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Mononuclear cells from the peripheral blood of patients with systemic lupus erythematosus (SLE) were transformed with the Epstein-Barr virus (EBV) and the resultant polyclonal B-lymphoblastoid cell lines were tested for antibody activity to membrane antigens of certain T-cell lines. B lymphoblastoid cell lines secreting specific antibodies were fused with (mouse x human) heteromyeloma SHM-D33 cells. Among the large number of hybridomas generated, one which produced a human monoclonal antibody (MAb) TONO-I (1gM, λ) was selected. MAb TONO-I proved to be reactive with 4 human T-cell lines, HPB-MLT, L-MAT, MOLT-3 and MOLT-4F, but not with B-leukemia, Burkitt's lymphoma, myelomonocytic leukemia, erythroleukemia or non-hematopoietic malignant cell lines. MAb TONO-I reacted positively with fresh leukemia cells from 2 of 7 patients with acute T-lymphocytic leukemia, but no reaction was observed in non-T-cell leukemia cases. Normal lymphocytes, monocytes, granulocytes, red blood cells and platelets in the peripheral blood did not demonstrate remarkable binding. Neither thymocytes nor bone-marrow cells from healthy volunteers were reactive. The antigens defined by MAb TONO-I were polypeptides of 57 kDa and 68 kDa. Immunohistological studies revealed no staining of thymocytes in the thymus of a 6-month-old child, but showed epithelial reticular cells and Hassall's corpuscles to stain positively. These results suggest that MAb TONO-I is directed to T-leukemic cells and some components of thymus tissue. © 1995 Wiley-Liss Inc.

清心蓮子飲投与によりインスリン非依存型糖尿病の血糖コントロールを行い, 5年の経過を追跡できた男性3例, 3年の経過の女性1例, および2年の経過の女性3例の計7例を報告し, 清心蓮子飲が有効に作用し得る条件を考察した。清心蓮子飲1日7.5gを食前30分に投与し, 体重およびHbA1の経過を記録した。清心蓮子飲投与による5～2年の経過中, HbA1が8%を越えて一時的悪化を呈した症例では, 悪化直前, または同時期に体重増加傾向を伴っていることが多かった。従って, 清心蓮子飲によるNIDDMの血糖コントロールにおいても, 西洋薬によるコントロールの時と同様に, 食事療法および運動療法を基本とした体重コントロールのための生活指導は不可欠であることが示唆された。生活指導により体重減少が始まった症例は, 虚証の傾向にあると考えられ, 清心蓮子飲投与は漢方医学的立場からも適することが示唆された。清心蓮子飲投与による副作用は認められなかった。

To evaluate the effectiveness of vinorelbine (NVB) in patients with non-small cell lung cancer (NSCLC), a late Phase II study was conducted. A total of 80 patients with Stage III or IV NSCLC who had no previous therapy were entered into the study. Seventy-nine patients were eligible for response and toxicity. NVB was administered weekly by intravenous injection at a dose of 25 mg/m 2 in 20 ml of saline and was generally administered in four cycles or more, unless patients had disease progression. Of the 79 eligible patients, 23 (29.1%) showed a partial response (95% confidence interval, 19.1–40.4%). The median duration of partial responses was 14.7+ weeks. The median survival time for all patients was 40.1+ weeks. The major toxicity was leukopenia. Grade 3 and 4 leukopenia occurred in 48 patients (60.8%). Other toxicities of grade 3 or more included anemia (6.3%), local cutaneous reaction (3.8%), pneumonitis (1.3%), nausea and vomiting (1.3%), mucositis (1.3%) and constipation (1.3%). The absolute dose-intensity of NVB was 22.33 mg/m 2 /week. A weekly schedule of intravenous administration of 25 mg/m 2 /week of NVB was reasonable for maintenance of activity, and acceptable for toxicity in the chemotherapy of advanced NSCLC.

Polymorphic metabolism of certain chemical carcinogens may result in differences in susceptibility to cancers. Human CYP2E1 (cytochrome P450IIE1) is an enzyme involved in the metabolic activation of precarcinogens such as nitrosamines. We detected a restriction fragment length polymorphism (RFLP) of the human CYP2E1 gene for the restriction endonuclease Dra I. The distribution of this polymorphism was examined among lung cancer patients (n = 91), patients with cancer of the digestive tract (n = 45) and controls (n = 76). A significant difference in the distribution was observed between lung cancer patients and controls (chi 2 = 11.4 with 2 df; p < 0.005). On the other hand, there was no significant difference between patients between cancer of the digestive tract and controls (chi 2 = 4.87 with 2 df; NS). This finding suggests that the Dra I polymorphism of the CYP2E1 gene is associated with susceptibility to lung cancer. In addition, an association was found between the amount of lifelong smoking exposure and the distribution of the genotypes of the RFLP among lung cancer patients. The distribution pattern seemed deviated from that of controls especially in the population of low smoking exposure. Our Northern blot analysis data using RNA from human liver autopsy samples suggest that the Dra I polymorphism might be associated with the gene expression of CYP2E1 at mRNA level.

Tuberculosis control law was enacted in 1951 and has been the basis for the management of TB cases over the long post-war period. This law has legalized the use of public founds for the treatment of TB patients for the first time and has provided the authentic basis for mandatory hospitalization, routine health examination, vaccination, notification and registration of TB cases. However, this law was abrogated in 2001 and was joined to the comprehensive infectious diseases control law, in order to facilitate a prophylactic measure against TB infection and to protect human rights of TB patients. Concurrently the medical care system and the formalities connected to hospitalization treatment of TB patients were reviewed. The purpose of the present overview is to explain how TB cases are managed under the newly-enacted law.

In order to study whether hyperplasia or hypertrophy of cells is responsible for the thickening of airway muscles, 3-D morphometry of airway muscle cells was performed on resin-embedded semithin serial sections of autopsied lungs from 10 asthmatics and five control subjects. There were five Type I and five Type II asthmatic lungs, as defined in an earlier study, thickened muscles being found only in the central bronchi in Type I and distributed over the whole airway tree in Type II. The analysis was based on "unbiased" 3-D morphometry to obtain the numerical density NV of muscle cells using a "disector," a spatial probe introduced by Sterio in 1984, which we modified into a stack of serial sections. The mean number NL of cells per unit airway length and the mean volume Vc of a single muscle cell were also determined. In Type I asthmatics, the number of cells increased in the larger bronchi unaccompanied by cellular hypertrophy at any level of the airway tree. In contrast, in Type II asthmatics, hypertrophy was shown to prevail over the whole airway, but it was most remarkable in the bronchioles, whereas hyperplasia was mild and localized only in the bronchi. The two types of asthmatic lungs may therefore result from different pathogeneses.

