This research is to estimate the toxicity of Atractylodis Rhizoma Alba (ARA) in F344 rats and to find a dose level for the 13 weeks toxicity study. A hot water extract of ARA (ARWE) was administered orally to F344 rats at dose levels of 0 (vehicle control), 500, 1000, 2000, 3500, and 5000 mg/kg/day for 2 weeks. Each group was composed to five male and five female F344 rats. According to the result, there were no ARWE-related adverse changes in mortality, body weights, food consumption, urinalysis, hematology, clinical chemistry, gross finding at necropsy, and organ weight examination. Salivation was observed in 3500 and 5000 mg/kg/day in male and female rats but it could not have found any relationship with ARWE administration. Based on our findings, ARWE may not cause toxicity in rats under the experimental conditions. Therefore, dose level of 5000 mg/kg/day as a highest treatment group in 13-week exposure study is recommended for further toxicity assessment.
Animals ; Body Weight ; Chemistry, Clinical ; Female ; Hematology ; Humans ; Male ; Mortality ; Organ Size ; Rats ; Rats, Inbred F344* ; Salivation ; Toxicity Tests ; Urinalysis ; Water

The objective of this study is to characterize a toxicity of Epimedii Herba (EH) in F344 rats and to find a dose levels for the 13 weeks toxicity study. EH is well known as medicinal herb in many Asian countries for traditional medicines of antibacterial and antiviral effects, estrogenic and antiestrogenic effects, and for treatment of osteoporosis, hypotensives, fatigue, kidney disorders, and related complications. However, the indispensable and basic information of toxicological evaluation of EH extract is insufficient to support its safe use. Therefore, we conducted toxicological evaluation of this drug in compliance with OECD and MFDS guideline in this study. The extract of EH was administered orally to F344 rats at dose levels of 0, 500, 1000, 2000, 3500, and 5000 mg/kg/day for 2 weeks. Each group was composed of 5 male and female rats. In this study, there were no treatment of EH-related adverse changes in clinical observations, mortality, body weights, food consumption, urinalysis, gross finding at necropsy, and organ weight examination. Total red blood cell count, hematocrit, mean corpuscular hemoglobin concentration, total cholesterol, and phospholipid were decreased in males and females at 5000 mg/kg/day compared to the control animals. Mean corpuscular volume and reticulocyte counts were increased in males and females at 5000 mg/kg/day compared to control animals. Therefore, we recommend that dose level of 5000 mg/kg/day is a highest treatment group in 13-week EH extract exposure study for further toxicity assessment.
Animals ; Asian Continental Ancestry Group ; Berberidaceae ; Body Weight ; Cholesterol ; Compliance ; Erythrocyte Count ; Erythrocyte Indices ; Estrogen Receptor Modulators ; Estrogens ; Fatigue ; Female ; Hematocrit ; Humans ; Kidney ; Male ; Mortality ; Organ Size ; Osteoporosis ; Plants, Medicinal ; Rats ; Rats, Inbred F344* ; Reticulocyte Count ; Toxicity Tests ; Urinalysis

PURPOSE: Leptomeningeal carcinomatosis occurs in about 5% of patients with solid tumor and is being diagnosed with increasing frequency as patients live longer and as neuro-imaging studies improve. In general, the most commom cancers that involved the leptomeninges are breast cancer, lung cancer, and malignant melanoma. MATERIALS AND METHODS: We investigated 25 patients presented with multiple neurologic symptoms and signs who were diagnosed with leptomeningeal carcinomatosis at the Yonsei Cancer Center from January 1990 to December 1999. RESULTS: The primary disease of leptomeningeal carcinomatosis were stomach cancer (10 cases), breast cancer (7 cases), lung cancer (5 cases), unknown primary cancer (2 cases) and common bile duct cancer (1 case). All patients were presented with multiple neurologic symptoms and signs involving the central nervous system (CNS), cranial nerve or spinal nerves. Twenty-one of twenty- five patients were treated with intrathecal chemotherapy, radiotherapy, or combination therapy. Fourteen of them (66.7%) experienced improvement or stabilization of neurologic symptom and sign. The median survival was 122 days (10-2190). CONCLUSION: In conclusion, although early diagnosis and active treatment of leptomeningeal carcinomatosis may improve the quality of life in selected patients, the median survival was relatively short. Therefore, new diagnostic and therapeutic strategy for leptomeningeal carcinomatosis were needed.
Breast Neoplasms ; Central Nervous System ; Common Bile Duct ; Cranial Nerves ; Drug Therapy ; Early Diagnosis ; Humans ; Lung Neoplasms ; Melanoma ; Meningeal Carcinomatosis* ; Neurologic Manifestations ; Quality of Life ; Radiotherapy ; Spinal Nerves ; Stomach Neoplasms

