Yasushi Shigeoka

Sulindac sulfide and caffeic acid phenethyl ester suppress the motility of lung adenocarcinoma cells promoted by transforming growth factor-β through Akt inhibition

Abstract Cell migration is essential for invasive and metastatic phenotypes of cancer cells. Potential chemopreventive agents of cancer—sulindac sulfide, caffeic acid phenethyl ester (CAPE), curcumin, and (+)-catechin—have been reported to interfere with several types of intracellular signaling. In this study, we examined the effects of these agents on transforming growth factor-β(TGF-β)-induced motility and Akt phosphorylation in A549 cells. Judged by gold particle phagokinesis assay, sulindac sulfide, CAPE, and curcumin suppressed the motility of A549 cells promoted by TGF-β. LY294002, a specific inhibitor of phosphatidylinositol 3-kinase(PI3K)/Akt signaling, also suppressed TGF-β-induced motility and Akt phosphorylation. Sulindac sulfide and CAPE, but not curcumin, suppressed TGF-β-induced Akt phosphorylation. We conclude that sulindac sulfide and CAPE suppress the motility promoted by TGF-β in lung adenocarcinoma cells through the suppression of Akt. Our observations raise the possibility that these agents, except for (+)-catechin, can be applied not only as chemopreventive agents but also as anti-metastatic therapy.

Elevated urinary 8‐hydroxydeoxyguanosine, a biomarker of oxidative stress, and lack of association with antioxidant vitamins in chronic obstructive pulmonary disease

Objective:  The purpose of this study was to investigate whether patients with COPD are under oxidative stress and to elucidate the relationship between the level of oxidative stress and antioxidant vitamins.

Expression of functional leukotriene B4 receptors on human airway smooth muscle cells

BACKGROUND Leukotriene B4 (LTB4) increases in induced sputum and exhaled breath condensate in people with asthma. Furthermore, the T(H)2-type immune response and airway hyperresponsiveness induced by ovalbumin sensitization is markedly suppressed in LTB4 receptor (BLT) 1 null mice. These studies suggest that LTB4 may contribute to asthma pathophysiology. However, the direct effects of LTB4 on human airway smooth muscle (ASM) have not been studied. OBJECTIVES We sought to determine the expression of LTB4 receptors on human ASM and its functional role in mediating responses of human ASM cells, and the effect of LTB4 on these cells. METHODS Immunohistochemistry, RT-PCR, Western blotting, and flow cytometry were used to determine the expression of LTB4 receptors. To determine the effect of LTB4 on human ASM cells, cell proliferation was assessed by counting cells, and chemokinesis was assessed by gold particle phagokinesis assay. RESULTS We confirmed expression of both BLT1 and BLT2 in human ASM cells in bronchial tissue and in cell culture. LTB4 markedly induced cyclin D1 expression, proliferation, and chemokinesis of human ASM cells. LTB4 also induced phosphorylation of both p42/p44 mitogen-activated protein kinase (MAPK) and downstream PI3 kinase effector, Akt1. However, we observed no induction of c-Jun N-terminal kinase or p38 MAPK. Notably, LTB4-induced migration and proliferation of ASM cells were inhibited by the BLT1 specific antagonist, U75302, and by inhibitors of p42/p44 MAPK phosphorylation (U1026), and PI3 kinase (LY294002). CONCLUSIONS These observations are the first to suggest a role for a LTB4-BLT1 signaling axis in ASM responses that may contribute to the pathogenesis of airway remodeling in asthma.

Phase II Study of Weekly Paclitaxel in Patients with Non-Small Cell Lung Cancer Who Have Failed Previous Treatments

Objective: New effective therapy is desirable for patients with non-small cell lung cancer (NSCLC) who have failed previous treatments. Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for NSCLC in a second-line setting. Methods: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and one or more prior therapies were enrolled. We administered weekly infusions of 80 mg/m2 paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, each patient was treated for a minimum of 4 cycles. Results: Of 39 patients enrolled, 1 patient achieved complete response and 11 patients achieved partial response (response rate, 31%: 95% confidence interval, 17–48%). The median survival time was 43 weeks (range, 7–128 weeks). Grade 3 or 4 leukopenia occurred in only 7 patients (18%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2.26 and 5%, respectively). Although all patients recovered rapidly with corticosteroid treatment, drug-induced pneumonitis was observed in 3 patients (8%). Conclusion: Low-dose weekly paclitaxel is a promising therapy with high effectiveness for advanced NSCLC in patients with NSCLC who have failed previous treatments.

