• Tuberculosis and Respiratory Diseases
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• v.49 no.1
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• pp.60-71
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• 2000

Backgrounds : Cathepsin D, an aspartic lysosomal proteinase, is believed to be involved in local invasion and metastasis of tumor cells by its proteolytic activity and has been described to be associated with tumor progression and prognosis in some human malignancies including breast cancer. But, its prognostic value for human lung cancer remains to be determined. The purpose of this study is to determine clinicopathological and prognostic significance of cathepsin D expression in non-small cell lung cancer. Method : Using a polyclonal antibody, immunohistochemical analysis of cathepsin D was performed on paraffin embedded sections of tumors obtained surgically from 54 patients with non-small cell lung cancer (37 squamous cell carcinoma, 14 adenocarcinoma, 2 large cell carcinoma, and 1 undifferentiated carcinoma). Results : Eighteen patients (33.3%) showed positive immunoreactivities of cathepsin D in tumor cells. No significant correlation of cathepsin D expression in tumor cells was found in p-stage (surgical-pathologic stage), tumor size, tumor factor, nodal involvement, and differentiation. Of 54 patients, 29 (53.7%) patients showed moderate to massive cathepsin D-positive stromal cells within the tumor tissues, while the rest (46.3%) showed few cathepsin D-positive stromal cells within the tumor tissues. Cathepsin D expression in stromal cells was significantly associated with p-stage in non-small cell lung canær (p=0.031). No significant correlation of the degree of cathepsin D-positive stromal cells was found in tumor size, T -factor, nodal involvement, differentiation Cathepsin D expression status in tumor cells and stromal cells was not significantly associated with prognosis expressed by survival rate. The results of multivariate analyses of variables possibly associated with prognosis showed that nodal involvement was the only independent prognostic factor in all patients. Conclusion : Cathepsin D expression in stromal cells was significantly associated with p-stage in non-small cell lung cancer. However, it was not related to other clinicopathologic features and prognosis, and Cathepsin D expression in tumor was not related to p-stage and prognosis.

• Nuclear Medicine and Molecular Imaging
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• v.41 no.4
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• pp.326-334
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• 2007

Purpose: The estrogen receptor (ER), which is over-expressed in ER-positive breast tumors, has been imaged by positron emission tomography (PET) using $[^{18}F]$ labeled estrogen ligands, especially $[^{18}F]FES$. However, $[^{18}F]$ has relatively short-lived half-life ($t_{1/2}$ =1.8 h) and the labeling yield of radio-fluorination is usually low compared with $^{64}Cu\;(t_{1/2}=12.7\;h)$. 1,4,7,10-tetraazacyclododecane (cyclen) is used to form stable metal complexes with copper, indium, gallium, and gadolinium. With these in mind, we prepared cyclen-based Cu complexes which mimic estradiol in aspect of two hydroxyl groups. Materials and Methods: 1.7-Protected cyclen, 1.7-bis (benzyloxycarbonyl)-cyclen was synthesized according to the reported procedure. After introducing two 4-benzyloxybenzyl groups at 4,10-positions, the benzyloxycarbonyl and benzyl groups were removed at the same time by hydrogenation on Pd/C to give 1,7-bis(4-hydroxybenzyl)-1,4,7,10-tetraazacyclododecane (1). Results: The prepared ligand 1 was fully characterized by $^1H,\;^{13}C$ NMR, and mass spectrometer. The synthesized ligand was reacted with copper chloride and copper perchlorate to give copper complexes $[Cu(1)]^{2+}2(CIO_4^-)\;and\;[Cu(1)Cl]^+Cl^-$ which were confirmed by high-resolution mass (FAB). Conclusion: We successfully synthesized a cyclen derivative of which two phenol groups are located on trans position of N-atoms. And, two Cu(ll) complexes of +2 and +1 overall charge, were prepared as a potential PET tracers for ER imaging.

• Tuberculosis and Respiratory Diseases
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• v.47 no.3
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• pp.331-338
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• 1999

Background: Nearly 10% of cancer patients will develop a second primary cancer within ten years after surgical removal of the primary tumor. The detection of risk factors for developing multiple primary tumors would be important This study was conducted to evaluate the clinical characteristics and abnormal p53 expression of lung cancer associated with multiple primary cancer(MPC). Method: Clinical characteristics and abnormal p53 expression were compared between 20 cases of lung cancer(NSCLC ; 16 cases, SCLC ; 4 cases) associated with MPC and 26 cases of primary non-small cell lung cancer. Result: MPC associated with lung cancer was gastric cancer(8), lung cancer(2), esophageal cancer(2), colon cancer(2), laryngeal cancer(1), bladder cancer(1), small bowel cancer(l), adrenal cancer(1), hepatocellular carcinoma(1), and breast cancer (1) in order. The clinical stage of primary NSCLC was relatively advanced, but NSCLC associated with MPC was even distribution at each stage. The detected incidences of abnormal p53 expressions were 62.5% in NSCLC associated with MPC and 76.9% in primary NSCLC(p>0.05). Conclusion: There was no difference in abnormal p53 expression between non-small cell carcinoma associated with multiple primary cancer and primary non-small cell carcinoma.

