Biomedical subjects

T S Kim

Publications and source records attributed to T S Kim.

At least 127 records · Page 7Linked to original sources

PubMed1999

Sulfasalazine prevents T-helper 1 immune response by suppressing interleukin-12 production in macrophages.

Interleukin-12 (IL-12) plays a pivotal role in the development of T-helper 1 (Th1) immune response, which may be involved in the pathogenesis of chronic inflammatory autoimmune disorders. In this study we investigated the effects of sulfasalazine, a drug for treating inflammatory bowel disease and rheumatoid arthritis, on the production of IL-12 from mouse macrophages stimulated with lipopolysaccharide (LPS). Sulfasalazine potently inhibited the production of IL-12 in a dose-dependent manner, in part through the down-regulation of nuclear factor kappaB (NFkappaB) activation in IL-12 p40 gene. Activation of macrophages by LPS resulted in markedly enhanced binding activities to the kappaB site, which significantly decreased upon addition of sulfasalazine as demonstrated by an electrophoretic gel shift assay. Importantly, macrophages pretreated with sulfasalazine either in vitro or in vivo reduced their ability to induce interferon-gamma (IFN-gamma) and increased the ability to induce IL-4 in antigen-primed CD4+ T cells. From these results, sulfasalazine may induce the Th2 cytokine profile in CD4+ T cells by suppressing IL-12 production in macrophages, and sulfasalazine-induced inhibition of IL-12 production in macrophages may explain some of the known biological effects of sulfasalazine.

Animals↗

PubMed1999

Absence of mRNA encoding estrogen receptor in the rat cochlea.

Based on changes in hearing thresholds and tinnitus that are co-related with the menstrual cycle, it has been suggested that the cochlea may respond directly to estrogen. For this to occur, the cochlea should express estrogen receptors. In situ mRNA hybridization was performed on normal female rat cochleas, using radiolabeled RNA probes complementary to mRNA encoding estrogen receptor, to determine whether estrogen receptors are present in the cochlea. Strong hybridization of the riboprobes to sections of uterus and hypothalamus indicated that the technique detected estrogen receptor mRNA. No hybridization to any cochlear tissues was observed. The results indicate that estrogen receptors are not expressed on cochlear cells, at least in rats. This in turn suggests that variation in cochlear responses during the estrus cycle are not the result of the direct effect of estrogen on the cochlea. Such variation may, however, be caused by systemic changes in fluid regulation induced by estrogen receptors at a distant site, or by other hormone receptors.

Animals↗

PubMed1999

Mucoepidermoid carcinoma of the tracheobronchial tree: radiographic and CT findings in 12 patients.

PURPOSE: To determine the radiographic and computed tomographic (CT) findings and clinical features of mucoepidermoid carcinoma of the tracheobronchial tree. MATERIALS AND METHODS: Chest radiographic and CT findings and clinical features of 12 histopathologically proved mucoepidermoid carcinomas in 12 consecutive patients (five male, seven female; age range, 9-72 years; mean age, 36 years) were reviewed retrospectively. RESULTS: The tumors were located at the distal trachea (n = 1) or at a main (n = 2), lobar (n = 1), or segmental (n = 8) bronchus. On chest radiographs, the tumors appeared as central masses with post-obstructive pneumonia or peripheral atelectasis in four patients and as solitary pulmonary or endotracheobronchial nodules in eight. At CT, the tumors were all smoothly oval (n = 6) or lobulated (n = 6) in shape (ranging 9-40 mm in diameter), adapting to the branching features of the airways. Punctate calcification within the tumor was seen in six patients. Neither metastasis nor recurrence was seen after the surgical resection (follow-up of 8-103 months; mean, 30 months). CONCLUSION: Mucoepidermoid carcinoma of the tracheobronchial tree, usually located in a segmental bronchus, appears at CT as a smoothly oval or lobulated airway mass. It adapts to the branching features of the airways.

Adolescent↗

PubMed1999

Cerebral infarction with ICA occlusion after Gamma Knife radiosurgery for pituitary adenoma: A case report.