We studied the effects of 5 kinds of catechins on the adhesion of mouse lung carcinoma 3LL cells to the monolayer of bovine lung endothelial cells. (-)-Epicatechin gallate and (-)-epigallocatechin gallate were active in inhibiting the 3LL cell adhesion, while (+)-catechin and (-)-epicatechin were inactive. (-)-Epigallocatechin showed a considerable cytotoxicity. These data suggest that the specific chemical structure is required to exert the inhibitory activity of catechins and the search for the cellular binding protein(s) bound to these inhibitory catechins would provide a clue to clarify the mechanism of interactions between tumor cells and endothelial cells.

Cell-adhesive protein laminin and its specific receptor play an important role in the processes of cancer proliferation, invasion and metastasis. In the present study, we cloned the cDNAs of the 67-kDa laminin receptor both from a human lung cell line (IMR90) and from a human lung cancer cell line (SBC3), and determined the nucleotide sequences. In comparison with both cDNA sequences of the protein-coding region, three nucleotide differences were found. These differences in the secondary structure of the protein, however, were caused by nucleotide substitutions. It was also demonstrated that the level of 67-kDa-laminin receptor mRNA was higher in SBC3 than in IMR90.

Serial serum erythropoietin (EPO) levels were measured in 12 adult lung cancer patients during cancer chemotherapy. In major cases, EPO levels increased significantly after chemotherapy while the hemoglobin (Hb) remained at initial levels. EPO fell gradually or rapidly to initial levels after a peak, although the patients were anemic. The increase of EPO levels was linearly related to the decrease in Hb (y = 17.48x + 1.003). The mechanism of the rapid increase of EPO is not simply explained by anemia, but might be related to new synthesis, corresponding to depressed bone marrow.

A case of pulmonary hyalinizing granuloma was presented. The patient was a 37-year-old male who was found to have abnormal chest roentgenograms showing multiple pulmonary nodules taken at the annual chest mass survey in October 1989. The largest nodule measured 35 mm in diameter. He was asymptomatic. No definite diagnosis was established either by brushing cytology, biopsy through bronchoscopy or percutaneous needle biopsy. No abnormalities were found in the GI tract, the urogenital system or the bone. Brain CT indicated an iso-density area surrounded by low density in the left fronto-parietal region. Two nodules of the lingula removed by open lung biopsy revealed a homogeneous cut surface. Histological diagnosis was pulmonary hyalinizing granuloma, consisting of hyalinized collagen fibers and bundles infiltrated with chronic inflammatory cells. No therapeutic effect was recognized with prednisolone. Craniotomy was performed and the brain lesion was removed. Anaplastic astrocytoma was the diagnosis. The brain lesion had no etiological correlation with pulmonary hyalinizing granuloma. Pulmonary hyalinizing granuloma itself is a rare benign disease with no specific therapy and is important in the differential diagnosis of lung diseases showing multiple pulmonary nodules.

Gene expression of the precursor of the 67kDa-laminin receptor was examined by Northern analysis using II established human lung cancer cell lines and 25 lung cancer tissues obtained by operation. As a result, one transcript, the size of which was 1.2kb was shown in all cell lines and tissues examined. An increased level of mRNA was demonstrated in cell lines which proliferated rapidly and in small cell lung cancer cell lines. It was also indicated that gene expression of the laminin receptor was up-regulated especially in small cell lung cancer tissue. In this context, 67kDa-laminin receptor appears to be a marker for biological aggressiveness of human lung cancer.

SUGAWARA, S., KUMANO, N., SAIJO, Y., SUZUKI, S., NUMATA, Y., SATO, G. and MOTOMIYA, M. Protein Kinase C Activity in Human Leukemia Cell Lines with Reference to Sensitivity to Antineoplastic Agents. Tohoku J. Exp. Med., 1992, 168 (2), 393-396- Protein kinase C (PKC) regulates many cellular processes. In view of its possible relevance to the drug resistance, the levels of PKC activity were assessed in human leukemia cell lines with reference to the sensitivity to antineoplastic agents. K562/ADM exhibited approximately 2-fold higher levels of PKC activity as compared with the parental K562. After a 1-hr preincubation with Adriamycin (ADM) (0.5, 1, 10μM), PKC activity in K562 tended to increase dose-dependently, while no substantial alteration was found in K562/ADM. Cisplatin (CDDP) or etoposide was of no effect. The activity in THP-1/E was slightly lower than THP-1, and the basal level stayed unchanged with any one of the above durgs. These results suggest that in K562 increase in PKC activity with ADM may play a role in the process of acquisition of resistance.- protein kinase C; antineoplastic agents; human leukemia cell lines; drug resistance

Human cytochrome P450IIE1 (CYP2E) is involved in the metabolic activation of procarcinogens such as N-nitrosodimethylamine, benzene and ethyl carbamate. We screened DNA from 28 individuals for restriction fragment length polymorphisms (RFLPs) is the human P450IIE1 gene and detected an RFLP for the restriction endonuclease DraI. The distribution of the genotypes of this polymorphisms among lung cancer patients (n = 74) differed from that among controls (n = 73) with statistical significance of p < 0.05. In addition, the distribution among patients with cancers of the digestive system (n = 38) was also different from that among controls. Our findings indicate an association between the DraI polymorphism of the IIE1 gene and susceptibility to cancers of the lung and the digestive system.