• The Journal of the Korean bone and joint tumor society
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• v.4 no.1
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• pp.13-21
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• 1998

Taxol, the extract from the Taxus brevifolia which is a Pacific yew tree has aroused the interest of the tumor investigators since the 1960s. As well, it is shown to have broad antitumor activity in preclinical experimental models. Its action mechanism is an anti-microtubule effect by duplication of tubulin. The most impressive antitumor activity of taxol has been observed in advanced ovarian cancer and metastatic breast cancer. The purpose of this study was to determine how taxol acts on malignant bone tumor cell lines, to compare its cytotoxic effect with those of other chemotherapeutic agents, and to ascertain the its combination effect with adriamycin. Cell lines used in this study were G-292(osteosarcoma, human), SaOS-2(osteosarcoma, primary, human), and HT-1080(fibrosarcoma, human). Methotrexate, adriamycin, cisplatinum, ifosfamide and taxol were used as testing chemotherapeutic agents and their maximum test concentration were $500{\mu}g/ml$, $200{\mu}g/ml$, $500{\mu}g/ml$, $1000{\mu}g/ml$, and $600{\mu}g/ml$, respectively. The media for cell culture was RPMI-1640 with 10% fetal bovine serum and gentamycin. The results were as follows. The $IC_{50}$ of methotrexate, ifosfamide, cisplatinum, adriamycin and Taxol in G-292 were $2.3{\times}10^{-1}{\mu}g/ml$, $8.0{\times}10^0{\mu}g/ml$, $3.5{\times}10^0{\mu}g/ml$, $9.8{\times}10^{-1}{\mu}g/ml$, $2.7{\times}10^{-2}{\mu}g/ml$ respectively, in SaOS-2 $3.5{\times}10^{-1}{\mu}g/ml$, $1.5{\times}10^1{\mu}g/ml$, $2.8{\times}10^0{\mu}g/ml$, $9.9{\times}10^{-2}{\mu}g/ml$, $1.0{\times}10^{-2}{\mu}g/ml$, respectively, in HT-1080 $4.2{\times}10^{-2}{\mu}g/ml$, $5.4{\times}10^1{\mu}g/ml$, $3.8{\times}10^0{\mu}g/ml$, $5.5{\times}10^{-3}{\mu}g/ml$, $1.1{\times}10^{-3}{\mu}g/ml$, respectively. In conclusion, taxol had very potent cytotoxic effect on the malignant bone tumor cell lines with adriamycin, and was more potent than methotrexate, cisplatinum and ifosfamide. There were synergistic antitumor effects on G-292 and SaOS-2 cell lines in combination test of taxol and adriamycin. From the above results, it would be estimated that taxol could be a new antitumor drug for the malignant bone tumors, providing measures against the side effects and followed by the clinical tests.

• Tuberculosis and Respiratory Diseases
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• v.41 no.4
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• pp.339-353
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• 1994

Background : The p53 gene codes for a DNA-binding nuclear phosphoprotein that appears to inhibit the progression of cells from the G1 to the S phase of the cell cycle. Mutations of the p53 gene are common in a wide variety of human cancers, including lung cancer. In lung cancers, point mutations of the p53 gene have been found in all histological types including approximately 45% of resected NSCLC and even more frequently in SCLC specimens. Mutant forms of the p53 protein have transforming activity and interfere with the cell-cycle regulatory function of the wild-type protein. The majority of p53 gene mutations produce proteins with altered conformation and prolonged half life; these mutant proteins accumulate in the cell nucleus and can be detected by immunohistochemical staining. But protein overexpression has been reported in the absence of mutation. p53 protein overexpression or gene mutation is reported poor prognostic factor in breast cancer, but in lung cancer, its prognostic significance is controversial. Method : We investigated the p53 abnormalities by nucleotide sequencing, polymerase chain reaction-single strand conformation polymorphism(PCR-SSCP), and immunohistochemical staining. We correlated these results with each other and survival in 75 patients with NSCLC resected with curative intent. Overexpression of the p53 protein was studied immunohistochemically in archival paraffin- embedded tumor samples using the D07(Novocastra, U.K.) antibody. Overexpression of p53 protein was defined by the nuclear staining of greater than 25% immunopositive cells in tumors. Detection of p53 gene mutation was done by PCR-SSCP and nucleotide sequencing from the exon 5-9 of p53 gene. Result: 1) Of the 75 patients, 36%(27/75) showed p53 overexpression by immunohistochemical stain. There was no survival difference between positive and negative p53 immunostaining(overall median survival of 26 months, disease free median survival of 13 months in both groups). 2) By PCR-SSCP, 27.6%(16/58) of the patients showed mobility shift. There was no significant difference in survival according to mobility shift(overall median survival of 27 in patients without mobility shift vs 20 months in patients with mobility shift, disease free median survival of 8 months vs 10 months respectively). 3) Nucleotide sequence was analysed from 29 patients, and 34.5%(10/29) had mutant p53 sequence. Patients with the presence of gene mutations showed tendency to shortened survival compared with the patients with no mutation(overall median survival of 22 vs 27 months, disease free median survival of 10 vs 20 months), but there was no statistical significance. 4) The sensitivity and specificity of immunostain based on PCR-SSCP was 67.0%, 74.0%, and that of the PCR-SSCP based on the nucleotide sequencing was 91.8%, 96.2% respectively. The concordance rate between the immunostain and PCR-SSCP was 62.5%, and the rate between the PCR-SSCP and nucleotide sequencing was 95.3%. Conclusion : In terms of detection of p53 gene mutation, PCR-SSCP was superior to immunostaining. p53 gene abnormalities either overexpression or mutation were not a significant prognostic factor in NSCLC patients resected with curative intent. However, patients with the mutated p53 gene showed the trends of early relapse.