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We established a drug sensitivity panel consisting of 24 human lung cancer cell lines. Using this panel, we evaluated 26 anti-cancer agents: three alkylators, three platinum compounds, four antimetabolites, one topoisomerase I inhibitor, five topoisomerase II inhibitors, seven antimitotic agents and three tyrosine kinase inhibitors. This panel showed the following: a) Drug sensitivity patterns reflected their clinically-established patterns of action. For example, doxorubicin and etoposide were shown to be active against small cell lung cancer cell lines and mitomycin-C and 5-fluorouracil were active against non-small cell lung cancer cell lines, in agreement with clinical data. b) Correlation analysis of the mean graphs derived from the logarithm of IC50 values of the drugs gave insight into the mechanism of each drug's action. Thus, two drug combinations with reverse or no correlation, such as the combination of cisplatin and vinorelbine, might be good candidates for the ideal two drug combination in the treatment of lung cancer, as is being confirmed in clinical trials. c) Using cluster analysis of the cell lines in the panel with their drug sensitivity patterns, we could classify the cell lines into four groups depending on the drug sensitivity similarity. This classification will be useful to elucidate the cellular mechanism of action and drug resistance. Thus, our drug sensitivity panel will be helpful to explore new drugs or to develop a new combination of anti-cancer agents for the treatment of lung cancer.

A new myeloid cell line, MTT-95, was established from the bone marrow of a patient with acute myelogenous leukemia (AML, M7). MTT-95 cells differentiate into mature basophilic cells in culture medium with no chemical component or cytokine. Surface phenotypes were as follows: CD11b 79.3%, CD13 92.4%, CD33 99.8%, CD34 87.9%, CD41a 77.6% and HLA-DR 0.3%. MTT-95 cells were strongly positive for glycoprotein IIb/IIIa by immunohistochemical staining and revealed metachromatic granules. MTT-95 cells seem to possess characteristics of both megakaryocytes and basophils. These findings suggest that MTT-95 cells are basophil progenitors. MTT-95 cells might be useful in the study not only of the biological aspects of basophils, but also of the diversities of AML (M7).

The effects of levocabastine, a novel histamine H1-receptor antagonist, on lipid mediator release induced by antigen-antibody reaction from actively sensitized guinea pig lung fragments were studied. Levocabastine dose-dependently inhibited the release of leukotriene C4 from guinea pig lung fragments induced by antigen. A significant effect was observed with levocabastine at a concentration of 10(-4) M. On the other hand, levocabastine produced no effect on the release of leukotriene E4 or thromoboxane B2. From these findings, it was concluded that levocabastine may be useful for relieving the nasal obstruction in allergic rhinitis caused by inhibition of leukotriene C4 release.

Genomic sequencing and chromosomal assignment of the gene encoding rat APEX nuclease, a multifunctional DNA repair enzyme, were performed. An active Apex gene and a processed pseudogene were isolated from a rat genomic library. The active Apex gene consists of 5 exons and 4 introns spanning 2.1 kb. The putative promoter region of the Apex gene lacks the typical TATA box, but contains CAAT boxes and a CpG island having putative binding sites for several transcription factors, such as Sp1, AP-2, GATA-1 and ATF. A putative O-sialoglycoprotease (a homologue of Pasteurella haemolytica glycoprotease, gcp; abbreviated as Prsmg1/Gcpl1) gene consisting of 11 exons and 10 introns spanning 7.3 kb lies immediately adjacent to the Apex gene in a 5'-to-5' orientation. The Apex gene locus was mapped to rat chromosome 15p12 using in situ hybridization. The processed pseudogene (designated as rat Apexp1) has a nucleotide sequence 87.1% identical to that of the rat Apex cDNA, although several stop codons interrupting the coding sequences and multiple nucleotide deletions were observed. The Apexp1 is located in an inactive LINE sequence. Calculation of nucleotide substitution rates suggests that the immediate, active progenitor of Apexp1 arose 23 million years ago and that the non-functionalization occurred 15 million years ago.

The influence of mild exercise on skeletal muscle fibers was investigated histochemically to assess the effects of exercise on steroid myopathy and its efficacy for preventing this disease. Twenty male Wistar rats were divided into 4 groups of 5 each: group T, which received exercise alone; group S which received steroid alone; group ST which received both exercise and steroid; and group C, the control group. In groups S and ST, hydrocortisone was administered subcutaneously at a dose of 10 mg/kg/day for 4 weeks. In the exercise groups, the animals were made to run at a speed of 15 m/min for about 1 h/day for 5 days a week on a treadmill. After the completion of treadmill exercise and steroid administration for 4 weeks, the rats were anesthetized with Nembutal, the soleus muscle (SOL) and the extensor digitorum longus muscle (EDL) were removed and prepared for examinations. The area of type I fibers in the SOL was significantly larger in group ST than in group S. The area of type IIa fibers in the EDL was significantly larger in group ST than in group S. In group S, the proportion of type I fibers in the SOL was significantly lower than in the other three groups. There was little difference in fiber type distribution between groups ST and C. These results suggest that steroid myopathy can be prevented by even mild exercise.

