commentary review reports research article HIF = hypoxia inducible factor; MAPK = mitogen-activated protein kinase; MMP = matrix metalloproteinase; NADPH = nicotinamide adenine dinucleotide phosphate, reduced form; NOS = nitric oxide synthase; ROS = reactive oxygen species; VEGF = vascular endothelial growth factor. Available online http://breast-cancer-research.com/content/3/5/323 IntroductionOxygen radicals are continuously generated within mammalian cells, this being a consequence of the use of oxygen in aerobic respiration. Superoxide is generated within the mitochondria and is sequentially reduced to hydrogen peroxide and hydroxyl radicals. These species damage DNA, producing the mutations that initiate tumours and sustain progression [1]. Epidemiological studies suggest that a diet that is rich in antioxidants may help to prevent the development of breast carcinoma; this evidence contributed to recent UK Government advice that individuals should consume at least five portions of fruit or vegetables each day. The UK Department of Health has now translated this recommendation into initiatives such as the National School Fruit Scheme and the Five-aday Community Projects (www.doh.gov.uk). The role of ROS in breast carcinoma may not be limited to early mutagenic events, however. Carcinoma cells are frequently under persistent oxidative stress. Human tumour cell lines in vitro produce ROS at a far greater rate than do nontransformed cell lines [2], and markers of constitutive oxidative stress have been detected in samples from in vivo breast carcinomas [3,4]. 8-Hydroxy-2′-deoxyguanosine, one of the major oxidatively modified DNA base products, is almost 10 times more prevalent in invasive ductal breast carcinoma cells than in normal control samples from the same patient [3]. It appears unlikely that such a high level of oxidatively modified DNA is exclusively due to the mutagens that initiated the tumour. Persistent oxidative stress within carcinoma cells may instead be responsible for the accumulation of 8-hydroxy-2′-deoxyguanosine. Causes of carcinoma cell oxidative stress Alterations to metabolic pathways in tumour cellsOxygen radicals are not only generated in the mitochondria. Neutrophils and macrophages produce ROS via a plasma membrane bound nicotinamide adenine dinucleotide phosphate, reduced form (NADPH)-oxidase. The radicals are generated for cell killing and bactericidal activities. The NADPH-oxidase is not exclusive to these cells, ReviewHypoxia and oxidative stress in breast cancer Oxidative stress: its effects on the growth, metastatic potential and response to therapy of breast cancer AbstractReactive oxygen species (ROS) damage DNA, but the role of ROS in breast carcinoma may not be limited to the mutagenic activity that drives carcinoma initiation and progression. Carcinoma cells in vitro and in vivo are frequently under persistent oxidative stress. In the present review, we outline potential causes of oxygen radical generation within carcinoma cells and explore the possible impact of oxidative...

Angiogenesis is the term used to describe the formation of new blood vessels from the existing vasculature. In order to attract new vessels, a tissue must release an endothelial-cell chemoattractant. 2-Deoxy-D-ribose is produced in vivo by the catalytic action of thymidine phosphorylase (TP) on thymidine and has recently been identified as an endothelial-cell chemoattractant and angiogenesis-inducing factor. TP, previously known only for its role in nucleotide salvage, is now known to be angiogenic. TP expression is elevated in many solid tumours and in chronically inflamed tissues, both known areas of active angiogenesis. There is evidence that TP is also involved in physiological angiogenesis such as endometrial angiogenesis during the menstrual cycle. The majority of known endothelial-cell chemoattractants are polypeptides that bind to endothelial-cell-surface receptors. In contrast, 2-deoxy-D-ribose appears to lack a cell-surface receptor. Glucose is another sugar that acts as an endothelial-cell chemoattractant. The migratory activity of glucose is blocked by ouabain. It is possible that 2-deoxy-D-ribose and glucose stimulate endothelial-cell migration via a similar mechanistic pathway.

The effect of induction therapy with multiple doses of rituximab on the subsequent efficacy and toxicity of anti-CD20 radioimmunotherapy is unknown. We evaluated a novel protocol using 4 weekly infusions of 375 mg/m 2 rituximab followed by 2 fractions of 131 I-rituximab, preceded by a 100-mg/m 2 predose of rituximab, in relapsed indolent B-cell lymphoma. Induction therapy with rituximab significantly increased the effective half-life of 131 I-rituximab (P ‫؍‬ .003) and high serum levels of rituximab after induction therapy correlated with increased effective half-life of the radioimmunoconjugate (P ‫؍‬ .009). Patients with large tumor burdens experienced significant increases in the effective half-life of 131 I-rituximab between delivery of the first and second fractions (P ‫؍‬ .007). Induction therapy with multiple doses of rituximab did not appear to compromise the clinical efficacy or increase toxicity of subsequent 131 I-rituximab radioimmunotherapy. The overall response rate was 94%, with complete response rate 50%.The median time to progression was 20 months, significantly longer than for the last qualifying chemotherapy (P ‫؍‬ .001). Fractionation of 131 I-rituximab allowed cumulative whole-body doses of more than 120 cGy, approximately 60% greater than those previously achieved with a single administration of a murine radioimmunconjugate, to be delivered without significant hematologic toxicity.