Safety and efficacy of two different doses of capecitabine in the treatment of advanced breast cancer in older women.

PURPOSE: To evaluate the safety and efficacy of capecitabine in older women with advanced breast cancer. PATIENTS AND METHODS: Seventy-three eligible patients (median age, 73 years; range, 65 to 89 years) were enrolled. The first 30 patients received oral capecitabine 1,250 mg/m(2) twice daily on days 1 to 14 every 21 days. Due to the occurrence of two toxic deaths, capecitabine 1,000 mg/m(2) twice daily was given to the subsequent 43 patients. RESULTS: All patients were assessable for safety and efficacy. A total of 351 treatment cycles were administered (median, six per patient; range, one to eight cycles). Dose reductions due to toxicities were required in 30% of patients in the standard-dose group, but capecitabine was given without a dose reduction to 95% of patients in the low-dose group. Capecitabine demonstrated a favorable safety profile. The overall incidence of grade 3/4 toxicities was low: the most common events reported in /= 24 weeks. In the low-dose group, the response rate was 34.9% (95% CI, 21% to 50.9%). An additional 15 patients had prolonged stabilization. The median time to disease progression was 4 months in either group. CONCLUSION: This study shows that capecitabine is safe and effective in the elderly breast cancer patient. Based on the overall results, the capecitabine dose of 1,000 mg/m(2) twice daily merits consideration as "standard" for older patients who do not have severely impaired renal function.     

Increased levels of circulating endothelial cells in chronic periaortitis as a marker of active disease

BACKGROUND: The pathogenesis of chronic periaortitis (CP) has not been clarified. The histologic features and the association with autoimmune diseases suggest an immune-mediated disorder with marked inflammatory vascular and perivascular lesions. To clarify the role of vascular damage we looked for the presence and the surface phenotype of circulating endothelial cells (CECs) in the peripheral blood of patients with chronic periaortitis. METHODS: Eleven patients with CP were evaluated for the presence of CECs; 9 patients had active and 2 inactive disease. Three patients with active disease were also evaluated 3 months after therapy. Ten atherosclerotic patients, 10 patients with renal insufficiency of variable degree and etiology, and 40 healthy subjects were evaluated as controls. Five-parameter, 3-color flow cytometry was performed with a FACScan. CECs were defined as CD45 negative, CD31, P1H12, and CD36 positive, and activated CECs as CD45 negative and P1H12, CD62 positive. RESULTS: The median number of CECs in patients with CP (10(6) cells/mL) was significantly higher than in healthy controls (16 cells/mL, P= 0.0004) and atherosclerotic patients (25 cells/mL, P= 0.0005) Two patients with inactive disease had a CEC count comparable to that of normal subjects. In 2 of the 3 patients reevaluated, 3 months after therapy CEC numbers normalized. Almost all CECs were microvascular in origin and showed an activated phenotype. CONCLUSION: The presence of a high number of CECs in the active phase of chronic periaortitis and their normalization during inactive disease suggest that endothelial damage may play a role in the pathogenesis of the disease.     

In vivo imaging of retinoic acid receptor beta2 transcriptional activation by the histone deacetylase inhibitor MS-275 in retinoid-resistant prostate cancer cells

BACKGROUND: In retinoid resistant epithelial tumors, the lack of retinoic acid receptor beta2 (RARbeta2) expression due to epigenetic silencing impairs the activation of retinoid target genes including RARbeta2, and has been associated with the development of cancer. In this study we developed a strategy to monitor the re-activation of RARbeta2 by chromatin remodeling agents combined with retinoids in real time, and to correlate the RARbeta2 re-activation with anti-tumor activity. METHODS: We selected the RARbeta2-negative retinoid resistant human prostate carcinoma cell line PC3 and stably transfected it with a luciferase expression vector under the control of a functional segment of RARbeta2 promoter (pGL2-RARbeta2-PC3). Then, we used the bioluminescence technology to monitor the reporter gene expression in real time both in vitro and in vivo following combination treatment with the histone deacetylase inhibitor MS-275 and 13-cis retinoic acid (CRA). Based on the effective dose for the RARbeta2 re-activation, we tested the anti-tumor activity of this drug combination. RESULTS: Following combination treatment with MS-275 and CRA, we observed endogenous RARbeta2 re-expression, acetylation at the RARbeta2 promoter level, and synergistic activation of the luciferase reporter gene by real time imaging both in vitro and in vivo. Combination treatment with MS-275 and CRA restored retinoid sensitivity in human prostate carcinoma cell lines, and had a greater inhibitory effect on tumor cell growth than single agents in vitro and in vivo. CONCLUSIONS: This study provides evidence that HDAC inhibitors restore retinoid sensitivity in prostate cancer cells, and in vivo real time imaging of RARbeta2 activation may represent a useful tool to study the pharmacodynamics of combination therapy with HDAC inhibitors and retinoids.     