PURPOSE: To overcome the limitations of cancer gene therapy using replication-incom- petent adenovirus, we generated E1B 55 kD-deleted adenovirus (YKL-1) by polymerase chain reaction (PCR) and homologous recombination. We then investigated tumor-specific virus replication and cytotoxicity of YKL-1 in vitro and in vivo. MATERIALS AND METHODS: YKL-1 was constructed by reintroducting E1A and E1B 19 kD into pTG-CMV El/E3-deficient adenoviral vector and inducing homologous recombination in E. coli. The recombinant vector pYKL-1 was transfected into 293 cells to generate YKL-1. The properties of newly constructed YKL-1 was defined by PCR and immuno- blotting analysis. Virus replication was examined by infecting human normal and cancer cells on 6-wells at multiplicity of infection (MOI) of 10 for 3 days. Virus was then recovered and titered. Cytopathic effect was analyzed by infecting human normal and cancer cells on 24-wells at MOIs of 10, 1 or 0.1 for 7 to 10 days and staining them with crystal violet solution. Inhibition of tumor growth was examined in human cancer cell xenografts in nu/nu mice by intratumoral injection of YKL-l. RESULTS: PCR and immunoblotting analysis confirmed that YKL-1 contained E1A and E1B 19 kD but not E1B 55 kD. In human normal cells, virus replication and subsequent cytopathic effect of E1B 55 kD-deleted adenovirus YKL-1 was markedly attenuated by larger than 2 to 3 log in magnitude, compared to that of wild-type ad-XJ. In contrast, YKL-1 was capable of replicating and inducing cytotoxicity i.n most human cancer cells. C33A and Hep3B containing p53 mutation were much more sensitive, whereas HeLa and H460 with wild type p53 were relatively resistant to YKL-1. Finally, the tumor growth was dramatically retarded by intratumoral injection of YKL-1 in C33A cervical cancer xenograft and the histology showed significant necrosis by intratumoral injection of YKL-1. CONCLUSION: The results here demonstrated the ability of preferential virus replication and cytotoxicity of ElB 55 kD-deleted adenovirus YKL-1 in human cancer cells. Therefore, these indicated a promising potential of YKL-1 as an antitumoral virus agent and a selective replication-competent virus vector.
Adenoviridae* ; Animals ; Genes, Neoplasm ; Genetic Therapy ; Gentian Violet ; Heterografts ; Homologous Recombination ; Humans ; Immunoblotting ; Mice ; Necrosis ; Polymerase Chain Reaction ; Uterine Cervical Neoplasms ; Virus Replication*