Cranial irradiation may lead to accelerated atherosclerotic changes to small or medium sized arteries, but stroke associated with pituitary irradiation is not frequent. A patient treated with Gamma Knife radio-surgery (GKRS) for a pituitary adenoma suffered a cerebral infarction with internal carotid artery occlusion 4 years after radiosurgery. The patient was a 35-year-old male presenting with a visual disturbance. Endocrinological tests were normal. MRI revealed a 4.3 by 4.3 cm diameter invasive macroadenoma of the pituitary, projecting toward the suprasellar region and with cavernous sinus involvement with encasement of both internal carotid arteries (ICAs). GKRS was performed for residual tumor after a transcranial resection. The maximum dose was 40 Gy and the dose to the right carotid artery was below 20 Gy. The delayed hemiparesis was accompanied by a right capsular lacunar infarct shown on MRI. The images also showed a marked reduction in tumor size. Total, right ICA occlusion was confirmed by Doppler ultrasound. The patient had no history or signs of heart disease or metabolic disorder which could predispose to cerebrovascular

Adenoma↗

PubMed1999

Nonspecific interstitial pneumonia with fibrosis: serial high-resolution CT findings with functional correlation.

OBJECTIVE: We assessed serial changes in high-resolution CT findings and pulmonary function in patients with nonspecific interstitial pneumonia with fibrosis. MATERIALS AND METHODS: Serial high-resolution CT findings in 13 patients with biopsy-proven nonspecific interstitial pneumonia with fibrosis (mean follow-up period, 11 months) and pulmonary function tests (mean follow-up period, 11 months) were retrospectively analyzed. On CT, the presence and extent of ground-glass opacity, irregular linear opacity, honeycombing, and consolidation were assessed. RESULTS: On initial CT, all patients had areas of ground-glass opacity (mean +/- SD, 21.6% +/-14.4) and irregular linear opacity (5.0% +/- 5.2). The areas of ground-glass opacity decreased significantly on follow-up CT (13.5% +/- 10.5, p = .003). The areas of irregular linear opacity decreased slightly (4.2% +/- 5.2, p > .05). Initial forced vital capacity (69.4% +/- 16.0) improved significantly on follow-up examination (83.9% +/- 16.5) (p = .003). The decrease in the extent of ground-glass opacity on CT correlated significantly with changes in forced vital capacity (r = -.702, p = .007) and diffusing capacity for carbon monoxide (r = - .597, p = .031). CONCLUSION: In patients with nonspecific interstitial pneumonia with fibrosis, areas of ground-glass opacity decrease on follow-up high-resolution CT, and the extent of decrease correlates significantly with that of functional improvement.

Adult↗

PubMed1999

Correlation between expression of matrix metalloproteinase-2 (MMP-2), and matrix metalloproteinase-9 (MMP-9) and angiogenesis in colorectal adenocarcinoma.

Matrix metalloproteinases-2 (MMP-2) and matrix metalloproteinase-9 (MMP-9), which degrade extracellular matrix, are believed to play a crucial role in tumor invasion and metastasis. Angiogenesis is also perceived as an important step in tumor growth and metastasis. To investigate the expression of MMPs and the correlation between the expression of MMPs and angiogenesis in colorectal adenocarcinoma, we studied 72 cases of colorectal adenocarcinoma in Inha University Hospital from 1996 to 1997. We evaluated the expression of MMPs by immunohistochemistry and angiogenesis by counting the microvessels. The expression of MMP-2 was increased according to the Astler-Coller stage (p< 0.05). Angiogenesis in the metastatic group was higher than that of the localized one (p<0.05). The expression of MMP-2 positively correlated with angiogenesis (p<0.05), and marked expression of MMP-9 positively correlated with angiogenesis (p<0.05). The present results suggest that the expression of MMP-2 provides clues for tumor progression and angiogenesis provides significant information to predict whether metastasis is present in colorectal adenocarcinoma.

Adenocarcinoma↗

PubMed1999

Two new genotypes of Plasmodium vivax circumsporozoite protein found in the Republic of Korea.