Plant genotype affects total antioxidant capacity and phenolic contents in fruit

OBJECTIVE: We wanted to determine the total antioxidant capacity (6-hydroxy-2,5,7,8-tetramethylchromane-2-carboxylic acid equivalent antioxidant assay; TEAC) of different species and cultivars (strawberry and apple) and to characterize the TEAC among fruits of the same varieties (peach and apricot) but grafted on different rootstocks. METHODS: The study was carried out with wild strawberry, six varieties of cultivated strawberry, and five varieties of apple and with apricot and peach grafted on five different rootstocks that are known to induce different plant vigor and fruit qualitative features. The TEAC (considering lipophilic and hydrophilic contributions) was determined for all fruit varieties, and total polyphenol contents were assayed. One-way analysis of variance was used to test differences among fruits and to identify possible correlations of TEAC versus total phenolics. RESULTS: The following hierarchy of antioxidant activities was found: wild strawberries > cultivated strawberries > kiwifruit = apples = apricots = peaches. Further, differences were found among strawberries with different genotypes and in apricots and peaches grafted from different rootstocks. CONCLUSIONS: These observations suggest the importance of genotype for determining antioxidant potential and phenolic contents. Variety manipulation may be a powerful tool for modifying antioxidant fruit patterns and contents.     

Total antioxidant capacity of the diet is inversely and independently related to plasma concentration of high-sensitivity C-reactive protein in adult Italian subjects

Inflammation, a risk factor for cardiovascular disease, is associated with low plasma levels of antioxidant vitamins. In addition to vitamins, other antioxidants modulate the synthesis of inflammatory markers in vitro and contribute to the total antioxidant capacity (TAC) of a diet. However, the relationship between dietary TAC and markers of inflammation has never been evaluated in vivo. We investigated the relationship between dietary TAC and markers of systemic (high-sensitivity C-reactive protein (hs-CRP), leucocytes) and vascular (soluble intercellular cell adhesion molecule-1) inflammation in 243 non-diabetic subjects. General Linear Model (GLM) analysis showed a significant (P=0.005) inverse relationship between hs-CRP and quartiles of energy-adjusted dietary TAC, even when recognized modulating factors of inflammation, namely alcohol, fibre, vitamin C, alpha-tocopherol, beta-carotene, BMI, waist circumference, HDL-cholesterol, hypertension, insulin sensitivity and plasma beta-carotene, were included in the model as covariates (P=0.004). The relationship was stronger for subjects with hypertension (P=0.013 v. P=0.109 for normotensive individuals). Among dietary factors, TAC was significantly higher (5.3 (sd 3.0) v. 4.9 (sd 2.7) mmol Trolox/d; P=0.026) in subjects with low plasma hs-CRP (range: 0.0-4.1 mg/l) than in subjects with high plasma hs-CRP (range: 4.2-27.8 mg/l). We conclude that dietary TAC is inversely and independently correlated with plasma concentrations of hs-CRP and this could be one of the mechanisms explaining the protective effects against CVD of antioxidant-rich foods such as fruits, whole cereals and red wine. This could be of particular significance for subjects with high blood pressure.     

Recombinant human nerve growth factor with a marked activity in vitro and in vivo

Recombinant human nerve growth factor (rhNGF) is regarded as the most promising therapy for neurodegeneration of the central and peripheral nervous systems as well as for several other pathological conditions involving the immune system. However, rhNGF is not commercially available as a drug. In this work, we provide data about the production on a laboratory scale of large amounts of a rhNGF that was shown to possess in vivo biochemical, morphological, and pharmacological effects that are comparable with the murine NGF (mNGF), with no apparent side effects, such as allodynia. Our rhNGF was produced by using conventional recombinant DNA technologies combined with a biotechnological approach for high-density culture of mammalian cells, which yielded a production of approximately 21.5 +/- 2.9 mg/liter recombinant protein. The rhNGF-producing cells were thoroughly characterized, and the purified rhNGF was shown to possess a specific activity comparable with that of the 2.5S mNGF by means of biochemical, immunological, and morphological in vitro studies. This work describes the production on a laboratory scale of high levels of a rhNGF with in vitro and, more important, in vivo biological activity equivalent to the native murine protein.