Targeted toxins for glioblastoma multiforme: pre-clinical studies and clinical implementation.

Glioblastoma multiforme (GBM) is the most common primary brain tumor in adults. GBM is very aggressive due to its poor cellular differentiation and invasiveness, which makes complete surgical resection virtually impossible. Therefore, GBM's invasive nature as well as its intrinsic resistance to current treatment modalities makes it a unique therapeutic challenge. Extensive examination of human GBM specimens has uncovered that these tumors overexpress a variety of receptors that are virtually absent in the surrounding non-neoplastic brain. Human GBMs overexpress receptors for cytokines, growth factors, ephrins, urokinase-type plasminogen activator (uPA), and transferrin, which can be targeted with high specificity by linking their ligands with highly cytotoxic molecules, such as Diptheria toxin and Pseudomonas exotoxin A. We review the preclinical development and clinical translation of targeted toxins for GBM. In view of the clinical experience, we conclude that although these are very promising therapeutic modalities for GBM patients, efforts should be focused on improving the delivery systems utilized in order to achieve better distribution of the immuno-toxins in the tumor/resection cavity. Delivery of targeted toxins using viral vectors would also benefit enormously from improved strategies for local delivery.

Coffee, green tea, black tea and oolong tea consumption and risk of mortality from cardiovascular disease in Japanese men and women.

BACKGROUND: The effects of coffee and green, black and oolong teas and caffeine intake on cardiovascular disease (CVD) mortality have not been well defined in Asian countries. METHODS: To examine the relationship between the consumption of these beverages and risk of mortality from CVD, 76,979 individuals aged 40-79 years free of stroke, coronary heart disease (CHD) and cancer at entry were prospectively followed. The daily consumption of beverages was assessed by questionnaires. RESULTS: 1362 deaths were documented from strokes and 650 deaths from CHD after 1,010,787 person-years of follow-up. Compared with non-drinkers of coffee, the multivariable HR and 95% CI for those drinking 1-6 cups/week, 1-2 cups/day and ≥ 3 cups/day were 0.78 (0.50 to 1.20), 0.67 (0.47 to 0.96) and 0.45 (0.17 to 0.87) for strokes among men (p = 0.009 for trend). Compared with non-drinkers of green tea, the multivariable HR for those drinking 1-6 cups/week, 1-2 cups/day, 3-5 cups/day and ≥ 6 cups/day were 0.34 (0.06-1.75), 0.28 (0.07-1.11), 0.39 (0.18-0.85) and 0.42 (0.17-0.88) for CHD among women (p = 0.038 for trend). As for oolong tea, the multivariable HR of those drinking 1-6 cups/week and ≥ 1 cups/day were 1.00 (0.65-1.55) and 0.39 (0.17-0.88) for total CVD among men (p = 0.049 for trend). Risk reduction for total CVD across categories of caffeine intake was most prominently observed in the second highest quintile, with a 38% lower risk among men and 22% among women. CONCLUSIONS: Consumption of coffee, green tea and oolong tea and total caffeine intake was associated with a reduced risk of mortality from CVD.