XU, Y., SHIRAISHI, K., MORI, M. and MOTOMIYA, M. Changes of Fibronectin in the Right and Left Ventricles of Rats Exposed to Chronic Normobaric Hypoxia. Tohoku J. Exp. Med., 1992, 168 (4), 573-582-Changes of fibronectin (FN) in the right and left ventricles of adult rats exposed to chronic normobaric hypoxia were observed by a peroxidase immunohistochemical stain technique and analyzed quantitatively by a point counting method. Fifty-six rats were randomly divided into control groups of day 0 (immediately prior to the experiment), day 5, day 15, and day 30 and hypoxia groups of day 5, day 15, and day 30. Rats of the hypoxia groups were put into a normobaric hypoxia chamber with oxygen concentration adjusted to 10 percent. The rats of the control groups breathed room air. From day 5 on, the ratio of the weight of the right ventricle (RV) to that of the left ventricle (LV) plus interventricular septum (SP), RV/(LV+SP), and the ratio of the weight of the right ventricle (RV) to the body weight (BW), RV/BW, in the hypoxia groups increased significantly as compared with those of the control groups. The amount of immunoreactive FN in the right ventricle increased significantly in the hypoxia groups after exposure to hypoxia environment for 15 days (10.31%±2.15%, mean±S.D.) and for 30 days (9.55%±1.65%) as compared with those in the day 0 control group (3.05%±1.15%, p

Electron microscopic observations of THP-1/E (an etoposide-resistant human monocytic leukaemia cell line) showed a remarkable change of mitochondrial structure. Mitochondria were swollen and cristae were relatively intact. There was no difference in the activity of cytochrome oxidase, an enzyme which contains three subunits coded by mitochondrial DNA (mtDNA) between THP-1/E and THP-1 (the parent cell of THP-1/E). No measurable quantitative change of mitochondrial RNA was observed, but the level of mtDNA in THP-1/E was increased by a factor of about 4 compared with that of mtDNA in THP-1. These results suggest that, on acquisition of resistance to etoposide, some factors affect mitochondria, change its morphology and amplify its DNA.

Phosphatidylinositol (PI), phosphatidylinositol 4-phosphate (PIP), phosphatidylinositol 4, 5-bisphosphate (PIP2), 1, 2-diglyceride (DG), lysophosphatidylcholine (LPC), and free fatty acids (FFA) contents, as well as their fatty acid composition, were measured in transient global cerebral ischemia. ATP and CTP were also studied. Male Wistar rats were subjected to 1, 5, and 30 min of ischemia and 10, 30, and 60 min of recirculation following 30 min of ischemia. In addition, for the quantification of PI, PIP, and PIP2, rats were also subjected to 30 and 60 min of recirculation following 5 min of ischemia. PIP2 and PIP decreased rapidly during 5 min of ischemia and recovered completely after recirculation. DG increased almost at the same rate during ischemia and returned to normal after recirculation. PI showed almost no changes throughout entire course. LPC increased during 5 min of ischemia and returned to normal after recirculation. Stearic acid and arachidonic acid contained in DG increased during 5 min of ischemia, whereas saturated fatty acids increased in LPC. Among the FFA accumulated during ischemia, stearic acid and arachidonic acid increased rapidly and were followed by increases of other FFA. From these results, the pathways for the increase of FFA during ischemia and the fate of FFA after recirculation are discussed. In addition, the importance of the changes of PIP, PIP2, and LPC is also discussed.

Under the assumption that the more hyperreactive the bronchial muscles are, the greater their work hypertrophy, we analyzed the distribution of hypertrophic smooth muscles along airways to see where in the bronchial tree asthmatic constrictions mainly occur. Autopsy lungs from 16 patients with bronchial asthma, 13 with other COPDs, and 20 controls were submitted to morphometry of the bronchial muscles. In microscopic slides, cross sections of airways were taken from the segmental bronchi to the terminal bronchioles. The perimeter length L of the basement membrane and the area S of muscles were measured, and the anatomic radius R and the muscular thickness D were calculated in a standardized circular state, in which the basement membrane was stretched into a circle without changing L or S. On bilogarithmic coordinates of D and R on which data from the asthmatics were pooled, it was shown that hypertrophy of muscles was the most pronounced in larger bronchi where constriction was most likely to occur. Closer analysis of patients, however, revealed that besides this typical pattern, which we designated Type I asthma, there was a group of patients (Type II) in whom hypertrophy involved the entire range of airways, including the bronchioles, suggesting that the site of asthmatic response varies among patients. In nonasthmatic patients with COPD, only mild hypertrophy of muscles was found in the large airways, despite the presence of obstructive lesions mainly in the small airways.

A morphometric pilot study was performed on airway smooth muscle in 20 autopsy lungs with no history of chronic obstructive pulmonary disease (COPD) to establish a basis for the systematic analysis of the behavior of airway muscles in bronchial asthma or COPD. A total of 514 samples of cross-sectioned airways were taken from these lungs, covering as uniformly as possible the whole range from segmental bronchi to terminal bronchioles. In each airway, the perimeter length L of the epithelial basement membrane and the area S of mural smooth muscles were measured using a digital image analyzer, and the thickness D of smooth muscles and the radius R were determined in a standardized state in which the airway was stretched into a circle without changing L or S. On bilogarithmic coordinates, D was found to correlate significantly with R not only in individual cases but also in the total pooled data. D/R, the relative thickness of muscles, increased toward the periphery of the airways. In a theoretical application of Laplace's law to the physical conditions dominating the airway wall, this tendency in D/R suggests that the activity of airflow regulation is highest in terminal airways.

The bacteriology of the isolates from the sputum or the throat swab of patients with respiratory infections visiting a doctor in private practice in Sendai city during the period from March in 1988 to February in 1989 was documented, and their sensitivity to 45 antimicrobial agents was determined. Of the 568 patients, 514 cases had acute pharyngitis, 8 cases each had acute tonsillitis and acute bronchitis, 7 cases were acute pneumonia, 6 cases had herpangina, 18 cases had hand-foot-mouth disease with the signs of respiratory infections, 5 cases had varicella with the signs of respiratory infections and 2 cases were mumps with the signs of respiratory infections. Three hundred strains of potential (greater than or equal to 10(7) CFU/ml) pathogens were recovered from 293 of the 568 cases, which consisted of 124 strains of Haemophilus influenzae, 58 strains of Streptococcus pneumoniae, 45 strains of Staphylococcus aureus, 26 strains of Branhamella catarrhalis, 25 strains of Streptococcus pyogenes, 9 strains of Klebsiella pneumoniae and 13 strains of other species, not including non-fermentile gram-negative bacteria such as Pseudomonas aeruginosa and Acinetobacter calcoaceticus. Staphylococcus aureus and other strains were documented simultaneously in 6 out of 7 cases in which multi-organisms were recovered. Many strains of Staphylococcus aureus were isolated from young patients throughout the year. On the other hand many strains of Branhamella catarrhalis were isolated from elderly patients in winter. The sensitivity of 45 antimicrobial agents of 231 of 300 strains was determined by sensitivity disks (EIKEN, Japan). No strain of the Haemophilus influenzae in this study was resistant to ampicillin. None of the Streptococcus pneumoniae and Streptococcus pyogenes was resistant to ampicillin or cefazolin. None of the Staphylococcus aureus was resistant to cloxacillin, cefazolin, gentamicin or ofloxacin. We conclude from the above results that antibiotic-resistant strains are found presumably only in a very few cases in primary care clinic.