In recent years it has been reported that free oxygen radicals play an important role in the pathogenesis of degenerative diseases and that antioxidant vitamins such as vitamins E or C prevent their harmful effects. In this study, we evaluated the following: Erythrocyte susceptibility to lipid peroxidation; the role of erythrocyte glutathione (GSH) as an antioxidant; plasma lipid fractions; and the relationship between plasma lipid peroxides and antioxidant vitamin levels. Thiobarbituric acid-reactive substance (TBARS) levels were measured to determine the levels of plasma lipid peroxides and the susceptibility to lipid peroxidation when erythrocytes were stressed by hydrogen peroxide for 2 h in vitro. Erythrocyte TBARS production was significantly higher in patients with coronary atherosclerosis than in the controls. On the other hand, the levels of plasma high-density lipoproteins, vitamin C, vitamin E and erythrocyte GSH were significantly lower, and the levels of plasma total cholesterol, triglycerides, low-density lipoproteins and TBARS were significantly higher in the patients with coronary atherosclerosis than in the controls. In conclusion, our results indicate that erythrocytes from patients with coronary atherosclerosis are more susceptible to oxidation than those of controls and that these patients have lowered antioxidant capacity as revealed by decreased plasma levels of vitamins C and E.

To better understand the nature of the symptoms of depression in the early stages of Pick's disease, we performed a retrospective study of the medical records of eight patients who were originally treated for major depressive disorders before being clinically diagnosed with Pick's disease. Six of the eight manifested psychomotor retardation and social withdrawal, seven of the eight were agitated and five of the eight showed hyperbulia too. However, only two of the eight showed melancholia or physical symptoms such as insomnia or loss of appetite. All patients were treated with antidepressants but these were not effective in relieving the symptoms of depression. The data we gathered in this study will be useful in the future for distinguishing between Pick's disease-related depression (in the early stages of the disease) and major depression.

To evaluate the efficacy and safety of additive triple disease modifying anti-rheumatic drug (DMARD) combination therapy of a low dose of sulfhydryl compounds inverted question markD-penicillamine, bucillamine or tiopronin inverted question mark, sulfasalazine (SSZ) and methotrexate (MTX) as a treatment for rheumatoid arthritis (RA) patients, we studied a total of 33 Japanese RA patients (6 males, 27 females). At 1 or 2 months after simultaneous administration of the 3 above-mentioned DMARDs was begun, significant improvements were seen in markers of joint inflammation, i.e., erythrocyte sedimentation rate and C-reactive protein in sera. At 6 months, clinical improvement judged by the physicians' overall assessment of joint symptoms and laboratory data was observed in 29 (88%) of the 33 RA patients. No marked effect was observed in the other 4 (12%) patients, however. We observed no significant adverse reaction to this therapy. This suggests that additive triple DMARD combination therapy of a low dose of sulfhydryl compounds, SSZ and MTX could be a useful drug therapy for the treatment of RA patients, even those who are refractory.

The aim of this study was to investigate the relationship between the strength of the foot muscles that control the toes and disorders such as shin splint. In order to this, we designed and built a toe dynamometer to compare the muscle power exerted through the toes in top female marathon runners and age-matched women not involved in sports. The subjects were 12 top-level female marathon runners (Group A) and 37 student nurses who were not involved in sports (Group B). We devised a dynamometer to measure the total power exerted by the flexor muscles of the 5 toes of a single foot (total flexor power) and the combined power of the abductors of the big (1st) and little (5th) toes (abductor power). In Group A, the total flexor power was 14.3 +/- 5.3 kg in the right foot and 15.4 +/- 4.7 kg in the left foot. The abductor power was 1.9 +/- 1.8 kg in the right foot and 2.2 +/- 1.9 kg in the left foot. In Group B, total flexor power was 18.3 +/- 6.7 kg in the right foot, while the abductor power was 1.9 +/- 1.7 kg. The subjects from Group A with an arch index < 1.0 (n = 8) or > 1.0 (n = 4) were respectively classified as Group I and Group II. In Group I, total flexor power was 14.9 +/- 5.3 kg (right) and 15.5 +/- 5.2 kg (left), while the abductor power was 2.6 +/- 1.9 kg (right), and 3.1 +/- 1.7 kg (left). In Group II, the total flexor power was 13.2 +/- 5.8 kg (right) and 15.1 +/- 4.2 kg (left), while the abductor power was 0.7 +/- 0.6 kg (right) and 0.3 +/- 0.2 kg (left). The abductor power of toes was significantly lower in Group II than in Group I. The incidence of posteromedial shin pain was higher in Group II (75.0%) than in Group I (12.5%).

