a recently identified metastasis-associated gene which has implications in the signal transduction or regulation of gene expression. However, the expression of MTA in osteosarcoma and its potential relationship with metastasis have not been examined, forming the basis of this study. MATERIALS AND METHODS: We compared the expression levels of the MTA1 protein between 32 cases of high- grade osteosarcomas and 21 cases of low-grade osteosarcomas by immunohistochemistry. In addition, the mRNA expression levels of MTA1, 2, 3 in these osteosarcoma cell lines and control fibroblasts were evaluated by real-time quantitative PCR. RESULTS: MTA1 immunoreactivity was present in 81.25% of high-grade osteosarcoma specimens. Its expression was predominantly localized to the nucleus or cytoplasm of osteosarcoma cells. Thirteen (86.6%) of 15 patients who died of osteosarcomas displayed strong MTA1 expression. Both primary bone and pulmonary metastatic lesions exhibited MTA1 expression. All low- grade osteosarcomas were negative for MTA1 except for focal weak reactivity in two cases. The tested high-grade osteosarcoma cell lines showed marked amplification of MTA1 and MTA2 mRNA compared to control cells. CONCLUSION: These results suggest that MTA might be involved in the progression of high-grade osteosarcoma, particularly in hematogenous metastasis of osteosarcoma.
Cell Line ; Cytoplasm ; Fibroblasts ; Gene Expression Regulation ; Humans ; Immunohistochemistry ; Neoplasm Metastasis ; Osteosarcoma* ; Polymerase Chain Reaction ; RNA, Messenger ; Signal Transduction ; Pemetrexed

PURPOSE: The matrix metalloproteinases (MMPs) are a family of proteolytic enzymes. MMPs are known to be involved in tumor invasion, and several have been implicated in tumor prognosis. The aim of this study was to evaluate the prognostic significances of the expressions of MMP-7 and -9 in rectal cancer. MATERIALS AND METHODS: The tumor tissues of 87 patients with stage II or III rectal carcinoma that underwent potentially curative resection followed by postoperative adjuvant chemoradiation and 5-fluorouracil based chemotherapy, were investigated immunohistochemically using monoclonal antibodies against MMP-7 and MMP-9. Clinical information, including tumor grades, carcinoembryonic antigen (CEA) levels, and disease-free survival and overall survival were evaluated with respect to the expressions of MMP-7 and -9. RESULTS: Median follow-up duration was 53.2 months, and median patient age was 55+/-11 years (range 32~75). MMP-7 expression in tumor tissue was found to be significantly correlated with the presence of nodal metastasis (p=0.029), whilst MMP-9 expression correlated with depth of tumor invasion (p=0.019). No relatio- nships were found between the expressions of MMP-7 or -9 and age, sex, tumor size, tumor grade, or CEA level. Univariate analysis showed that MMP-7 expression was associated with poor 5-year overall survival (12.8 months vs. 65.3 months, p=0.0405). Multivariate analysis confirmed that MMP-7 was independently associated with an adverse outcome (Relative risk: 1.415, p=0.027). However, MMP-9 expression was not found to be related to clinical outcome. CONCLUSION: MMP-7 expression in tumor tissue is associated with lymph node metastasis and a poor 5-year overall survival in rectal cancer patients.
Antibodies, Monoclonal ; Carcinoembryonic Antigen ; Disease-Free Survival ; Drug Therapy ; Fluorouracil ; Follow-Up Studies ; Humans ; Immunohistochemistry ; Lymph Nodes ; Matrix Metalloproteinase 7* ; Matrix Metalloproteinases ; Multivariate Analysis ; Neoplasm Metastasis ; Peptide Hydrolases ; Prognosis ; Rectal Neoplasms*

