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Drug delivery and penetration into neoplastic cells distant from tumor vessels are critical for the effectiveness of solid-tumor chemotherapy. We have found that targeted delivery to tumor vessels of picogram doses of TNF-alpha (TNF), a cytokine able to alter endothelial barrier function and tumor interstitial pressure, enhances the penetration of(More)
Because of its immunomodulatory and anticancer activities, IFNgamma has been used as an anticancer drug in several clinical studies, unfortunately with modest results. Attempts to increase the response by increasing the dose or by repeated continuous injection often resulted in lower efficacy, likely due to counterregulatory effects. We show here that(More)
The NGR peptide motif is an aminopeptidase N (CD13) ligand that targets angiogenic blood vessels. NGR-containing peptides have proven useful for delivering cytotoxic drugs, proapoptotic peptides, and tumor necrosis factor-alpha(TNF) to tumor vasculature. Given that CD13 is not only expressed in the angiogenic endothelium but also in other cell types, the(More)
NGR-TNF is a derivative of TNF-alpha, consisting of TNF fused to CNGRCG, a tumor vasculature-targeting peptide. Previous studies showed that NGR-TNF can exert synergistic antitumor effects with doxorubicin and with other chemotherapeutic drugs in murine models. In this study, we have investigated the role of endogenous IFN-gamma on the antitumor activity of(More)
PURPOSE Subnanogram doses of NGR-tumor necrosis factor (TNF), a TNF-alpha derivative able to target tumor neovessels, can enhance the antitumor activity of doxorubicin and melphalan in murine models. We have examined the antitumor activity of NGR-TNF in combination with various chemotherapeutic drugs acting via different mechanisms, including, besides(More)
Despite the impressive results obtained in animal models, the clinical use of tumor necrosis factor-alpha (TNF) as an anticancer drug is limited by severe toxicity. We have shown previously that targeted delivery of TNF to aminopeptidase N (CD13), a marker of angiogenic vessels, improved the therapeutic index of this cytokine in tumor-bearing mice. To(More)
High-dose endothelial-monocyte activating polypeptide II (EMAP-II), a tumor-derived antiangiogenic cytokine, can sensitize tumor vasculature to the damaging activity of high-dose tumor necrosis factor (TNF)-alpha. However, this combination cannot be used for systemic treatment of patients because of prohibitive toxicity. We have found that this limitation(More)
Asparagine deamidation in peptides or in fibronectin fragments containing the asparagine-glycine-arginine sequence generates isoaspartate-glycine-arginine (isoDGR), a new alphavbeta3 integrin-binding motif. Because alphavbeta3 is expressed in angiogenic vessels, we hypothesized that isoDGR-containing peptides could be exploited as ligands for targeted(More)
Targeted delivery of IFNgamma to tumors has been achieved by fusing this cytokine with GCNGRC, a tumor neovasculature homing peptide. Although the therapeutic efficacy of this protein (called IFNgamma-NGR) in animal models is greater than that of IFNgamma, frequent administrations of IFNgamma-NGR may result in lower efficacy and tumor resistance. We(More)
Tumor homing peptides containing the NGR motif, such as CNGRC and GNGRG, have been used for delivering cytokines, chemotherapeutic drugs, apoptotic peptides, and liposomes to a CD13 isoform expressed in tumor blood vessels. In view of the potential clinical applications of these drugs and considering the risk that NGR peptides could elicit blocking(More)