Life expectancy, mortality and longevity data related to height and body size for various US and world population samples are reviewed. Research on energy restriction, smaller body size and longevity is also examined. Information sources include various medical and scientific journals, books and personal communications with researchers. Additional information is presented based on research involving eight populations of the world noted for their health, vigor and longevity. This information includes the findings of one of the authors who led research teams to study these populations. While conflicting findings exist on the cardiovascular death rates for shorter people, many examples of short populations with very little heart disease are described. Most cancer studies indicate that shorter people have significantly lower mortality risk. Considerable data suggest that shorter people generally have greater longevity than taller people, and extensive animal research supports human longevity findings. Tall populations with low mortality rates are also described. Shorter stature and smaller body weight appear to promote better health and longevity in the absence of malnutrition and infectious diseases. Several theoretical reasons for this greater longevity potential are covered. Also discussed, is the role of socioeconomic status, diet, relative weight, environment and other factors in increasing or decreasing the longevity of individuals, regardless of their heights and weights.

The effects of exposure to cigarette smoke on the pharmacokinetics and pharmacodynamics of zonisamide, an antiepileptic drug, were investigated in rats. Absorption of oral zonisamide was significantly inhibited by exposure to cigarette smoke. The Cmax, T1/2 and the area under the plasma concentration-time curve 0-24 values in the cigarette smoke exposure group were significantly lower than those in the control group. Although tonic extension (TE) induced by maximal electroshock was completely blocked by the administration of zonisamide in the control group, 50% of rats showed TE in the cigarette smoke exposure group. Exposure to cigarette smoke influences both the pharmacokinetics and antiepileptic effects of zonisamide. The effects of smoking on epileptic patients using zonisamide warrants further attention.

In the present study, we aimed to obtain further evidence in favour of the hypothesis that nitric oxide (NO) is a major mediator of endothelium-dependent vasorelaxation and to clarify whether NO plays a role in papaverine-induced vasorelaxation. The relaxant effects of acetylcholine (Ach), acidified NaNO2 or papaverine were investigated on isolated helical strips of the rat thoracic aorta precontracted with phenylephrine in an organ bath containing Krebs solution aerated with 95% O2 and 5% CO2. The relaxation was quantified as % peak reduction of phenylephrine contracture. Saponin abolished the relaxant effects of Ach completely whereas it had no effect on the responses to acidified NaNO2 or papaverine. NG-nitro-L-arginine (L-NOARG) reduced the effects of Ach significantly, but it was ineffective on the relaxation induced by acidified NaNO2. The inhibitory action of L-NOARG was partly restored by L-arginine, but not by D-arginine. Hemoglobin, hydroxocobalamin and hydroquinone exhibited significant inhibition on the relaxation evoked by Ach and acidified NaNO2. L-NOARG, hydroxocobalamin and hydroquinone caused only limited but significant decrease in the relaxation due to papaverine. This phenomenon was also observed by increasing phenylephrine concentration leading to an enhancement in the contraction. Our findings strongly support the view that Ach-induced relaxation of rat aorta strips is mediated by free NO released from the endothelium and the results suggest that NO may indirectly contribute to papaverine-induced relaxation.

Three outbreaks and many isolated cases of enterohemorrhagic Escherichia coli O157:H7 occurred in 1996 and 1997 in Okayama Prefecture, Japan. In an attempt to investigate the route of these infections, the strains isolated from the 3 outbreaks (total 33 strains) and 15 isolated cases (total 15 strains) were investigated using random amplification of polymorphic DNA (RAPD) and pulsed-field gel electrophoresis (PFGE). In addition, 10 strains from an outbreak in Tojo Cho, Hiroshima Prefecture (June 1996), 2 strains from the particular types of meat in Kochi Prefecture, and 42 strains isolated from bovine feces in a farm in Okayama Prefecture were also investigated in the same manner. PFGE was much more useful than RAPD for molecular typing of the clinical isolates, in that it allowed us to classify them into 10 PFGE groups. We noted that the strains differed according to the time and place of the outbreaks (or isolated cases). This indicates that O157:H7 infections in Okayama Prefecture were caused by different strains (although some cases were aggravated by the same strains as were found in other areas). The isolates from bovine feces were classified into 5 groups by PFGE profiles, but none of them were identical to those of the clinical isolates.

