Vascular Disrupting Activity of Tubulin-Binding 1,5-Diaryl-1H-imidazoles

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Acupuncture in shoulder pain and functional impairment after neck dissection: A prospective randomized pilot study

OBJECTIVES/HYPOTHESIS: The efficacy of conventional physiotherapy and antiinflammatory/analgesic drugs in the management of shoulder pain and functional disability following neck dissection is often disappointing. Acupuncture is a safe and well-tolerated method. We report the results regarding our pilot trial of acupuncture versus conventional care in the management of postoperative shoulder pain and dysfunction after neck dissection. STUDY DESIGN: Pilot study. METHODS: Patients at a tertiary university center with chronic pain or dysfunction attributed to neck dissection were randomly assigned to either weekly acupuncture or usual care (eg., physical therapy, analgesia, and/or antiinflammatory drugs) for 5 consecutive weeks. The Constant-Murley score, a composite measure of pain, function, and activities of daily living, was the primary outcome measure. As secondary end point, The Neck Dissection Impairment Index (NDII) was used to quantify site-specific, self-reported quality of life (QOL). RESULTS: After randomization, 48 patients completed the study (23 and 25 patients on acupuncture and control arms, respectively). Constant-Murley scores improved more in the acupuncture group (gain difference between groups 13.6, P < 0.01), a statistically significant improvement in site-specific QOL was also recorded at NDII (gain difference between groups 11.5, P < 0.01). CONCLUSION: Acupuncture is safe and effective; it should be introduced and offered to patients suffering from neck pain and dysfunction related to neck dissection

Vascular-targeting activity of ZD6126, a novel tubulin-binding agent

The tubulin-binding agent ZD6126 is a novel vascular-targeting agent in clinical development for the treatment of solid tumors. In vivo, ZD6126 is rapidly converted into N-acetylcolchinol (ZD6126 phenol). In this study, we have explored the antivascular property of N-acetylcolchinol in vitro and ZD6126 in vivo. In cell culture, N-acetylcolchinol induced rapid changes in the morphology of human umbilical vein and lung microvessel endothelial cells. Within 40 min, the compound induced endothelial cell contraction, destabilization of the tubulin cytoskeleton, induction of actin stress fibers, and membrane blebbing. These effects occurred at noncytotoxic concentrations and were rapidly reversed on removal of the drug. Nonconfluent endothelial cells were more sensitive than confluent, quiescent cells. Among different cell types, endothelial cells were the most sensitive to the induction of morphological changes, whereas smooth muscle cells were not affected. In vitro, N-acetylcolchinol rapidly disrupted a network of newly formed cords. In vivo, ZD6126 caused shut down of newly formed vessels in the Matrigel plug assay, shortly after injection. This study indicates that rapid alteration of endothelial cell morphology may be responsible for the loss of tumor blood vessel integrity, vessel shut down, and extensive tumor necrosis induced by ZD6126 in experimental tumor models

Bioavailability of VEGF in Tumor-Shed Vesicles Depends on Vesicle Burst Induced by Acidic pH

Tumor angiogenesis is regulated by a dynamic cross-talk between tumor cells and the host microenvironment. Because membrane vesicles shed by tumor cells are known to mediate several tumor-host interactions, we determined whether vesicles might also stimulate angiogenesis. Vesicles shed by human ovarian carcinoma cell lines CABAI and A2780 stimulated the motility and invasiveness of endothelial cells in vitro. Enzyme-linked immunosorbent assay and Western blot analysis revealed relevant amounts of vascular endothelial growth factor (VEGF) and the two matrix metalloproteinases MMP-2 and MMP-9, but not fibroblast growth factor-2, contained in shed vesicles. An A2780 cell-derived clone transfected to overexpress VEGF shed the same amount of vesicles as did a control clone, but contained significantly more VEGF within the vesicles. Despite a greater amount of VEGF in vesicles of the over-expressing clone, vesicles of both clones stimulated endothelial cell motility to comparable levels, suggesting that VEGF was stored within the vesicle and was unavailable. Only following vesicle burst induced by acidic pH (a characteristic of the tumor microenvironment) was VEGF released, leading to significantly higher stimulation of cell motility. Thus, tumor-shed membrane vesicles carry VEGF and release it in a bioactive form in conditions typical of the tumor microenvironment

CCN-Based Therapeutic Peptides Modify Pancreatic Ductal Adenocarcinoma Microenvironment and Decrease Tumor Growth in Combination with Chemotherapy

The prominent desmoplastic stroma of pancreatic ductal adenocarcinoma (PDAC) is a determinant factor in tumor progression and a major barrier to the access of chemotherapy. The PDAC microenvironment therefore appears to be a promising therapeutic target. CCN2/CTGF is a profibrotic matricellular protein, highly present in the PDAC microenvironment and associated with disease progression. Here we have investigated the therapeutic value of the CCN2-targeting BLR100 and BLR200, two modified synthetic peptides derived from active regions of CCN3, an endogenous inhibitor of CCN2. In a murine orthotopic PDAC model, the two peptides, administered as monotherapy at low doses (approximating physiological levels of CCN3), had tumor inhibitory activity that increased with the dose. The peptides affected the tumor microenvironment, inhibiting fibrosis and vessel formation and reducing necrosis. Both peptides were active in preventing ascites formation. An increased activity was obtained in combination regimens, administering BLR100 or BLR200 with the chemotherapeutic drug gemcitabine. Pharmacokinetic analysis indicated that the improved activity of the combination was not mainly determined by the substantial increase in gemcitabine delivery to tumors, suggesting other effects on the tumor microenvironment. The beneficial remodeling of the tumor stroma supports the potential value of these CCN3-derived peptides for targeting pathways regulated by CCN2 in PDAC

Fibronectin fragments generated by pancreatic trypsin act as endogenous inhibitors of pancreatic tumor growth

Abstract Background The pancreatic microenvironment has a defensive role against cancer but it can acquire tumor-promoting properties triggered by multiple mechanisms including alterations in the equilibrium between proteases and their inhibitors. The identification of proteolytic events, targets and pathways would set the basis for the design of new therapeutic approaches. Methods and results Here we demonstrate that spheroids isolated from human and murine healthy pancreas and co-transplanted orthotopically with pancreatic ductal adenocarcinoma (PDAC) in mouse pancreas inhibited tumor growth. The effect was mediated by trypsin-generated fibronectin (FN) fragments released by pancreatic spheroids. Tumor inhibition was observed also in a model of acute pancreatitis associated with trypsin activation. Mass spectrometry proteomic analysis of fragments and mAb against different FN epitopes identified the FN type III domain as responsible for the activity. By inhibiting integrin α5β1, FAK and FGFR1 signaling, the fragments induced tumor cell detachment and reduced cell proliferation. Consistent with the mutual relationship between the two pathways, FGF2 restored both FGFR1 and FAK signaling and promoted PDAC cell adhesion and proliferation. FAK and FGFR inhibitors additively inhibited PDAC growth in vitro and in orthotopic in vivo models. Conclusions This study identifies a novel role for pancreatic trypsin and fibronectin cleavage as a mechanism of protection against cancer by the pancreatic microenvironment. The finding of a FAK-FGFR cross-talk in PDAC support the combination of FAK and FGFR inhibitors for PDAC treatment to emulate the protective effect of the normal pancreas against cancer