Nobuhiro Narita

Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells.

Saito S, Tsukaguchi N, Hasegawa T, Michimata T, Tsuda H, Narita N. Distribution of Th1, Th2, and Th0 and the Th1/Th2 cell ratios in human peripheral and endometrial T cells. AJRI 1999; 42:240–245

ABO blood group genotype and plasma von Willebrand factor in normal individuals

von Willebrand factor (vWF) is a multimeric plasma protein with ABO (H) blood group sugar chains. We investigated a total of 330 plasmas from normal individuals having various ABO genotypes, with special reference to vWF antigen and its platelet glycoprotein‐Ib‐related biological activities, termed ristocetin cofactor (RCof) and botrocetin cofactor (BCof). RCof reflects the biological activity of higher vWF multimers, while BCof reflects that of vWF of multimers of all sizes. Plasmas from normal individuals carrying one O gene (genotypes AO and BO) had slightly, but proportionally lower levels of vWF antigen, RCof, and BCof than those carrying no O gene (genotypes AA, AB, and BB). Normal plasmas from individuals carrying two O genes (genotype 00) showed much lower values for these parameters than the other plasmas, as previously reported. However, multimeric analysis of plasma vWF antigen revealed no differences among the different genotypes.

Mechanisms of action of the novel sulfonamide anticancer agent E7070 on cell cycle progression in human non-small cell lung cancer cells.

E7070 is a novel sulfonamide antitumoragent that exhibits potent antitumoractivity in vitro and in vivo.This compound affects cell cycleprogression in human tumor cells. Toelucidate the mechanisms by which E7070inhibits tumor cell growth, we establishedand characterized an E7070-resistantsubline, A549/ER, from a human non-smallcell lung cancer cell line A549. Flowcytometric analyses demonstrated anincrease in G0/G1 and a decrease in S phasepopulations in cells treated with E7070 at20 or 100 μg/ml for 24 h. Longerexposure to E7070, i.e. 48 and 72 h,increased the G2/M phase fraction in A549cells. These inhibitory actions of E7070on cell cycle progression were not observedin A549/ER cells. E7070 inhibited thephosphorylation of pRb, decreasedexpressions of cyclin A, B1, CDK2, and CDC2proteins, and suppressed CDK2 catalyticactivity with the induction of p53 andp21 proteins in A549 cells but not inA549/ER cells. Taken together, theseresults suggest that E7070 exerts itsantitumor effects by disturbing the cellcycle at multiple points, including boththe G1/S and the G2/M transition, in humanlung cancer cells.

Enhanced Interleukin Production after Long-Term Administration of Erythromycin Stearate

The effects of erythromycin stearate (10 mg/kg/day) were studied on productions of interleukin (IL)-1 and -2 in mice after a long-term treatment. A 28-day treatment resulted in higher levels of IL-1 production by macrophages and of IL-2 production by splenocytes, while a 7-day treatment did not increase them. T-cell growth factor activity of IL-2 preparation prepared on day 28 of treatment as determined by HT-2 cell proliferation was reduced by about 40% in the presence of anti-murine IL-4 monoclonal antibodies, while control IL-2 activity was not reduced. Furthermore, a 28-day treatment with erythromycin stearate increased concanavalin A-induced blastogenesis of splenocytes significantly. These results suggest that long-term treatment with erythromycin stearate can stimulate host defense by increasing interleukin production.

Adjuvant effect of clarithromycin on chemotherapy for murine lung cancer.

Clarithromycin (CAM) increased the median survival of patients with unresectable non-small-cell lung cancer who had received chemotherapy and/or radiotherapy [Chemotherapy 1997;43:288–296]. The present study was performed to ascertain whether CAM alone exhibits an antitumor effect against Lewis lung carcinoma (LLC) and to analyze the nature of its adjuvant effect on LLC-inoculated C57BL/6 mice. CAM at 10 mg/kg/day retarded the growth of subcutaneously inoculated LLC cells; consequently, the mean survival time of mice with LLC increased. This treatment was also effective in reducing the number of tumor nodules in the lung after intravenous inoculation with LLC cells. When tumor-bearing mice received an intravenous injection of vindesine sulfate (7 mg/kg) and cisplatin (6 mg/kg) 7 days after tumor inoculation, the chemotherapeutic effect was significantly enhanced by CAM treatment when it started 7 days after chemotherapy, but not when it started the day after chemotherapy. The delayed initiation of CAM treatment resulted in the enhancement of natural killer cell activity and CD8+ T cell cytotoxicity and increased the number of interferon-γ-producing T cells and interleukin-4-producing T cells. These findings indicate that CAM can exhibit an antitumor effect by itself and also induce the well-balanced expansion of helper T cell subsets in tumor-bearing mice recovering from the immunosuppression caused by chemotherapy. CAM may therefore be a promising adjuvant drug in anticancer chemotherapy, and treatment with this macrolide should be initiated at some interval after basic cancer therapy.