The gene encoding Plasmodium vivax circumsporozoite protein (PvCSP) exhibits polymorphism in many geographical isolates. The present study was designed to investigate polymorphism in PvCSP gene of P. vivax isolates in Korea. Thirty isolates, obtained from indigenous cases in Yonchon-gun, Kyonggi-do in 1997, were subjected for sequencing and RFLP analysis of the repeat and post-repeat regions of PvCSP gene and two genotypes (SK-A and SK-B) were identified. The genotype of 19 isolates was SK-A and that of 11 isolates was SK-B. Although the number of 12-base repeats present in SK-A was three while two were found in a Chinese strain CH-5, the repeat sequence of SK-A was identical to that of CH-5 except for one base substitution. Compared with known data there was no identical isolates with SK-B, but the sequence of SK-B was similar to that of a North Korean (NK) isolate. These results indicate that two genotypes of PvCSP coexist in the present epidemic area of Korea and the present parasite may originate from East Asia. RFLP would be useful to classify genotypes of P. vivax population instead of gene sequencing.

Animals↗

PubMed1999

Enzyme histochemical study of germanium dioxide-induced mitochondrial myopathy in rats.

The purpose of this study were 1) to determine the earliest pathological changes of germanium dioxide (GeO2)-induced myopathy; 2) to determine the pathomechanism of GeO2-induced myopathy; and 3) to determine the minimal dose of GeO2 to induce myopathy in rats. One hundred and twenty five male and female Sprague-Dawley rats, each weighing about 150 gm, were divided into seven groups according to daily doses of GeO2. Within each group, histopathological studies were done at 4, 8, 16, and 24 weeks of GeO2 administration. Characteristic mitochondrial myopathy was induced in the groups treated daily with 10 mg/kg of GeO2 or more. In conclusion, the results were as follows: 1) The earliest pathological change on electron microscope was the abnormalities of mitochondrial shape, size and increased number of mitochondria; 2) The earliest pathological change on light microscope was the presence of ragged red fibers which showed enhanced subsarcolemmal succinate dehydrogenase and cytochrome c oxidase reactivity; 3) GeO2 seemed to affect the mitochondrial oxidative metabolism of muscle fibers; 4) GeO2 could induce mitochondrial myopathy with 10 mg/kg of GeO2 for 4 weeks or less duration in rats.

Animals↗

PubMed1999

Modulation of biological phenotypes for tumor growth and metastasis by target-specific biological inhibitors in gastric cancer.

For tumor progression, a cascade of linked sequential biological events is essential. We tried to test whether biological therapy can modulate specific biological phenotypes and increase the anti-tumor effect when combined with chemotherapy. Five human gastric cancer cell lines (YCC-1, YCC-2, YCC-3, YCC-7, AGS) were used in these studies. Pentosan polysulfate (PPS) as a heparin-binding growth factor inhibitor, Tranexamic acid as a plasmin inhibitor, Lovastatin as an adhesion inhibitor and Adriamycin as a chemotherapeutic agent were selected. The effects of each drug on colony formation and tumor cell proliferation were evaluated by soft agar assay and cell proliferation assay, respectively to test direct anti-tumor effect. The expression of uPA, PAI-1 was determined by ELISA, while MMPs activity was evaluated by zymography. PPS suppressed the colony-forming activity as much as Adriamycin did, but it showed only cytostatic effects in cell proliferation assay. Migration capacity using Boyden chamber assay was more closely correlated with adhesive capacity than uPA or MMP-2 expression. The motility inhibitory effect of Tranexamic acid was observed in the YCC-7 cell line, which expressed all the required biological phenotypes for migration. In AGS, with high cell motility and adhesiveness, the adhesion was inhibited by Lovastatin and most of the inhibitory effect was recovered by Mevalonate. When PPS was combined with Adriamycin on the Adriamycin-resistant, midkine (MK) gene expressing YCC-7 cell line, the growth inhibition rate increased up to 84%, while that for a single treatment of PPS or Adriamycin was 40% and 22%, respectively (p=0.001). When we combined Tranexamic acid and Adriamycin, we observed the synergistic effect in YCC-3 and YCC-7, while no combined effect was found in YCC-1. The combination of Lovastatin and Adriamycin did not show any combined effects in any of the cell lines. In conclusion, a synergistic anti-proliferative effect (chemo-sensitization) with combined chemo-biotherapy was found in cancer cells with specific biological target, MK. The anti-motility effect was the greatest when the gastric cancer cells expressed all the specific biological phenotypes.

