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1.  Sodium glucose cotransporter 1 ligand BLF501 as a novel tool for management of gastrointestinal mucositis 
Molecular Cancer  2014;13:23.
Recent studies demonstrated that engagement of sodium glucose transporter 1 (SGLT-1) by orally administered D-glucose protects the intestinal mucosa from lipopolysaccharide (LPS)-induced injury. We tested whether SGLT-1 engagement might protect the intestinal mucosa from doxorubicin (DXR)- and 5-fluorouracil (5-FU)-induced injury in animal models mimicking acute or chronic mucositis.
Mice were treated intraperitoneally with DXR, alone or in combination with 5-FU, and orally with BLF501, a glucose-derived synthetic compound with high affinity for SGLT-1. Intestinal mucosal epithelium integrity was assessed by histological analysis, cellular proliferation assays, real-time PCR gene expression assays and Western blot assays. Student’s t-test (paired two-tailed) and χ2 analyses were used for comparisons between groups. Differences were considered significant at p < 0.05.
BLF501 administration in mice treated with DXR and/or 5-FU decreased the injuries to the mucosa in terms of epithelial integrity and cellular proliferative ability. Co-treatment with BLF501 led to a normal expression and distribution of both zonula occludens-1 (ZO-1) and beta-catenin, which were underexpressed after treatment with either chemotherapeutic agent alone. BLF501 administration also restored normal expression of caspase-3 and ezrin/radixin/moesin (ERM), which were overexpressed after treatment with DXR and 5-FU. In SGLT1-/- mice, BLF501 had no detectable effects. BLF501 administration in wild-type mice with growing A431 tumors did not modify antitumor activity of DXR.
BLF501-induced protection of the intestinal mucosa is a promising novel therapeutic approach to reducing the severity of chemotherapy-induced mucositis.
PMCID: PMC3937063  PMID: 24495286
Gastrointestinal mucositis; SGLT-1; Synthetic D-glucose analogs; Chemotherapy; Inflammation
2.  Approaches to improve tumor accumulation and interactions between monoclonal antibodies and immune cells 
mAbs  2013;5(1):34-46.
Monoclonal antibodies (mAb) have become a mainstay in tumor therapy. Clinical responses to mAb therapy, however, are far from optimal, with many patients presenting native or acquired resistance or suboptimal responses to a mAb therapy. MAbs exert antitumor activity through different mechanisms of action and we propose here a classification of these mechanisms. In many cases mAbs need to interact with immune cells to exert antitumor activity. We summarize evidence showing that interactions between mAbs and immune cells may be inadequate for optimal antitumor activity. This may be due to insufficient tumor accumulation of mAbs or immune cells, or to low-affinity interactions between these components. The possibilities to improve tumor accumulation of mAbs and immune cells, and to improve the affinity of the interactions between these components are reviewed. We also discuss future directions of research that might further improve the therapeutic efficacy of antitumor mAbs.
PMCID: PMC3564884  PMID: 23211740
monoclonal antibodies; immune cells; cancer; accumulation; affinity; therapy; mechanism of action; ADCC
3.  Peptide-Mediated Targeting of Cytokines to Tumor Vasculature: The NGR-hTNF Example 
Biodrugs  2013;27:591-603.
A growing body of evidence suggests that the efficacy of cytokines in cancer therapy can be increased by targeting strategies based on conjugation with ligands that recognize receptors expressed by tumor cells or elements of the tumor microenvironment, including the tumor vasculature. The targeting approach is generally conceived to permit administration of low, yet pharmacologically active, doses of drugs, thereby avoiding toxic reactions. However, it is becoming clear that, in the case of cytokines, this strategy has another inherent advantage, i.e. the possibility of administering extremely low doses that do not activate systemic counter-regulatory mechanisms, which may limit their potential therapeutic effects. This review is focused on the use of tumor vasculature-homing peptides as vehicles for targeted delivery of cytokines to tumor blood vessel. In particular, we provide an overview of peptide-cytokine conjugates made with peptides containing the NGR, RGD, isoDGR or RGR sequences and describe, in more details, the biological and pharmacological properties of NGR-hTNF, a peptide-tumor necrosis factor-α conjugate that is currently being tested in phase II and III clinical studies. The results of preclinical and clinical studies performed with these products suggest that peptide-mediated vascular-targeting is indeed a viable strategy for delivering bioactive amounts of cytokines to tumor endothelial cells without causing the activation of counter-regulatory mechanisms and toxic reactions.