Significant Survival Benefit to Patients with Advanced Non-Small-Cell Lung Cancer from Treatment with Clarithromycin

We carried out a randomized study of 49 consecutive patients with unresectable primary lung cancer to determine whether clarithromycin (CAM), a 14-membered ring macrolide, can improve outcome. A total of 49 patients (42 patients with non-small-cell lung cancer and 7 patients with small-cell lung cancer) had received prior chemotherapy, radiotherapy or both during their hospital stay. They were randomly allocated into two study groups on the first visit after discharge: 25 patients (22 patients with non-small-cell lung cancer, 3 patients with small-cell lung cancer) were assigned to receive CAM (400 mg/day, orally), and 24 patients (20 patients with non-small-cell lung cancer, 4 patients with small-cell lung cancer) did not receive CAM. CAM treatment after randomization was open and the treatment was to be continued as long as the patients could tolerate CAM. There was no significant difference in the median survival time for small-cell lung cancer between the CAM group and the non-CAM group. However, CAM treatment significantly increased the median survival time for non-small-cell lung cancer patients, the median survival for the CAM group was 535 days and that for the non-CAM group was 277 days. Analyses of prognostic factors showed that only treatment with CAM was predictive of longer survival for non-small-cell lung cancer, and other tested covariates had no effects on the prognosis. There were no remarkable side effects observed in the CAM group throughout treatment. We conclude that long-term treatment using CAM is beneficial for unresectable non-small-cell lung cancer patients and that it can increase the median survival of patients with advanced disease.

Frequent mutations of Ki‐ras but no mutations of Ha‐ras and p53 in lung lesions induced by N‐nitrosobis(2‐hydroxypropyl)amine in rats

Point mutations of the Ki‐ras and p53 genes in rat lung lesions induced by N‐nitrosobis(2‐hydroxypropyl)amine (BHP) were investigated by polymerase chain reaction‐single‐strand conformation polymorphism analysis followed by direct sequencing using paraffin‐embedded tissues. Male Wistar rats 6 wk old were given 2000 ppm BHP in drinking water for 15 wk. Another group was given drinking water without BHP. The rats were killed 20–27 wk after the beginning of the experiment. Lung adenomatous and squamous lesions, including carcinomas, were induced. The frequencies of Ki‐ras mutations were 40% (six of 15) in alveolar hyperplasias, 36% (five of 14) in adenomas, 72% (18 of 25) in adenocarcinomas, 20% (three of 15) in squamous metaplasias, 50% (three of six) in squamous cell carcinomas, and 50% (five of 10) in adenosquamous carcinomas. The mutations were all G → A transitions at the second position of codon 12; no other mutations were detected. However, Ha‐ras mutations in exons 1 and 2 and p53 mutations in exons 5, 6, and 7 were not detected in adenocarcinomas and squamous cell carcinomas. These results indicate that Ki‐ras mutation is an early genetic event in some adenomatous and squamous lung carcinogenesis and that Ki‐ras mutations can cause benign lesions to convert to malignant lesions. The results also show that Ha‐ras and p53 mutations are not involved in rat lung carcinogenesis induced by BHP.

T‐Cell Receptors Are Expressed but Down‐Regulated on Intradecidual T Lymphocytes

PROBLEM: Dietl et al. considered “intradecidual T cell tolerance towards fetal antigens” with their observation that intradecidual T cells lack immunohistochemically detectable amounts of T cell receptor (TCR) molecules while expressing normal amounts of CD3 molecules during early normal pregnancy.

The relation of fat-free mass to maximum exercise performance in patients with chronic obstructive pulmonary disease.

To assess the factors determining maximum exercise performance in patients with chronic obstructive pulmonary disease (COPD), we examined nutritional status with special reference to body composition and pulmonary function in 50 stable COPD patients. Nutritional status was evaluated by body weight and body composition, including fat mass (FM) and fat-free mass (FFM) assessed by bioelectrical impedance analysis (BIA). Exercise performance was evaluated by maximum oxygen uptake (Vo2max) on a cycle ergometer. A total of 50 patients (FEV1= 0.98 L) was divided randomly into either a study group (group A, n= 25) or validation group (group B, n= 25). Stepwise regression analysis was performed in group A to determine the best predictors of Vo2max from measurements of pulmonary function and nutritional status. Stepwise regression analysis revealed that Vo2max was predicted best by the following equation in group A: Vo2max (mL/min) = 10.223 × FFM (kg) + 4.188 × MVV (L/min) + 9.952 × DLco (mL/min/mmHg) − 127.9 (r= 0.84, p < 0.001). This equation was then cross-validated in group B: Measured Vo2max (mL/min) = 1.554 × Predicted Vo2max (mL/min) − 324.0 (r= 0.87, p < 0.001). We conclude that FFM is an important factor in determining maximum exercise performance, along with pulmonary function parameters, in patients with COPD.

Antitumor Effect of Erythromycin in Mice

Oral administration of erythromycin in the dose range of 1-10 mg/kg increased the survival times of tumor-bearing mice in both allogeneic and syngeneic mouse systems by two- to three-fold as compared with those of vehicle control mice, with the maximum effect at a dose of 5 mg/kg/day. During the early phase of tumor transplantation, tumoricidal macrophages and natural killer cells were active in the antitumor resistance of erythromycin-treated mice. Thereafter, the tumoricidal activity of macrophages became stronger as serum levels of interleukin-4 (IL-4) rose. Furthermore, treatment of mice with anti-IL-4 monoclonal antibody abolished the antitumor resistance conferred by erythromycin. These results indicate that erythromycin exhibits an indirect antineoplastic activity by enhancing the production of IL-4 which augments the tumoricidal activity of macrophages.