Anticoagulants↗

PubMed1999

Changes of telomerase and telomere lengths in paired normal and cancer tissues of breast.

To attain the immortal phenotype, cancer cells must overcome the mitotic clock. Telomerase activity has been identified to be activated in malignant tumors including breast cancer. Telomerase activity was evaluated in 71 breast cancer tissues and paired normal tissues with the TRAP (telomerase repeat amplification protocol) assay. Telomerase activity was calculated and translated into arbitrary units by computer-assisted densitometry with the control of telomerase activity in the 293 control cell line. In 59 paired breast tissues with telomerase activity, terminal restriction fragment (TRF) lengths were measured using Southern blotting. Relative inhibition (RI), the ratio of inhibited telomerase activity in each tumor tissue compared to that of the 293 control cell line after pre-treatment with 150 microg/ml of RNAse A, was measured. Sixty-three of 71 cancer tissues showed telomerase activity (88.7%) with 75.3+/-17.9 units in densitometry, while no telomerase activity was detected in their paired normal tissues. Telomerase activity was correlated to node metastasis (p=0.02) and stage (p=0.005), but not to tumor size or the hormonal receptor status. TRF lengths were 11. 0+/-4.7 kb in 59 tumor tissues and 11.7+/-2.2 kb in paired normal tissues. TRF lengths did not correlate to any of the clinical parameters. However changes of TRF lengths in tumor tissues compared to those of normal tissues correlated to telomerase activity. RI in the tumor tissues was proportional to telomerase activity without RNAse A pre-treatment. In breast cancer, telomerase activity was specific to tumor tissues and increased with tumor progression. Telomerase activity and changes in TRF lengths can be used as guidelines in detecting candidates for the telomerase inhibitor.

Adult↗

PubMed1999

An intervention study to enhance medication compliance in community-dwelling elderly individuals.

OBJECTIVE: To determine whether daily videotelephone or regular telephone reminders would increase the proportion of prescribed cardiac medications taken in a sample of elderly individuals who have congestive heart failure (CHF). METHODS: The authors recruited community-dwelling individuals age 65 and older who had the primary or secondary diagnosis of CHF into a randomized controlled trial of reminder calls designed to enhance medication compliance. There were three arms: a control group that received usual care; a group that received regular daily telephone call reminders; and a group that received daily videotelephone call reminders. Compliance was defined as the percent of therapeutic coverage as recorded by Medication Event Monitoring System (MEMS) caps. Subjects were recruited from 2 sources: a large urban home health care agency and a large urban ambulatory clinic of a major teaching hospital. Baseline and post-intervention MOS 36-Item Short-Form Health Survey (SF-36) scores and Minnesota Living with Heart Failure (MLHF) scores were obtained. RESULTS: There was a significant time effect during the course of the study from baseline to post-intervention (F[2,34] = 4.08, p < .05). Over time the elderly individuals who were called, either by telephone or videotelephone, showed enhanced medication compliance relative to the control group. There was a trend, but no significant difference between the two intervention groups. Both SF-36 and MLHF scores improved from baseline to post-intervention for all groups. There was no significant change in the SF-36 scores for the sample, but there was a significant change for the MLHF scores (p < .001). The control group had a significant fall off in the medication compliance rate during the course of the study, dropping from 81% to 57%. CONCLUSIONS: Telephone interventions are effective in enhancing medication compliance and may prove more cost effective than clinic visits or preparation of pre-poured pill boxes in the home. Technologic advances which enable clinicians to monitor and enhance patient medication compliance may reduce costly and distressing hospitalization for elderly individuals with CHF.

Aftercare↗

PubMed1999

Ring-down artifacts posterior to the right hemidiaphragm on abdominal sonography: sign of pulmonary parenchymal abnormalities.