PURPOSE: We conducted a multi-center, phase II trial to evaluate the efficacy and safety of using Padexol (a paclitaxel formulation) combined with cisplatin for the patients suffering with advanced gastric adenocarcinoma. MATERIALS AND METHODS: 39 patients (median age: 60 years; males: 90%) who were diagnosed with advanced gastric cancer were enrolled from 5 hospitals. Padexol 175 mg/m2 was administered as a 3-hr infusion, and this was followed by cisplatin 75 mg/m2 as an intravenous infusion on day 1, once every 3 weeks. RESULTS: Out of these 39 patients, 34 patients were assessable for treatment efficacy and 39 patients were assessable for the toxicity. Objective responses occurred in 13 patients (33%); 1 patient (3%) had a complete response and 12 patients (31%) had partial responses. 6 patients (15%) achieved a stable disease state. The median duration of response was 7.1 months, and the median time to progression and the overall survival were 4.8 months and 6.7 months, respectively. The major treatment-related adverse events were hematologic toxicity, including WHO grade 3 or 4 neutropenia in 13 patients (33%). However, febrile neutropenia occurred in only 1 patient and the non-hematologic toxicity was usually mild. CONCLUSION: The combination of Padexol and cisplatin was found to be active and it seems to be a relatively well-tolerated regimen for the treatment of advanced gastric cancer.
Adenocarcinoma ; Cisplatin* ; Febrile Neutropenia ; Humans ; Infusions, Intravenous ; Male ; Neutropenia ; Paclitaxel ; Stomach Neoplasms* ; Treatment Outcome

PURPOSE: Breast-conserving therapy (BCT) is a practical alternative to mastectomy for treating ductal carcinoma in situ (DCIS). We reviewed our experience for treating patients with DCIS of the breast to evaluate the outcome after performing breast-conserving surgery plus radiotherapy (BCS-RT). MATERIALS AND METHODS: Between January 1983 and December 2002, 25 patients with clinically or mammographically detected DCIS were treated by BCS-RT. One patient was diagnosed with bilateral DCIS. Thirteen cases (50%) had symptomatic lesions at presentation. All 26 cases of 25 patients underwent BCS such as lumpectomy, partial mastectomy or quadrantectomy. All of them received whole breast irradiation to a median dose of 50.4 Gy. Twenty-four cases (92.3%) received a boost to the tumor bed for a median total dose of 59.4 Gy. The median follow up period was 67 months (range: 38 to 149 months). RESULTS: Two cases (7.7%) experienced ipsilateral breast tumor recurrence (IBTR) after BCS-RT. The histology results at the time of IBTR showed invasive ductal carcinoma (IDC), and the median time to IBTR was 25.5 months. On the univariate analysis, there were no significant factors associated with IBTR in the DCIS patients. The three-year local recurrence free survival rate was 96.0% and the overall survival rate was 96.3%. CONCLUSION: After the treatment for DCIS, the IBTR rate in our study was similar to other previous studies. Considering that we included patients who had many symptomatic lesions, close or positive margins and less that complete early data, our result is comparable to the previous studies. We could not find the prognostic significant factors associated with IBTR after BCS-RT. A longer follow up period with more patients would be required to evaluate the role of any predictive factors and to confirm these short-term results.
Breast Neoplasms ; Breast* ; Carcinoma, Ductal* ; Carcinoma, Intraductal, Noninfiltrating* ; Follow-Up Studies ; Humans ; Mastectomy ; Mastectomy, Segmental* ; Radiotherapy* ; Recurrence ; Survival Rate