We determined the MICs of ampicillin, methicillin, cefaclor, cefixime, cefteram, ofloxacin and ciprofloxacin against a total of 1,448 strains from 11 species: 464 strains of Staphylococcus aureus, 306 strains of Streptococcus pneumoniae, 114 strains of Streptococcus pyogenes, 37 strains of Branhamella catarrhalis, 329 strains of Haemophilus influenzae, 32 strains of Escherichia coli, 66 strains of Klebsiella pneumoniae, 26 strains of Enterobacter cloacae, 20 strains of Serratia marcescens, 12 strains of Pseudomonas aeruginosa and 42 strains of Acinetobacter calcoaceticus, isolated from the throat swab and the sputum of 2,539 patients with respiratory infections who visited 21 private clinics in Tohoku district of Japan during the period from January to April in 1989. Ciprofloxacin and ofloxacin were more active against S. aureus, B. catarrhalis, P. aeruginosa and A. calcoaceticus than other antibiotics. Ampicillin and cefteram were more active against S. pneumoniae and S. pyogenes than other antibiotics. New-quinolones and cephems of new-generation were active against H. influenzae, E. coli, K. pneumoniae, E. cloacae and S. marcescens. Of 30 strains of S. aureus which were resistant (MIC greater than or equal to 12.5 micrograms/ml) to ampicillin, only one strain was resistant (MIC greater than or equal to 12.5 micrograms/ml) to methicillin. Twenty strains (6.5%) of S. pneumoniae and 49 strains (14.9%) of H. influenzae were resistant (MIC greater than or equal to 1.56 micrograms/ml) to ampicillin. Of 101 strains of H. influenzae of which their beta-lactamase activity was determined by Nitrocephin-method, 27 (26.7%) were beta-lactamase-positive strains. The above results indicated that MRSA is only rarely found in primary care clinics but the incidence of ampicillin-resistant H. influenzae in primary care clinics is almost the same as that of the intensive care clinic, i.e. medical school-affiliated hospitals. Therefore caution should be exercised as regards antibiotic resistance of the causative organism even in primary care clinics.

Cytochrome P450IIE1 (P450IIE1) is involved in metabolic activation of carcinogenic nitrosamines, aniline and benzene. We detected a restriction fragment length polymorphism of the human P450IIE1 gene with the restriction endonuclease DraI. The population was thus divided into three genotypes, namely, heterozygotes (CD) and two forms of homozygotes (CC and DD). The distribution of these genotypes among lung cancer patients differed from that among controls with statistical significance of P less than 0.05 (chi 2 = 7.01 with 2 degrees of freedom). This result strongly suggests that host susceptibility to lung cancer is associated with the DraI polymorphism of the P450IIE1 gene.

Pulmonary fibrosis is a chronic inflammatory disorder characterized by diffuse fibrous remodeling of alveolar spaces. Although much interest is focused on mechanisms of the inflammatory process in pulmonary fibrosis, little is known about the repair and regenerative process. Hepatocyte growth factor (HGF), originally discovered as a mitogen for hepatocyte regeneration, is now recognized as a multifunctional mesenchymal factor for epithelial regeneration, including the regeneration of alveolar type II epithelial cells. Involvement of HGF and its receptor (c-met) is evident in animal models of acute lung injury produced by hydrochloride inhalation. We studied the role of HGF in patients with idiopathic pulmonary fibrosis (IPF) (25 cases), lung fibrosis associated with rheumatoid arthritis (22 cases), and sarcoidosis (39 cases). Immunohistochemical evaluation demonstrated that hyperplastic alveolar type II epithelial cells, as well as alveolar macrophages, were strongly stained with anti-HGF antibody in tissues of patients with IPF. The concentration of HGF in bronchoalveolar lavage fluid (BALF) was significantly higher than in normal controls (0.23 +/- 0.09 pg/microg) in patients with IPF (0.77 +/- 0.88 pg of HGF/microg of albumin, P < 0.001), lung fibrosis associated with rheumatoid arthritis (0.50 +/- 0.64 pg/microg, P < 0.01), and sarcoidosis (0.41 +/- 0.61 pg/microg, P < 0.05). In situ hybridization revealed mRNA for HGF in alveolar macrophages (especially small monocytelike macrophages). These results indicate that the increase in HGF concentration in patients' peripheral air spaces is due to augmented HGF production by alveolar epithelial cells and alveolar macrophages. HGF, through a paracrine mechanism, may play an important role in the repair and healing of the inflammatory lung damage in pulmonary fibrosis.

WATANABE, A., OIZUMI, K., MOTOMIYA, M. and NUKIWA, T. Daily Single-Dose Regimen and Alternate-Two-Week Triple-Dose/Day Regimen of Oral Ofloxacin for the Prophylaxis and Control of Exacerbations of Chronic Respiratory Tract Infections. Tohoku J. Exp. Med., 1995, 176 (1), 25-33-Two different oral ofloxacin regimens, a daily single-dose regimen with 200mg (Regimen I) and an every-two-week multidose regimen with 3×200mg/day (Regimen II) was compared as to the efficacy in controlling repeated acute exacerbations of chronic respiratory tract infections. Fifty-eight patients consisting of 19 patients each of bronchiectasis and pulmonary emphysema, 10 patients of chronic bronchitis, 5 patients of old pulmonary tuberculosis, 4 patients of diffuse panbronchiolitis and 1 patient of multiple pulmonary bullae were evaluated: 32 patients in Regimen I and 26 patients in Regimen II. The corrected mean incidence of exacerbations per case decreased from pre-study 2.47 to intra-study 0.59 in Regimen I, and from pre-study 2.66 to intra-study 0.95 in Regimen II, respectively, with a statistically significant difference (p

An attempt was made to identify Mycobacterium avium and Mycobacterium intracellulare in the M. avium intracellulare complex (MAC) isolated in the Tohoku (38 strains) and Tokai (30 strains) districts of Japan by using DNA probes which are specific for M. avium, M. intracellulare and M. tuberculosis complex, respectively. The incidence of M. avium infection (82%) by far exceeded that of M. intracellulare infection in the Tohoku district of eastern Japan. In the Tokai district of central Japan, the incidence of M. avium infection (57%) were slightly larger than that of M. intracellulare infection. Five of 68 strains showed a positive reaction with two different DNA probes. Thus a possibility of mixed infection could not be ruled out, because reference strains showed a positive reaction with only one species-specific DNA probe.