PMCID: PMC3832761  PMID: 23743670
5.  Influence of the Duration of Intravenous Drug Administration on Tumor Uptake 
Frontiers in Oncology  2013;3:192.
Enhancing tumor uptake of anticancer drugs is an important therapeutic goal, because insufficient drug accumulation is now considered to be an important reason for unresponsiveness or resistance to antitumor therapy. Based on a mechanistic tumor uptake model describing tumor exposure to molecules of different molecular size after bolus administration, we have investigated the influence of the duration of intravenous administration on tumor uptake. The model integrates empirical relationships between molecular size and drug disposition (capillary permeability, interstitial diffusivity, available volume fraction, and plasma clearance), together with a compartmental pharmacokinetics model and a drug/target binding model. Numerical simulations were performed using this model for protracted intravenous drug infusion, a common mode of administration of anticancer drugs. The impact of mode of administration on tumor uptake is described for a large range of molecules of different molecular size. Evaluation was performed not only for the maximal drug concentration achieved in the tumor, but also for the dynamic profile of drug concentration. It is shown that despite a lower maximal uptake for a given dose, infusion allows for a prolonged exposure of tumor tissues to both small- and large-sized molecules. Moreover, infusion may allow higher doses to be administered by reducing Cmax-linked toxicity, thereby achieving a similar maximal uptake compared to bolus administration.
PMCID: PMC3722550  PMID: 23898461
tumor; uptake; size; infusion; affinity
6.  The association of hepatitis B virus infection with B-cell non-Hodgkin lymphoma – a review 
Epidemiological studies performed over the last decade have demonstrated a positive association between persistent, hepatitis B surface antigen (HBsAg)-positive hepatitis B virus (HBV) infection and B-cell non-Hodgkin lymphoma (NHL), with HBV-infected patients having a 2-3-fold higher risk to develop NHL than non-infected patients. Moreover, there is evidence that also occult HBV infection (HBsAg-negative, HBV DNA-positive) associates with NHL. An association with HBV infection may exist also for other hematological malignancies, but available evidence is much less persuasive than for NHL. In this review article we will discuss available results on the association between HBsAg-positive HBV infection and NHL, as well as the significance of other serological markers of HBV infection in these subjects. We will also discuss the possible etiopathogenic role of HBV, and propose a multifactorial model for lymphomagenesis. Experimental evidence for multifactorial etiopathogenesis has been obtained in recent years for HBV-associated hepatocellular carcinoma (HCC), and we suggest that a similar model may apply to HBV-associated lymphoma as well. Eventually, we will also address some unresolved questions. Two of these are of particular relevance. First, do HBV-positive NHL patients show regression of their hematologic malignancy upon antiviral therapy? A positive answer would represent a direct demonstration of the necessary etiological role of the virus in the development of NHL, as has been shown previously for HCV-associated lymphomas. Second, if HBV plays a necessary role in lymphomagenesis, then expansion of HBV vaccination is expected to reduce the number of incident NHL cases, even though this effect might become evident only after a long time interval. Studies in those countries which have introduced universal HBV vaccination about two decades ago, like Italy, may soon provide results on this important point.
PMCID: PMC3301438  PMID: 22432084
Hepatitis B virus; occult infection; anti-HBs antibodies; anti-HBe antibodies; anti-HBc antibodies; non-Hodgkin lymphoma; hematologic malignancies; antiviral therapy; multicausal etiology; vaccination

Results 1-6 (6)