PURPOSE: When used in the second-line setting, single- agent chemotherapy has produced response rates of more than 10% or median survival times greater than 4 months. We studied the safety and efficacy of using second-line single docetaxel (75 mg/m2) for advanced NSCLC patients who were previously treated with platinum-based chemotherapy in Korea. MATERIALS AND METHODS: Thirty-three patients with advanced NSCLC received chemotherapy from May 2002 to January 2005. We retrospectively reviewed the charts of these patients. The patients received 75 mg/m2 of doxetaxel on day 1 and this was repeated at 3-week intervals. RESULTS: The median age was 63 years (range: 42~77 years); 16 patients had adenocarcinoma and 8 patients had squamous cell carcinoma. The median number of cycles was 4 (range: 1~7 cycles). Of the 33 patients, 6 patients had partial responses, 13 patients had stable disease and 14 patients had progressive disease. The response rate was 18.2%. The median overall survival was 11 months (range: 7~15 months), and the median progression free survival was 5 months (range: 3~7 months). The median response duration was 5 months (range: 4~9 months). A total of 137 cycles were evaluated for toxicity. We observed grade 3 or 4 neutropenia in 79 cycles (57.6%), grade 3 or 4 leukopenia in 46 cycles (33.6%), and grade 3 febrile neutropenia in 2 cycles (1.5%). The median nadir day was day 9 (range: day 5~19), and the median number of G-CSF injections was 2 (range: 0~6). The most common non-hematologic toxicities were myalgia/arthralgia and neurotoxicity, but any grade 3 or 4 non-hematologic toxicity was not observed. The major toxicity of this therapy was neutropenia. The absolute neutrophil count decreased relatively rapidly, but neutropenic fever or related infection was rare. There were no treatment-related deaths. CONCLUSION: These results revealed a satisfactory response rate (18.2%) with using docetaxel as the second- line chemotherapy for NSCLC. The second-line docetaxel was an active and well-tolerated regimen in patients with advanced NSCLC pretreated with platinum-based chemotherapy.
Adenocarcinoma ; Carcinoma, Non-Small-Cell Lung* ; Carcinoma, Squamous Cell ; Disease-Free Survival ; Drug Therapy* ; Febrile Neutropenia ; Fever ; Granulocyte Colony-Stimulating Factor ; Humans ; Korea ; Leukopenia ; Neutropenia ; Neutrophils ; Retrospective Studies

PURPOSE: The novel heat shock protein tumor necrosis factor receptor-associated protein 1 (TRAP1) is associated with multidrug resistance in colorectal cancer (CRC) cells in vitro. Excision repair cross-complementation group 1 (ERCC1) expression levels in tumor tissues also predict clinical outcomes in metastatic CRC patients receiving combination oxaliplatin and 5-fluorouracil treatment. We investigated whether TRAP1 and ERCC1 protein expression by immunohistochemistry predict clinical outcomes in CRC patients. MATERIALS AND METHODS: The study population consisted of 56 patients with metastatic CRC who received first-line oxaliplatin/5-fluorouracil therapy. Clinical response and overall survival (OS) by levels of the markers TRAP1 and ERCC1 were evaluated. RESULTS: The rates of TRAP1 and ERCC1 expression were 21% and 52%, respectively. Patients negative for ERCC1 expression showed a tendency to respond to chemotherapy (p=0.066). Median OS was significantly longer in patients negative for TRAP1 than those positive for TRAP1 (p=0.023). Patients negative for ERCC1 expression also had a better OS than those positive for ERCC1 (p=0.021). The median OS was 30.9 months for patients negative for TRAP1 and ERCC1 compared to 13.2 months for those positive for TRAP1 and/or positive for ERCC1 expression (p=0.006). The combination of TRAP1 and ERCC1 expression was significantly associated with the response to chemotherapy (p=0.046) and independently predicted median OS in multivariate analysis (hazard ratio, 2.98; 95% confidence interval, 1.18 to 7.49). CONCLUSION: The present study demonstrates that the combination of TRAP1 and ERCC1 expression predicts the survival of metastatic CRC patients who were treated with oxaliplatin/5-fluorouracil.
Colorectal Neoplasms* ; DNA Repair ; Drug Resistance, Multiple ; Drug Therapy ; Fluorouracil ; Heat-Shock Proteins ; Humans ; Immunohistochemistry ; Multivariate Analysis ; Tumor Necrosis Factor-alpha