The aim of our study was to verify whether ring-down artifacts posterior to the right hemidiaphragm on abdominal sonography reflected pulmonary parenchymal abnormalities. Forty patients (group 1) with abdominal diseases and 32 patients (group 2) with proved various pulmonary abnormalities involving the right lung base underwent abdominal sonography with 2-4 MHz transducers. In these two groups, the presence and number of ring-down artifacts were assessed and correlated with peridiaphragmatic lung findings on chest radiographs or computed tomographic scans. In 21 patients (group 3) with multiple (more than five) or numerous (10 or more) ring-down artifacts, chest radiographs were reviewed to see if any peridiaphragmatic pulmonary abnormalities were present. In group 1, one or several (less than five) ring-down artifacts were shown in 27 of 40 (68%) patients. In these patients, computed tomography showed insignificant focal intra- and interlobular septal thickening in the peridiaphragmatic right lung. In group 2, 31 of 32 (97%) patients showed multiple or numerous ring-down artifacts. In group 3, chest radiographs showed various pulmonary abnormalities in 20 of 21 (95%) patients, including emphysema, idiopathic interstitial pneumonia, bronchopneumonia, and interstitial edema. Although nonspecific, ring-down artifacts posterior to the right diaphragm on abdominal sonography may be used to predict pulmonary abnormalities when encountered on abdominal sonography in patients without specific pulmonary symptoms.

Abdomen↗

PubMed1998

Augmentation of therapeutic antitumor immunity by B16F10 melanoma cells transfected by interferon-gamma and allogeneic MHC class I cDNAs.

The cDNAs for interferon-gamma (IFN-gamma) and allogeneic H-2Kd molecules were transfected into highly metastatic B16F10 melanoma cells (H-2b), and the synergistic effects of the antitumor immune responses by the doubly transfected cells (B16/Kd/IFN-gamma cells) were investigated in C57BL/6 mice (H-2b). The singly transfected B16F10 cells with either IFN-gamma or H-2Kd cDNA (B16/IFN-gamma or B16/Kd cells) were used as controls. The B16/Kd/IFN-gamma cells secreted biologically active IFN-gamma, and strongly expressed both syngeneic and allogeneic MHC class I antigens (H-2Kb and H-2Kd) on the same cell construct. Immunization with the doubly transfected B16/Kd/IFN-gamma cells induced higher anti B16F10 cellular cytotoxic responses than the single transfected B16/IFN-gamma or B16/Kd cells. Lyt-2.2 (CD8)+ T-cells were a major effector cell-type involved in the anti B16F10 responses and their cytotoxic activities were augmented in the immunized mice with the B16/Kd/IFN-gamma cells, as demonstrated by in vitro depletion experiments. The survival period of melanoma-bearing mice treated with the B16/Kd/IFN-gamma cells was significantly longer than that treated with the B16/IFN-gamma or B16/Kd cells. Furthermore, the treatment with the B16/Kd/IFN-gamma cells was capable of greatly inhibiting lung metastasis from small, established B16F10 footpad tumors. These results suggest that the augmented immunotherapeutic potentials can be achieved by the vaccination with IFN-gamma and allogeneic MHC class I genes transfected B16F10 melanoma cells.

Animals↗

PubMed1998

Synthesis and evaluation of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines as potential prodrugs of penciclovir.