Nipradilol (3,4-dihydro-8-(2-hydroxy-3-isopropylamino) propoxy-3-nitroxy-2H-1-benzopyran) is a newly synthesized chemical agent designed to possess beta-adrenoceptor blocking and vasodilating actions. Nipradilol decreased left ventricular contractility index (Emax, slope of the ventricular end-systolic pressure-volume relation), systolic pressure-volume area (PVA, a measure of ventricular total mechanical energy) and oxygen consumption in cross-circulated excised dog hearts. However, nipradilol did not decrease total coronary resistance. These results indicate that nipradilol, like propranolol, depresses myocardial mechanoenergetics and that the vasodilating action of nipradilol could not be detected in the present study.

Efficacy of the percutaneous transluminal coronary recannalization (PTCR) therapy was evaluated by weighting infarct-related coronary artery segments in 28 consecutive patients with acute myocardial infarction. The study focused on the influences of the time interval from the onset of chest pain to PTCR (PTCR-Time) and on the post-infarct left ventricular regional wall motion in conjunction with the serum levels of GOT, LDH and CPK and with PTCR-Time. PTCR success rate was 84.0%, and re-occlusion rate was 4.0%. The thrombolysis in myocardial infarction grade 2, however, was observed in 7 (33.3%) of 21 cases with successful PTCR. There was no significant difference in PTCR-Time between the PTCR success and nonsuccess groups. Significant correlations were observed between the PTCR-Time and each peak value of standardized serum levels of LDH and CPK, and between the PTCR-Time and the post-infarct regional wall motion abnormality. There were also significant correlations between the standardized serum level of each of these three enzymes and the post-infarct regional wall motion abnormality. It was clearly demonstrated that the earlier the recannalization of the infarcted artery was achieved, the less extensive the myocardial damage in quantitative and qualitative aspects.

A 44-year-old man with alcohol-induced chronic pancreatitis was referred to our institute for evaluation of severe anemia. The hemoglobin was 2.6g/dl. The results of upper gastrointestinal and colonic examination were negative. Computed tomography and ultrasound examination revealed a pseudocyst in the head of the pancreas. A pseudoaneurysm of the anterior superior pancreaticoduodenal artery shown by angiography appeared to have caused gastrointestinal bleeding by rupturing into the pancreatic cyst connected to the main pancreatic duct. A pyrorus-preserving pancreaticoduodenectomy was performed successfully.

The effects of centrally administered interleukin-1 beta (IL-1) or platelet activating factor (PAF) on adrenocorticotropin (ACTH) and catecholamine secretion, blood pressure and heart rate were examined to determine if these agents stimulate similarly the hypothalamic-pituitary-adrenal (HPA) axis or the sympathetic-adrenomedullary system. Intra-third ventricular administration of IL-1 (50, 200 ng) evoked significant ACTH secretion. Centrally administered IL-1 (50 ng) elevated plasma noradrenaline and adrenaline levels, systolic blood pressure and heart rate. Plasma ACTH, noradrenaline and adrenaline levels were also increased by the higher dose (200 ng) of IL-1 while systolic blood pressure and heart rate were not affected. Intra-third ventricular administration of 9 micrograms of PAF elevated the plasma ACTH level while 3 micrograms of PAF did not stimulate ACTH secretion. Neither dose of centrally administered PAF affected any plasma catecholamine level or systolic blood pressure. These results suggest that central IL-1 stimulates both the HPA axis and the sympathetic-adrenomedullary system, that a higher dose of IL-1 stimulates a mechanism to antagonize the elevation of blood pressure and heart rate and that central PAF is not involved in the control of the sympathetic-adrenomedullary system. Thus, IL-1 and PAF do not interact in the brain, although they interact peripherally.

Lymphokine activated killer (LAK) cells can destroy not only tumor cells but also syngeneic liver cells. In this study, the effects of passive transfer of LAK cells on liver regeneration were examined by the 3H-thymidine uptake and bromodeoxyuridine (BrdU) labeling methods after resection of 70% of the volume of the liver. LAK cells were infused 12h after hepatectomy and the effects on regeneration of liver cells were examined 36 h later. The transfusion of LAK cells induced significant inhibition of liver regeneration at a dose of 5-10 x 10(7) cells. Neuraminidase treatment of lymphocytes is desirable to enhance the selective entrapment of LAK cells into the liver. When LAK cells were treated with neuraminidase (0.5 units/ml), and transfused into hepatectomized mice, more potent suppression of liver regeneration was induced in comparison with the same dose of LAK cells. The intraperitoneal injection of recombinant interleukin 2 (rIL-2) after partial hepatectomy also inhibited the regeneration of remnant liver. From these results, lymphocytes such as LAK cells appear to regulate liver regeneration.