PURPOSE: Osteosarcoma is one of the most common juvenile malignant tumors in Korea. Combined modality treatment [pre-operative chemotherapy + surgery (limb salvage or amputation) + adjuvant chemotherapy] had improved the overall survival and quality of life. To improve the local control rate, we introduced pre-operative chemotherapy combined with intra-arterial (IA) cisplatin and continuous intravenous infusion (CI) of adriamycin. We evaluated the efficacy and feasibility, such as limb salvage rate, recurrence pattern and the survival impact, based on the histologic response of pre-operative chemotherapy. MATERIALS AND METHODS: Fourty-one patients with histologically-proven high grade osteosarcoma of the extremities were enrolled from January 1990 to June 1996. Pre-operative chemotherapy, cisplatin 120 mg/m2 IA and adriamycin 75 mg/m2/72hrs CI, was administered for 3 cycles with 3 week interval, followed by surgery. Post-operative chemotherapy was applied by the tumor necrosis rate. If the tumor necrosis of the specimen was more than 90%, the same regimen af the preoperative one was administered for 3 cycles. A salvage regimen (Ifosfamide 7.5 gm/m2/5d IV + high dose MTX 10 gm/m2 IV VP-16 360 mg/m2/3d IV) was administered every 3 weeks for 6 cycles if the tumor necrosis was <90%. RESULTS: Of 41 patients, 37 were evaluable for efficacy and toxicities, because 4 refused further chemotherapy after 1 or 2 cycles. Twenty-one patients were male and 16 female, with the median age of 16 years (8-41). The tumor locations were as follows: distal femur 20, proximal tibia 8, humerus 6, distal tibia 2 and 1 in proximal femur. All but one patient, who died of neutropenic sepsis, completed the planned pre-operative therapy. Of the 36 patients who received surgery, limb salvage surgery was possible in 30 patients (83.3%) and 27 patients (75%) showed a good response (10 with grade III, 27.8%; 17 with grade IV, 47.2%). With a median follow-up of 23 months, 3-year disease-free survival rate was 54.7% and overall survival rate was 78.3%. Of the 15 patients who recurred, the major metastatic site was the lungs. No operation-related mortality was observed. Most patients experienced grade III-IV nausea, vomiting and hematologic toxicities, which were reversible with supportive care. CONCLUSION: Pre-operative chemotherapy combined with IA cisplatin and CI adriamycin induced higher good response rate without survival benefits. To improve the survival rate, the design of good salvage chemotherapy with a non-cross resistant regimen should be considered.
Cisplatin* ; Disease-Free Survival ; Doxorubicin* ; Drug Therapy ; Etoposide ; Extremities ; Female ; Femur ; Follow-Up Studies ; Humans ; Humerus ; Infusions, Intravenous ; Korea ; Limb Salvage ; Lung ; Male ; Mortality ; Nausea ; Necrosis ; Osteosarcoma* ; Quality of Life ; Recurrence ; Sepsis ; Survival Rate ; Tibia ; Vomiting

PURPOSE: We determined the clinical significance of telomerase activity and telomere length in breast cancer patients and also developed the measuring system of telomerase activity change with RNAse A pre-treatment. MATERIALS AND METHODS: We measured the telomerase activity in 71 breast cancer tissues and paired normal tissues with TRAP (Telomeric Repeat Amplification Protocol) assay. Telomerase activity was calculated by computer-assisted densitometry compared to telomerase activity of the 293 control cell line. To develop the measuring system of telomerase activity modulation, we measured the telomerase activity after the treatment with RNAse A, 150microgram/ml, which inhibited 70% of telomerase activity compared to control in the 293 control cell line. In 59 paired tissues with telomerase activity, terminal restriction fragment (TRFs) length were measured using Southern blotting. RESULTS: Sixty-three out of 71 cancer tissues showed telomerase activity (88.7%), while no telomerase activity was detected in their paired normal tissues. Telomerase activity was correlated to the node metastasis (p=0.02) and stage (p=0.005), but not to the tumor size or the hormonal receptor status. TRFs were neither specific to tumor tissues nor related to any of the clinical parameters. However, changes of TRFs of the tumor tissues from their paired normal tissues were correlated to the telomerase activities. Also the patients with different TRFs between cancer and normal tissues were in more advanced stage. After pre-treatment with the 150microgram/ml of RNAse A, telomerase activity in the tumor tissues showed variable inhibition. Relative inhibition, the ratio of inhibited telomerase activity in each tumor tissue compared to the inhibition of 293 control cell line, was proportional to the telomerase activity. CONCLUSION: In breast cancer, telomerase activity was specific to the tumor tissues and correlated to tumor progression. A combination of telomerase activity and TRFs changes can be used as a guidline in detecting a better candidate for telomerase inhibition. Semi-quantitative assay with RI system can be used in evaluating the changes of telomerase activity after treatment with a new telomerase inhibitor with TRAP assay.
Biological Therapy* ; Blotting, Southern ; Breast Neoplasms* ; Breast* ; Cell Line ; Densitometry ; Humans ; Neoplasm Metastasis ; Ribonuclease, Pancreatic ; Telomerase* ; Telomere