Phase II Trial of Weekly Paclitaxel in Previously Untreated Advanced Non-Small-Cell Lung Cancer

Objective: New effective therapy is desirable for outpatients with advanced non-small-cell lung cancer (NSCLC). Fractionated administration of paclitaxel may be less toxic and more active against NSCLC. The aim of this study was to evaluate the activity and toxicity of weekly paclitaxel therapy for chemotherapy-naive NSCLC. Methods: Patients with pathological or cytological diagnosis of NSCLC, measurable lesions, and no prior therapy were enrolled. We administered weekly infusions of 80 mg/m2 paclitaxel 3 times in a 4-week cycle. In the absence of progressive disease or intolerable toxicity, we treated each patient for a minimum of four cycles. Results: Of 35 patients enrolled, 17 patients achieved partial response, although no complete responses were observed (response rate 49%; 95% confidence interval 32–66%). The median survival time was 55 weeks (range 6–93 weeks). Grade 3 or 4 leukopenia occurred in only 1 patient (3%). Neurotoxicity was the most frequent adverse effect (grades 1 and 2, 26 and 3%, respectively). Serious toxicity, observed in 2 patients (6%), was interstitial pneumonia, and 1 patient died from sequela. Conclusion: Low-dose weekly paclitaxel is a promising therapy for advanced NSCLC with high effectiveness and low toxicity.

The influence of granisetron on the pharmacokinetics and pharmacodynamics of docetaxel in Asian lung cancer patients.

BACKGROUNDDocetaxel, which undergoes hepatic metabolism via cytochrome P450 3A4, is a promising anticancer agent. Toxicity is serious problem, however, because it is difficult to predict the cytochrome P450 3A4 activity of the drug. Moreover, drug-drug interactions involving cytochrome P450 3A4 enzymes are important. Granisetron, a selective antagonist of the 5-hydroxytryptamine3 receptor, also undergoes hepatic metabolism via cytochrome P450 3A4. In this study, we investigated the influence of granisetron on the pharmacokinetics and pharmacodynamics of docetaxel in Asian patients with lung cancer. METHODSSix patients with advanced lung cancer were treated with doses of docetaxel (60 mg/m2). In the first course of treatment, no antiemetic agents were administered. In the second course, all patients received 3.0 mg of granisetron before 30-minute administration of docetaxel. In each of the treatment courses, blood samples (5 mL) were obtained for pharmacokinetic study at the following times: 0, 0.5, 1.5, 2.0, 3.0, 5.0, 8.0, and 24 hours after the start of the docetaxel infusion. RESULTSSix patients were enrolled in this pharmacokinetics study. The mean ± SD systemic clearance of docetaxel administered alone or in combination with granisetron was 32.9 ± 8.3 and 28.2 ± 5.9, respectively. The area under the concentration-versus-time curve of plasma docetaxel (alone or in combination with granisetron) ranged from 1.355 to 2.773 and 1.647 to 3.079 μg × h/mL (mean ± SD: 1.936 ± 0.541 and 2.219 ± 0.510 μg × h/mL), respectively. There was no significant difference in mean residence time (or invariance of residence time) between the single dose of docetaxel and the combination of docetaxel and granisetron. DISCUSSIONWe found no significant difference in the pharmacokinetic and pharmacodynamic parameters of docetaxel between the single dose of docetaxel and the combination of docetaxel and granisetron. However, a wide interindividual variation existed in cytochrome P450 3A4 activity. It is clear that the results of the present study should be confirmed in a population study involving a larger number of subjects addressing the genetic variations of drug metabolizing enzymes, drug receptors, and drug transporters.

UFT plus vinorelbine in advanced non-small cell lung cancer: a phase I and an elderly patient-directed phase II study.

Purpose: The combination of tegafur-uracil (UFT) with vinorelbine has provided synergistic activity against non-small cell lung cancer (NSCLC) in experimental models. The recommended dose of UFT in combination with vinorelbine in NSCLC was determined in a phase I study. The phase II study evaluated efficacy and tolerability of this combination in elderly patients. Methods: Vinorelbine was infused on days 1 and 8, and UFT was administered twice daily on days 2 to 6 and days 9 to 13 of a 3-week cycle. UFT and vinorelbine were increased during the phase I study from 400 to 600 mg/d and 20 to 25 mg/m2, respectively, in 12 patients. In the phase II portion, previously untreated elderly patients were treated with 600 mg/d UFT and 20 mg/m2 vinorelbine. Results: At the dose level of 600 mg/d UFT and 25 mg/m2 vinorelbine, dose-limiting toxicity of neutropenia or neutropenic fever was observed in two of three patients, determining the recommended dose of 600 mg/d UFT and 20 mg/m2 vinorelbine. In 30 evaluable elderly patients of the phase II study, the response rate was 27% (8/30). The median survival and progression-free survival time was 11.8 (range 2.7–34.8) and 5.0 (range 0.5–32.5) months, respectively. Grade 3 or grade 4 neutropenia and grade 3 anemia occurred in 40% and 7% of phase II patients, respectively. Gastrointestinal toxicity was frequent but mild. As the most serious toxicity, pneumonitis was observed in three patients. Conclusion: This combination of UFT and vinorelbine is both feasible and active in the treatment of elderly patients with advanced NSCLC.