The pattern of distribution of bacteria, Mycoplasma pneumoniae and virus isolated from the same specimen recovered from the throat swab or the sputum of 479 patients with respiratory infections who were seen in six private clinics in Sendai City of Japan during the period from October to November in 1992 (period I) and from January to February in 1993 (period II) was documented. Of the 479 patients, 234 had acute pharyngitis, 145 had acute bronchitis, 96 had influenza, 21 had acute tonsillitis, 5 had acute pneumonia and 9 had other respiratory infections. One hundred (42.4%) strains of potential pathogen and one strain of M. pneumoniae were recovered from 236 cases in period I, and 66 (27.2%) strains of potential pathogen, one strain of M. pneumonae and 73 strains of Influenza virus (30.0%: 43 of type A Hong-Kong and 30 of type B) from 243 cases in period II. Of the 166 strains, major isolates were Staphylococcus aureus (56 strains), Streptococcus pneumoniae (12 strains), Streptococcus pyogenes (15 strains), Haemophilus influenzae (17 strains), Esherichia coli (4 strains), Klebsiella spp. (35 strains), Pseudomonas aeruginosa (4 strains) and Acinetobacter spp. (23 strains). Only one strain of S. aureus was resistant to methicillin (MIC: 50 micrograms/ml). None of S. pneumoniae was resistant to 1 microgram/ml of ampicillin. Ciprofloxacin was administered to 113 cases and roxythromycin to 220 cases by doctors in charge.(ABSTRACT TRUNCATED AT 250 WORDS)

We devised a new method for measuring esophageal pressure (Pes) with use of a flexible tube without a balloon at a constant rate of airflow through the tube into the esophagus (balloonless method). A study with 133Xe showed that the air that accumulated in the esophagus did not interfere with the measurement of Pes. We measured dynamic compliance (Cdyn) and pulmonary resistance (RL) with the balloonless method in 19 subjects and obtained a static deflation pressure-volume curve (P-V curve) in 10 other subjects. Cdyn was 0.243 +/- 0.099 l/cmH2O and RL was 1.52 +/- 0.42 cmH2O.l-1.s. In 6 of the 10 subjects, a P-V curve was also obtained with the balloon tube (balloon method). K, the index of compliance in the exponential function V = V0(1-e-KP) where V0 is volume at infinite pressure, was 0.136 +/- 0.040 cmH2O-1 with the balloonless method and 0.153 +/- 0.023 cmH2O-1 with the balloon method. No statistically significant difference was found between these two values. In conclusion, Cdyn, RL, and the P-V curve can be obtained precisely with the balloonless method.

In the present study, we investigated the expression of laminin in three murine neoplastic cell lines; 3LL-SA (Lewis lung carcinoma), NA (neuroblastoma) and F9 (teratocarcinoma). Both Western and Northern blot analyses demonstrated that parietal endoderm-like F9 expressed three laminin chains A, B1 and B2. On the other hand, 3LL-SA cells synthesized two laminin chains B1 and B2, and NA cells only B2 chain. The analyses of the restriction fragment length polymorphism indicated that the genes for coding regions of all chains were present and grossly intact both in 3LL-SA and in NA just as in F9. These findings suggest that expression of laminin seems to be transcriptionally regulated in each neoplastic cell line specifically. Since these cell lines produce different forms of laminin, they can be used for investigation of the multifunctions of laminin molecule.

We investigated the expression of laminin in two cell lines with different metastatic potentials established from murine Lewis lung carcinoma. Immunostaining of the cells with anti-laminin antibody and Northern blot analysis of laminin mRNA demonstrated that the high metastatic clone expressed less laminin than the low metastatic one. In contrast, expressions of 67 kDa-laminin receptor were at similar levels between these two lines. These findings show the possibility that endogenous laminin may contribute to the difference in metastatic properties in the murine Lewis lung carcinoma cell lines examined.

NAKAI, Y., KOINUMARU, S., SUZUKI, S., SAITO, J., SUGAWARA, S., NUMATA, Y., SATO, J., MATSUBARA, N. and MOTOMIYA, M. Chemotherapy in Small Cell Lung Cancer - From View Point of Dose Intensity - Tohoku J. Exp. Med., 1992, 168 (2), 427-430 - Results of chemotherapy trials for small cell lung cancer carried out for the past 5 years were analyzed from view point of dose intensity. Early study of CDDP+EP+ADM (1985 to 1987) showed moderate response rate (RR) of 72% with MST of 369 days. Succeeding alternative protocol of CDDP+EP+ VCR/CPM+ADM+MTX (1989-1990) showed improved RR of 88% and MST of 13 months. Actual dose and interval for the alternating regiman was superior to the single arm regimen. Projected relative dose intensity against MAOP protocol including 6 drugs common to our regimen was 0.86 and delivered RDI was 0.61 with comparable RR and MST. The results may indicate that change of dose intensity within the conventional renge does not result in major advantage or disadvantage for substantial prolongation of the survival in SCLC patients. - small cell lung cancer; chemotherapy; dose intensity

The efficacy, safety and usefulness of cefepime (CFPM), a new cephem antibiotic, in bacterial pneumonia, were evaluated in a comparative study against ceftazidime (CAZ). Each drug was administered by intravenous drip infusion at a dose of 1.0 g (nominal potency) twice daily for 14 days, and the following results were obtained. 1. A total of 183 cases were enrolled in this study. Efficacy rates ("good" or better responses) as evaluated by the subcommittee were 90.3% (65/72) in the CFPM group and 94.0% (63/67) in the CAZ group, with no significant difference between the 2 groups. 2. Efficacy rates ("good" or better responses), as evaluated by attending physicians, (in the same bacterial pneumonia cases which were subjected to evaluation by the subcommittee) were 87.5% (63/72) in the CFPM group and 89.6% (60/67) in the CAZ group, with no significant difference between the 2 groups. 3. Bacteriologically, eradication rates were 96.9% (31/32) in the CFPM group and 96.7% (29/30) in the CAZ group with no significant difference between the 2 groups. 4. The incidence of side effects was 5.9% (5/85) in the CFPM group and 4.8% (4/84) in the CAZ group, with no significant difference between the 2 groups. No significant difference was also found between the 2 groups in the incidence of abnormal laboratory findings; 28.4% (23/81) of the case in the CFPM group and 34.1% (28/82) in the CAZ group. 5. As for overall usefulness of the drug in bacterial pneumonia cases, utility rates ("useful" or better evaluations) as evaluated by the subcommittee were 88.9% (64/72) in the CFPM group and 92.5% (62/67) in the CAZ group. The rates as evaluated by investigators (in cases judged as evaluable by the subcommittee) were 87.5% (63/72) and 85.1% (57/67), respectively. There were no significant differences between the 2 groups. These results indicated that CFPM is very useful for the treatment of bacterial pneumonia.