A series of 2-amino-9-(3-hydroxymethyl-4-alkoxycarbonyloxybut-1-yl)purines (4-10) and 2-amino-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (1) were synthesized as potential prodrugs of penciclovir and evaluated for their oral penciclovir bioavailability in mice and rats. Treatment of 2-(2-benzyloxyethyl)propane-1,3-diol (11) with 1,1'-carbonyldiimidazole in THF followed by hydrogenolytic removal of the benzyl group of the resulting cyclic carbonate 12 gave 5-(2-hydroxyethyl)-1,3-dioxan-2-one (13). Mesylation of the alcohol 13 and then a coupling reaction of the resulting mesylate 14 with 2-amino-6-chloropurine using anhydrous Cs2CO3 in DMF afforded 2-amino-6-chloro-9-(2-(2-oxo-1,3-dioxan-5-yl)ethyl)purine (16) after purification by flash column chromatography on silica gel using EtOAc/MeCN/Et3N as eluent. Hydrogenation of the 6-chloro cyclic carbonate 16 followed by a ring-opening reaction of the 6-deoxy cyclic carbonate 1 in a mixture of an appropriate alcohol and CHCl3 using activated SiO2 as a Lewis acid afforded the corresponding alkyl monocarbonate derivatives 3-10 in fair to good yields. Of the prodrugs tested in mice, the isopropyl monocarbonate 6 achieved the highest mean urinary recovery of penciclovir (53%), followed in order by the propyl monocarbonate 5 (51%), the isopentyl monocarbonate 10 (51%), the ethyl monocarbonate 4 (50%), and famciclovir (48%). In rats, the methyl monocarbonate 3, 4, 6, the n-butyl monocarbonate 7, and 10 (39-41%) showed levels of mean urinary recovery of penciclovir similar to that from famciclovir (40%). The alkyl monocarbonates 4-10 were found to be quite stable in the aqueous buffer solutions, and among them, 6 was the most stable with the half-lives (t1/2) of 88, >200, 61, and 26 days at pH 1.2, 6.0, 7.4, and 8.0, respectively. In addition, 6 was highly soluble in H2O (138.8 mg/mL, 20 degrees C).

Acyclovir↗

PubMed1998

Steroid receptor coactivator-1 coactivates activating protein-1-mediated transactivations through interaction with the c-Jun and c-Fos subunits.

Steroid receptor coactivator-1 (SRC-1) specifically bound to the transcription factor AP-1 subunits c-Jun and c-Fos, as demonstrated by the yeast two-hybrid tests and glutathione S-transferase pull down assays. The c-Jun and c-Fos binding sites were localized to the C-terminal subregion of SRC-1 (amino acids 1101-1441) that encompasses the previously described histone acetyltransferase and receptor-binding domains. In mammalian cells, SRC-1, similar to the previous results with CBP-p300 (Arias, J., Alberts, A. S., Brindle, P., Claret, F. X., Smeal, T., Karin, M., Feramisco, J., and Montminy, M. (1994) Nature 370, 226-229; Bannister, A. J., and Kouzarides, T. (1995) EMBO J. 14, 4758-4762), potentiated the AP-1-mediated transactivations in a dose-dependent manner and derepressed the mutual inhibitions between nuclear receptors and AP-1. Furthermore, coexpression of p300 further enhanced this SRC-1-potentiated level of transactivations. Thus, we concluded that at least two distinct coactivator molecules may cooperate to regulate AP-1-dependent transactivations and mediate transrepression between AP-1 and nuclear receptors in vivo.

Acetyltransferases↗

PubMed1998

Structure-function relationships and localization of the Na/Ca-K exchanger in rod photoreceptors.

The structural and functional properties of the bovine rod photoreceptor Na/Ca-K exchanger and its distribution in vertebrate photoreceptor cells were studied using a panel of monoclonal antibodies. Antibodies that bind to distinct epitopes along the large hydrophilic N-terminal segment of the exchanger labeled the extracellular surface of the rod outer segment plasma membrane, whereas antibodies against a large hydrophilic loop between the two membrane domains labeled the intracellular side. Enzymatic deglycosylation studies indicated that the exchanger primarily contains O-linked sialo-oligosaccharides located within the N-terminal domain. Removal of the extracellular domain with trypsin or the large intracellular domain with kallikrein did not alter the Na+- or K+-dependent Ca2+ efflux activity of the exchanger when reconstituted into lipid vesicles. Anti-exchanger antibodies were also used to visualize the distribution of the exchanger in the retina by light and electron microscopy. The exchanger was localized to the plasma membrane of rod outer segments. No labeling was observed in the disk membranes, cone photoreceptor cells, or other retinal neurons, and only faint staining was seen in the rod inner segment. These results indicate that the O-linked glycosylated rod Na/Ca-K exchanger is specifically targeted to the plasma membrane of rod photoreceptors and has a topological organization similar to that reported for the cardiac Na/Ca exchanger. The large intracellular and extracellular domains do not directly function in the transport of ions across the rod outer segment plasma membrane, but instead may play a role in protein-protein interactions that maintain the spatial organization of the exchanger in the plasma membrane or possibly regulate transport activity of the exchanger.