PURPOSE: Transforming growth factor-Bs (TGF-Bs) are prototypic multifunctional negative growth factors that inhibit the growth of many cell types. TGF-B type I and II receptors(RI, RII) are transmembrane receptors containing cytoplasmic serine/ threonine kinase domain and have been implicated in mediating TGF-B activity. Because a heteromeric complex of RI and RII is required for TGF-B signal transduction, cancer cells may reduce the expression of either RI or RII to escape from growth inhibition of TGF-B. We examined the correlation between the growth inhibitory activity of TGF-B1 and the genetic expression of RI &RII genes in human breast cancer cell lines. MATERIALS AND METHODS: We examined the growth inhibitory activity of TGF-B1 in 5 breast cancer cell lines by incorporation of [3H] thymidine. To investigate the correlation between TGF-B1 insensitivity and genetic change of TGF-B receptor genes (RI, RII), Southem blot analysis, Northern blot analysis, and Western blot analysis were performed. We also examined whether microsatellite instability(RER) was associated with RII mutation. RESULTS: We found that 3 breast cancer cell lines (MCF-7, YCC-B101, YCC-B151) were resistant to growth inhibitory effect of TGF-B1. MCF-7 cell line expressed no detectable RII mRNA and RII protein, but showed normal structure of RII gene and normal expression of RI gene. And we did not find any abnormal expression of mRNA, protein, and genetic structure of RI &RII in YCC-B101 and YCC-B151. CONCLUSION: Our results suggest that aquired resistance to the growth inhibitory effect of TGF-B1> could be transcription regulation system of RII in MCF-7 cell line, and could be postreceptor signal transduction pathway in YCC-B101 and YCC-B151 cell lines.
Blotting, Northern ; Blotting, Western ; Breast Neoplasms* ; Breast* ; Cell Line ; Cytoplasm ; Genetic Structures ; Humans* ; Intercellular Signaling Peptides and Proteins ; MCF-7 Cells ; Microsatellite Repeats ; Negotiating ; Protein-Serine-Threonine Kinases ; RNA, Messenger ; Signal Transduction ; Thymidine ; United Nations

PURPOSE: Gastric cancer is the most common malignancy in Korea. Although treatment such as surgery, chemotherapy, and immunotherapy has greatly improved, the mortality rate of gastic cancer is still high, A new therapeutic trial is necessary to improve the cure rate of gastric cancer. Therefore we investigated the pre-clinical significance of HSV-tk gene therapy using retroviral vector for gastric cancer cell lines. MATERIALS AND METHODS: LNC/HSV-tk retroviral vector and PA317/LNC/HSV-tk producer cell line were constructed. HSV-tk gene transduction and expression were detected by PCR. An in vitro ganciclovir(GCV) sensitivity test was performed by MTT assay. To evaluate in vivo GCV sensitivity, GCV was intraperitoneally injected after tumor formation in the nude mice. Bystander effect was observed in vitro MTT assay using YCC- S-2 cell line and in vivo using N87 and YCC-S-2 cell lines. RESULTS: The in vitro GCV sensitivity test showed that the growth inhibition was 30~32% with 0.5 uM GCV and 52~77% with 500 uM GCV in the HSV-tk transduced cell line in comparison with 0- 5% with 0.5 and 500 uM GCV in the parent cell line. The in vivo GCV administration showed that the tumors induced by HSV-tk transduced N87 cell line and YCC-S-2 cell line decreased completely, while the tumors with the parent cell lines continued to grow in nude mice. We observed no tumor cells in tissue specimen of the tumor induced by the N87/HSV-tk cell line after. GCV administration. In vitro and in vivo bystander effects were observed in HSV-tk/GCV system due to the resultant cell death exceeding the proportion of HSV-tk transduced cells in the mixtures of HSV-tk transduced and parent cells. CONCLUSION: HSV-tk transduced gastric cancer cell lines showed sensitivity to GCV and a bystander effect was observed. These results suggested that HSV-tk/GCV system should be evaluated in the clinical settings.
Animals ; Bystander Effect ; Cell Death ; Cell Line* ; Drug Therapy ; Ganciclovir* ; Genetic Therapy ; Herpes Simplex* ; Humans ; Immunotherapy ; Korea ; Mice ; Mice, Nude ; Mortality ; Parents ; Polymerase Chain Reaction ; Stomach Neoplasms* ; Thymidine Kinase* ; Thymidine* ; Zidovudine