The clinical efficacy, safety and usefulness of Cefepime (CFPM), a new cephem antibiotics, in chronic respiratory infections were evaluated in a comparative study against Ceftazidime (CAZ). Each drug was administered by intravenous drip infusion at a dose of 1.0 g (nominal potency), twice daily for 14 days, and the following results were obtained: 1. A total of 170 cases were enrolled in this study. Efficacy rates ("good" or better responses) as evaluated by the subcommittee were 86.2% (56/65) in the CFPM group and 84.5% (60/71) in the CAZ group, with no significant difference between the two groups. 2. Efficacy rates ("good" or better responses) as evaluated by attending physicians were 83.3% (55/66) in the CFPM group and 84.5% (60/71) in the CAZ group with no significant difference between the two groups. 3. Bacteriologically, eradication rates were 83.3% (40/48) in the CFPM group and 88.2% (45/51) in the CAZ group, with no significant difference between the two groups. 4. Side effects occurred in none of the patients in the CAZ group and in 4 of the 66 patients in the CFPM group. There was a significant difference between the two groups (Fisher's test p = 0.0489). The incidence of abnormal laboratory findings were 17.6% (12/68) in the CFPM group and 21.1% (16/76) in the CAZ group. There was no significant difference between the two groups. 5. The utility rates evaluated by the subcommittee were 81.8% (54/66) in the CFPM group and 84.5% (60/71) in the CAZ group with no significant difference between the two groups. Only in the incidence of side effects, there was a significant difference between the two groups (Fisher's test p = 0.0489), but there was no significant difference in other items of efficacy, safety and usefulness between the two groups. These results indicate that CFPM is useful for the treatment of chronic respiratory tract infections.

We investigated the possibility of shortening the interval between courses of the commonly prescribed 28-day MVP (mitomycin C, vindesine, and cisplatin) regimen in patients with non-small-cell lung cancer (NSCLC). We conducted a nonrandomized phase II study using recombinant human granulocyte colony-stimulating factor (G-CSF, Chugai) to explore the possibility of shortening the cycle length to 21 days and compared the results with those obtained in historical controls who had received the standard 28-day regimen. A total of 40 patients, 37 of whom were evaluable, were entered in the 21-day treatment group of the trial and were compared with 38 historical controls who had received standard 28-day cycles of MVP at our institution. Patients in the 21-day group received mitomycin C at 8 mg/m2 on day 1, vindesine at 3 mg/m2 on days 1 and 8, and cisplatin at 80 mg/m2 on day 1, with the schedule being repeated every 21 days. Controls had received the same regimen, albeit at 28-day intervals. G-CSF was given s.c. to the patients in the 21-day group at a daily dose of 2 micrograms/kg from day 2 to day 21 of every MVP cycle. The administration of G-CSF to these patients accelerated neutrophil recovery as compared with that observed in the historical controls. Significant differences were found between the two groups in terms of mean neutrophil nadirs (2666/microliters in the first cycle and 1369/microliters in the second for the G-CSF group vs 416/microliters in the first cycle and 685/microliters in the second cycle for the control group; P0.0001) and the mean duration of neutropenia (or = 1000/microliters; 1.0 day in the first cycle and 1.7 days in the second for the G-CSF group vs 8.0 days in the first cycle and 6.9 days in the second for the control group; P0.0001). This enabled 32 (86%) of 37 patients in the G-CSF group to completeor = 2 cycles on schedule. In 10 patients, the bone marrow aspirates taken after G-CSF administration showed increases in band neutrophil and myelocyte percentages. In conclusion, MVP treatment of patients with NSCLC at 21-day intervals is possible with the support of G-CSF.

The presence or absence of a methicillin resistance gene in 58 clinical isolates of Staphylococcus aureus was examined by the polymerase chain reaction (PCR) and Southern blot analyses. The results were analyzed in relation to those of the MIC assay of methicillin and oxacillin. PCR assay results were identical to those of Southern blot analysis of genomic DNA digested with HindIII (positive, 28 strains; negative, 30 strains). Among the 28 PCR-positive strains, 6 strains showed methicillin susceptibility by the conventional susceptibility test (MICs, less than or equal to 8 micrograms/ml). Culturing of the six strains with ceftizoxime led to an increase in the phenotypic level of resistance to methicillin and oxacillin, indicating that these strains should be classified as methicillin-resistant S. aureus (MRSA). The PCR assay was found to be a sensitive and reliable procedure for the rapid diagnosis of MRSA infection, even in cases in which the conventional MIC assay failed to detect MRSA.

We studied the effects of various protein kinase inhibitors on the attachment of mouse lung carcinoma 3LL cells to the fibronectin (FN) substratum. Calmodulin antagonists (W-7 and W-13) and myosin light chain kinase inhibitors (ML-7 and ML-9) exhibited the inhibitory effect for the attachment, while inhibitors of protein kinases A and C were ineffective. Since Arg-Gly-Asp-containing hexapeptide blocked the attachment, cell surface FN receptor appeared to be involved in this mechanism. These results support the hypothesis that the cell attachment requires the rearrangement of the cytoskeleton in association with the phosphorylation of myosin light chain which would lead to the clustering of the cell surface FN receptors.

The incidence of pulmonary embolism was retrospectively studied in a University Chest Institute and its affiliated hospital in Sendai, Japan, whose annual numbers of discharged patients from chest medical wards and lung operations as a whole are about 600 and 400, respectively. Before 1975 there was no documented patient with pulmonary embolism. Since then 70 patients had been clinically suspected of having pulmonary embolism and 31 of the 70 were diagnosed as having pulmonary embolism; 15 without and 16 with surgical operations in the immediate past. Fourteen of the 31 patients required combined perfusion and aerosol inhalation lung imaging for diagnosis. Twelve postoperative patients could be diagnosed as pulmonary embolism by comparing postoperative perfusion lung images taken at the time of suspicion with preoperative perfusion counterparts. Although it is said to be rising, the incidence of pulmonary embolism in a chest hospital still seems to remain low compared with that in western countries. For postoperative patients, comparison with preoperative studies was found very useful in diagnosing postoperative pulmonary embolism. The importance of preoperative perfusion lung imaging cannot be overstressed not only as a preoperative lung function test but as a baseline study to be compared with postoperative perfusion images when pulmonary embolism is clinically suspected in postoperative patients.