Animals↗

PubMed1998

Vaccination with an ovalbumin/interleukin-4 fusion DNA efficiently induces Th2 cell-mediated immune responses in an ovalbumin-specific manner.

To more effectively drive immune responses toward antigen-specific T helper type 2 (Th2) cell-mediated responses, we constructed a mammalian expression vector (pOVA/IL4) carrying a fused gene in which the ovalbumin (OVA) cDNA was covalently linked to murine interleukin-4 (IL-4) cDNA. A biologically active OVA/IL4 protein was expressed by the transfected COS cells with the pOVA/IL4 DNA, as demonstrated by Western blotting and cytokine bioassay. Intramuscular injection of BALB/c mice with the pOVA/IL4 DNA increased both the production of OVA-specific IL-4 by CD4+ T cells and the ratio of anti-OVA IgG1 to anti-OVA IgG2a isotypes, while the injection with the pOVA DNA alone, or with the mixture of the pOVA and pIL4 DNA did no or little increase. Furthermore, the OVA-specific, Th2 cell-mediated immune responses were significantly enhanced by multiple injections with the pOVA/IL4 DNA. These studies indicate that the direct linkage of an OVA gene to an IL-4 gene in the expression plasmid confines the effects of IL-4 to the OVA-specific cells, efficiently driving the immune response toward OVA-specific, Th2 cell-mediated responses.

Animals↗

PubMed1998

Influence of exposure and infusion times on the cytotoxicity and pharmacokinetics of cis-malonato[(4R, 5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolane]platinum(II) .

The effect of exposure time on the in vitro cytotoxicity of a new platinum complex, cis-malonato[(4R,5R)-4,5-bis(aminomethyl)-2-isopropyl-1,3-dioxolan e]platinum(II) (SKI 2053R) and cisplatin (CDDP) toward two human lung-adenocarcinoma cell lines (PC-9, PC-14) and two human stomach-adenocarcinoma cell lines (KATO III, MKN-45) was investigated by variation of the exposure time (1, 4, 12, and 24 h) and drug concentration to yield a constant product of drug concentration times exposure time (C x T). Exposure of cancer cells to low concentrations of SKI 2053R for 12 or 24 h resulted in a greater killing effect than did 1- or 4-h exposure to 24- or 6-fold higher concentrations; the inhibitory effects of SKI 2053R on the colony formation of all tumor cell lines except for KATO III were significantly increased with increasing exposure time (P < 0.05). However, the inhibitory effects of CDDP against all tumor cell lines tested except for PC-14 were inversely correlated with increasing exposure time (P < 0.05). The intracellular accumulation of SKI 2053R and CDDP was measured under the same conditions used in the cell-survival assay using MKN-45 cells. The amount of platinum accumulated from SKI 2053R into MKN-45 cells was greater for the treatment involving low concentrations and long-term exposures (12 and 24 h) than for that using high concentrations and short-term exposures (1 and 4 h) at the constant C x T values; however, the increased accumulation of CDDP was more prominent as the concentration was increased, even if the exposure time became shorter. The pharmacokinetics studies of SKI 2053R following 1-, 4-, 12-, and 24-h infusions were performed in beagle dogs. A single dose of SKI 2053R (5.0 mg/kg) was successively given over various infusion periods to three beagle dogs at 3-week intervals. The peak levels of ultrafiltrable platinum observed for SKI 2053R at the 1-, 4-, 12-, and 24-h infusions were 3.10+/-0.49 (mean +/- SD), 1.24+/-0.06, 0.43+/-0.07, and 0.25+/-0.04 microg/ml, respectively. The mean binding ratios of platinum from SKI 2053R to plasma protein at the end of 1-, 4-, 12-, and 24-h infusions were approximately 91%, 73%, 53%, and 51%, respectively. The steady-state level of free platinum was maintained during long-term infusions (12 and 24 h) after short periods (1-3 h) from the start of the infusion. This study strongly suggests that the therapeutic efficacy of SKI 2053R given by continuous long-term infusion should be investigated in future clinical studies.

Adenocarcinoma↗