Paclitaxel, one of the most commonly prescribed chemotherapeutic agents, is active against a wide spectrum of human cancer. The mechanism of its cytotoxicity, however, remains controversial. Our results indicate that paclitaxel treatment increases levels of superoxide, hydrogen peroxide, nitric oxide (NO), oxidative DNA adducts, G 2 -M arrest, and cells with fragmented nuclei. Antioxidants pyruvate and selenium, the NO synthase inhibitor N W -nitro-L-arginine methyl ester, and the NO scavenger manganese (III) 2-(4-carboxyphenyl)-4,4,5,5-tetramethyl-imidazoline-1-oxyl-3-oxide all decreased paclitaxel-mediated DNA damage and sub-G 1 cells. In contrast, the glutamylcysteine synthase inhibitor buthionine sulfoximine (BSO) and the superoxide dismutase (SOD) inhibitor 2-methoxyestradiol (2-ME) increased the sub-G 1 fraction in paclitaxel-treated cells. These results suggest that reactive oxygen and nitrogen species are involved in paclitaxel cytotoxicity. This notion is further supported with the observation that concentrations of paclitaxel required to inhibit cell growth by 50% correlate with total antioxidant capacity. Moreover, agents such as arsenic trioxide (As 2 O 3 ), BSO, 2-ME, PD98059, U0126 [mitogen-activated protein/extracellular signal-regulated kinase inhibitors], and LY294002 (phosphatidylinositol 3-kinase/Akt inhibitor), all of which decrease clonogenic survival, also decrease the total antioxidant capacity of paclitaxel-treated cells, regardless whether they are paclitaxel sensitive or paclitaxel resistant. These results suggest that paclitaxel chemosensitivity may be predicted by taking total antioxidant capacity measurements from clinical tumor samples. This, in turn, may then improve treatment outcomes by selecting out potentially responsive patients. (Cancer Res 2005; 65(18): 8455-60)

Abstract:Background. Although the results of gastric cancer treatment have markedly improved, this disease remains the most common cause of cancer death in Korea. Methods. Clinicopathologic characteristics were analyzed for 10 783 consecutive patients who underwent operation for gastric cancer at the Department of Surgery, Seoul National University Hospital, from 1970 to 1996. We also evaluated survival and prognostic factors for 9262 consecutive patients operated from 1981 to 1996. The clinicopathologic variables for evaluating prognostic values were classified as patient-, tumor-, and treatment-related factors. The prognostic significance of treatment modality [surgery alone, surgery ؉ chemotherapy, surgery ؉ immunotherapy ؉ chemotherapy (immunochemosurgery)] was evaluated in patients with stage III gastric cancer (according to the International Union Against Cancer TNM classification of 1987). For the assessment of lymph node metastasis, both the number of involved lymph nodes and the ratio of involved to resected lymph nodes were analyzed, as a quantitative system. Results. The mean age of the 10 783 patients was 53.5 years and the male-to-female ratio was 2.07 : 1. Resection was performed in 9058 patients (84.0% resection rate). The 5-year survival rates were 55.9% for all patients and 64.8% for patients who received curative resection. Age, sex, preoperative hemoglobin and albumin levels, type of operation, curability of operation, tumor location, Borrmann type, tumor size, histologic differentiation, Lauren's classification, perineural invasion, lymphatic invasion, vascular invasion, depth of invasion, number of involved lymph nodes, ratio of involved to resected lymph nodes, and distant metastasis had prognostic significance on univariate analysis. Radical lymph node dissection, with more than 25 resected lymph nodes improved survival in patients with stage II and IIIa disease. As postoperative adjuvant therapy, immunochemotherapy was most effective in patients with stage III disease. Patients with identical numbers of lymph nodes -either the number of involved lymph nodes or the number of resected lymph nodes-were divided according to their ratios of involved-to-resected lymph nodes. In each numeric group, there were significant survival differences according to the ratio of involved-toresected lymph nodes. However, patients who had the same involved-to-resected lymph node ratio did not show significant differences in survival rate according to either the number of involved or the number of resected lymph nodes. On multivariate analysis, curability of operation, depth of invasion, and ratio of involved to resected lymph nodes were independent significant prognostic factors. Conclusions. Curative resection, depth of invasion, and lymph node metastasis were the most significant prognostic factors in gastric cancer. With regard to the status of lymph node metastasis, the ratio of involved to resected lymph nodes had a more precise and comprehensive prognostic value than only the number of involved or resec...

We explored whether substance P (SP) via neurokinin (NK) receptor facilitates bladder afferent signaling and reactive oxygen species (ROS) formation in bladder in association with neurogenic inflammation. We evaluated ROS activity and cystometrograms as well as pelvic nervous activity in anesthetized rat bladder with SP stimulation. Our results showed that endogenous SP via NK(1), not NK(2), receptor mediated a micturition reflex. An increase in SP by electrical stimulation of the pelvic nerve or an increase in exogenous SP by intra-arterial or intrathecal administration can facilitate myogenic and neurogenic bladder contractions. Furthermore, exaggerated SP release increased ROS in the bladder and whole blood via increased mast cell degranulation, intercellular adhesion molecule expression, and leukocyte adhesion, a primary source of ROS in the inflamed bladder. Treatment with NK(1)-receptor antagonists or ROS scavengers reduced bladder intercellular adhesion molecule expression and ROS and ameliorated the hyperactive bladder response. Our study indicates that the mechanism by which SP participates in the neurogenic bladder may be complicated by its proinflammatory activity and its ability to stimulate ROS generation.

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What's known on the subject? and What does the study add?Silodosin administered by 4 mg twice daily is as effective as tamsulosin 0.2 mg daily in treating patients with LUTS associated with BPH.Relative to tamsulosin, silodosin has less cardiovascular side effects as judged by the minimal changes of blood pressure and pulse rats after treatment. OBJECTIVE• To test the hypothesis that the efficacy of silodosin would not be inferior to tamsulosin in treating patients with lower urinary tract symptoms associated with benign prostate hyperplasia (BPH). PATIENTS AND METHODS• At nine medical centres, 209 patients with an International Prostate Symptom Score (IPSS) of ≥ 13 were randomized to silodosin (4 mg twice daily) or tamsulosin (0.2 mg once daily) for 12 weeks.• The primary efficacy measure was the mean change from baseline to endpoint in IPSS.• The non-inferiority margin of the IPSS change was set at 1.0.• Secondary efficacy measures included change in maximal urinary flow rate (Q max ) and health-related quality of life (HRQL) score. RESULTS• Of the 170 (81.3%) patients who completed the study, 86.2% in the silodosin group vs 81.9% in the tamsulosin group achieved a ≥ 25% decrease in IPSS ( P = 0.53).• The mean difference (silodosin minus tamsulosin) in IPSS change from baseline was − 0.60 (95% confidence interval − 2.15, 0.95), inferring the non-inferiority of silodosin to tamsulosin.• The mean changes in the Q max and HRQL score from baseline were comparable between the groups (both, P > 0.05). Although patients receiving silodosin had a significantly higher incidence of abnormal ejaculation (9.7% vs tamsulosin 1.0%, P = 0.009), only 1.9% discontinued treatment.• Tamsulosin treatment resulted in a significant reduction in mean systolic blood pressure ( − 4.2 mmHg, within-group P = 0.004) relative to the negligible change of silodosin ( − 0.1 mmHg, within-group P = 0.96) CONCLUSION• The trial shows the non-inferiority of silodosin 4 mg twice daily to tamsulosin 0.2 mg once daily in patients with symptoms of BPH.