Efficacy and safety of a new injectable cephem antibiotic, cefpirome sulfate (hereafter, CPR), against respiratory tract infections were examined and compared with those of a control drug, ceftazidime (hereafter, CAZ). As a rule, CPR 0.5 g twice a day, 1.0 g twice a day, or CAZ 1.0 g twice a day (hereafter CPR 0.5 g group, CPR 1.0 g group, and CAZ group) was administered for 14 days and the following results were obtained. 1. The total number of cases was 470 (155 cases in the CPR 0.5 g group, 160 cases in the CPR 1.0 g group, and 155 cases in the CAZ group). Among them 390 cases were subjected to analyses of clinical efficacy by the efficacy evaluation committee (131 cases in the CPR 0.5 g group, 131 cases in the CPR 1.0 g group and 128 cases in the CAZ group). 2. Efficacy rates determined by the efficacy evaluation committee were 82.4% (108/131) for the CPR 0.5 g group, 81.7% (107/131) for the CPR 1.0 g group, and 83.6% (107/128) for the CAZ group. Efficacy rates determined by the physician in charge were 82.0% (105/128) for the CPR 0.5 g group, 80.5% (99/123) for the CPR 1.0 g group, and 88.5% (108/122) for the CAZ group. No statistically significant difference was observed among the 3 groups. In evaluation of equivalency, clinical efficacy for the CPR 0.5 g group and the CPR 1.0 g group determined by the clinical efficacy evaluation committee was proved to be statistically equivalent to that for the CAZ group. 3. In patients with pneumonia, efficacy rates determined by the efficacy evaluation committee were 87.1% (61/70) for the CPR 0.5 g group, 80.7% (71/88) for the CPR 1.0 g group, and 78.9% (56/71) for the CAZ group. Efficacy rates determined by the physician in charge were 85.3% (58/68) for the CPR 0.5 g group, 80.7% (67/83) for the CPR 1.0 g group, and 86.2% (56/65) for the CAZ group and no statistically significant difference was observed among the 3 groups. In patients with chronic respiratory tract infection, efficacy rates determined by the efficacy evaluation committee were 77.0% (47/61) for the CPR 0.5 g group, 83.7% (36/43) for the CPR 1.0 g group, and 89.5% (51/57) for the CAZ group. Efficacy rates determined by the physician in charge were 78.3% (47/60) for the CPR 0.5 g group, 80.0% (32/40) for the CPR 1.0 g group, and 91.2% (52/57) for the CAZ group. No statistically significant difference was observed among the 3 groups.(ABSTRACT TRUNCATED AT 400 WORDS)

In order to determine the optimal dose of cefpirome sulfate (HR810, CPR) against respiratory tract infections (RTI), an optimal dose-finding study was conducted on cases of chronic RTI, and the clinical properties of the drug were compared with those of ceftazidime (CAZ). Inpatients with chronic RTI were randomly assigned to 3 groups: an HR 0.5 g group, receiving 0.5 g X 2/day of CPR an HR 1.0 g group, receiving 1.0 X 2/day of CPR and a CAZ group, receiving 1.0 g X 2/day of CAZ. As a rule, the drugs were administered by intravenous drip infusion for 14 days, after which period clinical efficacy, bacteriological response, safety, and utility were investigated. Of the total 121 cases, 106 were subject to analysis of clinical efficacy, including 38 cases in the HR 0.5 g group, 32 in the HR 1.0 g group, and 36 in the CAZ group. Efficacy rates in the assessment by the committee were 84.2% for the HR 0.5 g group, 75.0% for the HR 1.0 g group, and 86.1% for the CAZ group, without any significant difference between the 3 groups. The bacterial elimination rates were 73.9%, 75.0% m and 88.5%, respectively, without any significant difference between the 3 groups. Associated reactions were noted in 2 of 36 cases in the HR 1.0 g group (eruption and diarrhea), but not in the other 2 groups. The incidence of abnormal clinical laboratory findings was 23.1% in the HR 0.5 g group, 22.2% in the HR 1.0 g group, and 22.5% in the CAZ group, without any significant difference between the 3 groups. Utility rates were 84.2% for the HR 0.5 g group, 74.2% for the HR 1.0 g group, and 86.1% for the CAZ group, without any significant difference between the 3 groups. The HR 0.5 g and 1.0 groups showed no difference in clinical efficacy, bacteriological response, safety, and utility against RTI, and the results of both groups were about equal to those of the CAZ group.

We investigated the effects of phenytoin on the rate of enzymatic release of free fatty acids and on the levels of energy metabolites and nucleoside phosphates in ischemic brain. Phenytoin (10 mg/kg i.v.) was administered 30 minutes before the onset of ischemia induced in 30 male Wistar rats by occluding the basilar and both common carotid arteries. The rats' brains were frozen in situ after 0, 5, or 30 minutes of ischemia or 10, 30, or 60 minutes of recirculation following 30 minutes of ischemia (n = 5 at each time). Nucleoside triphosphate levels were higher in the phenytoin-treated rats than in corresponding untreated rats at each time during and after ischemia. Phenytoin significantly attenuated the accumulation of lactate and free fatty acids (arachidonic acid and stearic acid) during ischemia and accelerated their recovery during recirculation. These results suggest that phenytoin has favorable protective effects on ischemic brain and that phenytoin may inhibit calcium-mediated phenomena, especially the inositol cycle, in cerebral ischemia.

The purpose was to study whether procaterol, a beta 2-stimulator, facilitated mucociliary transport on the ciliated airways in the human lungs. From immediately after inhalation of [99mTc]albumin aerosol, radioactivity of the thorax was continuously measured anteriorly by a gamma camera with the examinee in the supine position; the data were sequentially stored in a computer in 10-s frame mode. Three puffs (30 micrograms) of procaterol were inhaled from a metered dose inhaler at 60 min in the same supine position, and measurement of radioactivity was continued for 30 min more. Spirometry was performed before and after the measurement of radioactivity. A group of 8 normal subjects and 34 patients with various lung diseases, including 6 with bronchial asthma in remission, were studied. In addition to observation of mucus transport on the large airways by radioaerosol inhalation lung cinescintigraphy, the time-activity curve from the right lung was evaluated and the quantitative parameters for evaluating mucociliary clearance were calculated for the right lung. Following inhalation of procaterol, there were neither significant acceleration in mucus transport on the large airways by cinescintigraphy nor significant changes in the slope of time-activity curves. Quantitative parameters did not show any significant changes either, although spirometry indicated significant bronchodilation. We conclude that three puffs of inhaled procaterol neither necessarily accelerate mucus transport nor facilitate mucociliary clearance in the human lung.

