Therapeutic efficacy of curcumin/TRAIL combination regimen for hormone-refractory prostate cancer.

Because of lack of effective treatment options for hormone-refractory prostate cancer at the present time, the need for developing novel therapeutic strategies and targets to treat and prevent the progression of hormone-sensitive prostate cancer to the hormone-refractory stage is paramount. Our previous in vitro studies have shown that curcumin sensitizes both hormone-sensitive and hormone-resistant prostate cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and that combined curcumin/TRAIL treatment induces apoptosis in cancer cells by inhibiting antiapoptotic p-Akt and nuclear factor-kappaB (NF-kappaB). In the present study, we demonstrate that curcumin and TRAIL combination regimen is also the most effective treatment for inhibiting the growth of PC3 xenografts compared to curcumin or TRAIL monotherpy. The inhibition of PC3 tumors by combined treatment correlated with significant reduction in expression of p-Akt and NF-kappaB in tumor tissue. Furthermore, tumor growth inhibition by curcumin/TRAIL combination regimen was associated with significant decrease in cell proliferation and an increase in terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells in the tumors without significant change in microvessel density. Based on the significant efficacy in this preclinical model, combined curcumin/TRAIL regimen may be an effective adjuvant therapy for hormone-refractory prostate cancer.

Novel NAD(P)H oxidase inhibitor suppresses angioplasty-induced superoxide and neointimal hyperplasia of rat carotid artery.

Neointimal proliferation occurring after vascular or endovascular procedures is a major complication leading to end-organ or limb ischemia. In experimental models, balloon injury has been shown to induce NAD(P)H oxidase to produce vascular superoxide anion (O2*-) production, which has been implicated in cell proliferation, but a direct link is still unclear. We postulated that inhibition of arterial NAD(P)H oxidase, resulting in decreased O2*-, would lessen the neointimal hyperplasia caused by balloon injury to the common carotid artery (CCA). Sprague-Dawley rats were implanted with osmotic minipumps containing either vehicle, a cell-permeant peptide that inhibits NAD(P)H oxidase (gp91ds-tat, 10 mg/kg per day), or a scrambled peptide control (scrmb-tat). Two days after pump implantation, the left CCA was injured using an intravascular balloon embolectomy catheter (2F Fogarty). Systolic blood pressure was monitored by tail cuff. Fourteen days after injury, CCAs were harvested and analyzed by digital morphometry. Rats in both groups remained normotensive, with no significant differences in systolic blood pressure. Reactive oxygen species measurements after injury indicated a significant reduction in vascular O2*- in rats infused with gp91ds-tat, and the neointima/media area and thickness ratios were significantly lower in their arteries compared with control. On the contrary, no significant change in overall CCA diameter was observed in any group. Our data indicate that in response to balloon injury of the rat carotid artery, NAD(P)H oxidase activity contributes to neointimal hyperplasia and is involved in vascular cell proliferation and migration during restenosis.

Equivalent secondary patency rates of upper extremity Vectra Vascular Access Grafts and transposed brachial-basilic fistulas with aggressive access surveillance and endovascular treatment.

OBJECTIVES: The 2006 update of the DOQI guidelines has stated that in patients with end-stage renal disease, autogenous radial-cephalic, or brachial-cephalic fistulas are the preferred access modalities, followed by transposed brachial-basilic (TBB) fistulas and prosthetic arteriovenous (AV) grafts. AV grafts are in general least preferred; however, there is very limited data comparing directly the last two modalities. The aim of the present study is to compare outcomes of the TBB fistula and the Vectra Vascular Access Graft. METHODS: Seventy-six patients had a prosthetic brachial-axillary Vectra graft placed, while in 41 patients brachial-basilic upper arm transposition was performed. Graft surveillance to detect a failing/failed access was followed by endovascular treatment, rheolytic thrombectomy (AngioJet, Possis Medical), and/or angioplasty +/- stenting of the responsible anatomical lesion(s). RESULTS: Use of Vectra grafts and TBB fistulas started after a median (interquartile range) of 14 (7-30) and 70 (52-102) days, respectively (P < .001), as early as the operative day in some patients with grafts. Postoperative complications were more frequent in TBB fistulas and late complications (mainly access thrombosis) in Vectra grafts. Total number of thrombectomy sessions performed for graft or fistula occlusion was 45 and 7, respectively (P = .032); total number of isolated angioplasty sessions, performed for failing graft or fistula was 31 and 45, respectively (P = .004). Although primary patency of the two access modalities was equivalent, primary assisted patency was significantly reduced in Vectra grafts (70% at 12 months and 58% at 18 months), compared with TBB fistulas (82% at 12 months and 78% at 18 months, P = .033); however, as a result of endovascular intervention, secondary patency rates at 12 months (87% vs 88%) and 18 months (87% vs 83%) were equivalent (P = .91). Presence of arterial anastomosis stenosis treated with angioplasty at any stage had a significant negative predictive value on secondary patency rates at 12 and 18 months which were 61%, compared with 96% for Vectra grafts that had any intra-graft, venous outflow, draining or central vein stenosis treated with angioplasty at any stage (P = .010). CONCLUSIONS: Aggressive graft surveillance and endovascular treatment methods can yield equivalent long-term secondary patency rates between Vectra graft and TBB fistulas. The advantage of earlier use of Vectra graft must be balanced against the need for more frequent secondary interventions and the risk of graft infection.