We report a case of synchronous gastric adenocarcinoma and abdominal non-Hodgkin's lymphoma in a 56-year-old man. An explo-laparotomy was performed for the purpose of palliative resection of the stomach and to evaluate the nature of splenic and peri-pancreatic mass lesions. The pathologic stage of the gastric carcinoma was stage IB (T2N0M0) and the clinical stage of the diffuse large cell type lymphoma was IIA2S. Following surgery and chemotherapy, the patient is now in a disease-free state.
Abdominal Neoplasms/pathology ; Abdominal Neoplasms/diagnosis* ; Adenocarcinoma/pathology ; Adenocarcinoma/diagnosis* ; Case Report ; Human ; Lymphoma, Non-Hodgkin/pathology ; Lymphoma, Non-Hodgkin/diagnosis* ; Male ; Middle Age ; Neoplasm Staging ; Neoplasms, Multiple Primary/pathology ; Neoplasms, Multiple Primary/diagnosis* ; Stomach Neoplasms/pathology ; Stomach Neoplasms/diagnosis* ; Tomography, X-Ray Computed

Soluble forms of ICAM-1 (sICAM-1) and VCAM-1 (sVCAM-1) have been reported from the supernatant of cytokine-activated endothelial cells, cancer cells and from sera of cancer patients. We measured sICAM-1 and sVCAM-1 from the serum of 20 healthy volunteers and 142 gastric cancer patients by ELISA assay. Ninety-five patients were operable and 47 patients were in-operable at the time of this study. Particularly in the 28 operable patients, we sampled both portal and peripheral blood simultaneously and measured the levels of the soluble forms of cell adhesion molecules (sCAMs). The sCAMs level and sero-positivity rate increased with cancer progression in order of the healthy controls, operable patients, and inoperable patients. In in-operable cancer, the sICAM-1 level increased more with liver metastasis. sICAM-1 and sVCAM-1 did not correlate with each other in either portal or peripheral blood. A total of 58.3% of patients with liver metastasis and 22.9% of patients without liver metastasis showed synchronous expression of both sCAMs (p = 0.03). Synchronous sero-positivity of sCAMs and alpha FP was higher with liver metastasis (p = 0.01). The median overall survival duration which co-expressed both sCAMs was 9 months. This showed a significant difference compared with the sICAMs non-expressing group, where the median survival was not reached until 24 months follow-up (p = 0.002). The synchronous expression of sCAMs was an independent risk factor in gastric cancer patients. We raise the possibility that synchronous sICAM-1 and sVCAM-1 elevation may be a useful monitor to determine tumor burden in gastric cancer.
Adult ; Aged ; Female ; Human ; Intercellular Adhesion Molecule-1/blood* ; Liver Neoplasms/secondary ; Male ; Middle Age ; Stomach Neoplasms/mortality ; Stomach Neoplasms/blood* ; Survival Rate ; Vascular Cell Adhesion Molecule-1/blood*