A water-soluble fraction was isolated from delipidated cells of Mycobacterium bovis strain BCG by extraction with hot water. Chemical analyses revealed that the above fraction presumably consisted of a peptidoglycan containing 5-10% of nucleic acids. When it was injected into guinea pigs with Freund's incomplete adjuvant plus egg white albumin as antigen, an increase of circulating antibody was observed as shown by the augmented titers of precipitin and hemagglutinin. The results of skin test and corneal reaction indicated that the fraction mentioned above induced delayed hypersensitivity to egg white albumin. Footpad reaction in mice demonstrated that the above fraction induced delayed hypersensitivity to sheep red blood cells. It was confirmed in addition that the adjuvant activity of this fraction was not due to the presence of nucleic acids. This adjuvant-active fraction was designated as HSA (hot-water soluble adjuvant).

The incidence and clinical features of drug fever induced by antibiotics were investigated. Of a total of 390 patients analyzed, 193 had malignant diseases (lung cancer in most cases) and the remaining 197 had non-malignant diseases, of which the majority comprised pulmonary infectious diseases such as pneumonia, lung abscess and chronic infections. beta-Lactams most frequently induced drug fever. Piperacillin induced drug fever in 18 of 108 (17%), cefotaxime in 11 of 72 (15%), ceftizoxime in 7 of 49 (14%) and cefoperazone in 6 of 74 patients (8%). In contrast, the incidence of drug fever caused by ampicillin and that by cefazolin were in one of 39 (3%) and in none of 44 (0%), respectively. On the other hand, antimicrobial agents other than beta-lactams only rarely induced drug fever. The higher incidence of drug fever caused by newer derivatives of beta-lactam antibiotic suggests that the side chain attached to their core moiety might be involved in the mechanism of drug fever. In patients with malignancy who were on antibiotics, respiratory infection was the most frequent cause of fever exceeding 38 degrees C. In contrast, in patients with non-malignant diseases, the use of antibiotic per se was the most frequent cause of the fever which recurred during antibiotic therapy after a previous febrile episode had subsided. The most common feature of drug fever induced by the use of an antibiotic was as follows: A low-grade fever at the time of onset is followed by a high and remittent fever. The highest diurnal body temperature rises gradually, and then the fever subsides promptly after cessation of the causative antibiotic. The fever of this type accounted for 70% of all the drug fever in this study. A transient elevation of serum level of lactic dehydrogenase was associated with drug fever in one half (25/49, 51%) of the patients. A transient and slight decrease from the normal range in counts of neutrophils and platelets were observed in 11 (23%) and in 4 (8%) of 48 patients with drug fever, respectively. These changes in laboratory findings were considered as the possible consequence of allergic processes involved in the development of drug fever and thus seem to be a helpful index for establishing the diagnosis of drug fever.

A VP-16-resistant subline was established from THP-1 human monocytic leukemia cells by subculturing in stepwise increasing concentrations of the drug. The resistant cells (THP-1/E) were capable of sustaining continuous growth in 1.0 microgram/ml VP-16. The 50% inhibition dose (IC50) was 1.4 micrograms/ml or a 35-fold of the parent cells. A more than 18-fold IC50 was also obtained with teniposide (VM-26). However, no substantial cross-resistance was observed with 5 other antineoplastic drugs, IC50 values being limited below several times of THP-1.

小細胞肺癌に対するvincristine+cyclophosphamide+mitomycin-c (VEM療法) におけるPSK併用の有効性を検討する目的で無作為化比較試験を行なった. PSK群46例, 対照群47例で, それぞれの有効率は45%, 46%で有意差はなく、効果持続期はPSK群がすぐれていた. 生存期間は両群で有意差はないが、層別すると有効例, 予後因子良好例でPSK群の生存期間延長傾向がみられた.

We attempted to find out whether there is a correlation between viral infection and secondary bacterial infection on the basis of the analysis of the results of the culture of virus and bacteria in the same specimen from the throat swabs of 95 patients who had an acute upper respiratory inflammation when they visited a doctor in private practice in Sendai city during the epidemic caused by influenza virus. Viral culture was performed by a microplate-method devised originally by Numazaki. The influenza virus was recovered from 56 cases (59%) consisting of 43 cases of type A (Hong-Kong) and 13 cases of type B. From 73 cases, (77%), 79 strains of possibly pathogenic bacteria were recovered, consisting of 43 strains of H. influenzae, 18 strains of S. aureus, seven strains of S. pneumoniae, four strains each of C. freundii and S. liquefaciens and one strain each of beta-haemolytic Streptococcus and B. catarrhalis. The incidence of positive culture of both virus and possibly pathogenic bacteria was high already at the early stage (2-3 days) of the disease. We found no correlation between the type of virus and the species of the microbial isolates. There was no difference in the incidence of positive bacterial culture in relation to age group. We suggest that a secondary bacterial infection occurs already at the early stage of the disease after viral infection because the incidence of positive culture of possibly pathogenic bacteria was high at the above stage.

SAIJO, Y., KUMANO, N., TOKUE, Y., SATOH, K., OIZUMI, K. and MOTOMIYA, M. Characterization of Resistance to VP-16 in Human Leukemic Cell Line. Tohoku J. Exp. Med., 1989, 159 (4), 299-306-Resistance mechanism was studied in the VP-16-resistant human leukemic cell line (THP-1/E) which was developed by continuous drug exposure. The drug uptake and efflux studies revealed no decrease in net cellular drug accumulation. VP-16-induced DNA single- and double-strand breaks in the whole THP-1/E cells decreased significantly compared to the sensitive counterpart as assessed by alkaline elution methods. Decrease in DNA SSBs was also observable in the isolated nuclei from the THP-1/E cells. The resistance to VP-16 in THP-1/E appeared to be independent of altered membrane permeability, and more likely to be associated with decreased VP-16-mediated DNA cleavage.