Co-expression of different types of Fc receptors on murine peritoneal macrophages

Simultaneous expression of particular immunoglobulin Fc receptors (FcR) was studied on the plasma membranes of murine peritoneal macrophages. This was facilitated by the use of sheep red blood cells (SRBC) and/or synthetic microspheres coated with monoclonal antibodies of different isotypes. It was concluded that a majority of macrophages bear more than one type of FcR; macrophages bearing at least three types of FcR were present in the peritoneal cavity; macrophages bearing Fc mu R did not bind IgE, IgA or IgG; all macrophages bearing Fc alpha R also expressed Fc gamma 2bR, Fc gamma 3R and Fc epsilon R; all macrophages bearing Fc epsilon R also expressed Fc gamma 2bR and Fc alpha R. Except for Fc alpha R, essentially equivalent numbers of FcR-bearing macrophages were detected when antibody-coated SRBC or polymeric microspheres were used. Simultaneous applications of these reagents permitted the most detailed and direct investigations yet performed of multiple FcR expression on individual cells.     

Tumor immunology and cytokines

Abstracts of the 4th International Congress of the Metastasis Research Society: Science and Medicine in Cancer MetastasisSymposium 3

Tumor immunology and cytokines     

In situ orientation study of xanthate on copper under potential control

Adsorption and orientation of ethyl xanthate on a copper electrode was studied using an in situ spectroelectrochemical set up. Cuprous xanthate was identified to be the major product over the potential range ?0.5 to ?0.1 V (SCE). A further increase in electrode potential to 0.1 V resulted in the formation of dixanthogen in addition to cuprous xanthate. The characteristic dixanthogen bands disappeared and the intensity of cuprous xanthate bands increased when the potential was brought back and held at ?1.0 V. With polarized radiation, the spectral appearance of cuprous xanthate changed in contrast to that of dixanthogen, suggesting preferential orientation of cuprous xanthate molecules but random orientation for dixanthogen.     

Antimetastatic activities of modified heparins: selectin inhibition by heparin attenuates metastasis

Heparin, which is traditionally used as an anticoagulant but has a variety of additional biological activities, was shown in several retrospective and prospective clinical trials to have an effect on cancer survival. Experimental evidence from animal models consistently demonstrates that heparin is an efficient inhibitor of metastasis. To clarify the mechanism of heparin antimetastatic activity, several biological effects are being investigated. Cancer progression and metastasis are associated with enhanced expression of heparanase, which is inhibited efficiently by heparin. Heparin is also a potent inhibitor of selectin-mediated interactions. P- and L-selectin were shown to contribute to the early stages of metastasis, which is associated with platelet-tumor cell thrombi formation. To delineate the biological activities of heparin contributing to metastasis inhibition, modified heparins with specific activities were evaluated. Low anticoagulant heparin preparations still inhibited metastasis efficiently, indicating that anticoagulation is not a necessary component for heparin attenuation of metastasis. Modified heparins characterized for heparanase inhibitory activity are also potential inhibitors of selectins. Selectin inhibition is a clear component of heparin inhibition of metastasis. The contribution of selectin or heparanase inhibition by heparin can provide evidence about its antimetastatic activity.     

Sulfated Hexasaccharides Attenuate Metastasis by Inhibition of P-selectin and Heparanase

Development of compounds that target both heparanase and selectins is emerging as a promising approach for cancer therapy. Selectins are vascular cell adhesion molecules that mediate tumor cell interactions with platelets, leukocytes, and the vascular endothelium. Heparanase is an endoglycosidase that degrades heparan sulfate in the tumor microenvironment, cell surfaces, and vessel wall. Acting together, these molecules facilitate tumor cell arrest, extravasation, and metastasis. Here, we report the preparation of novel semisynthetic sulfated tri mannose C-C-linked dimers (STMCs) endowed with heparanase and selectin inhibitory activity. The P-selectin specificity of the STMC was defined by the anomeric linkage of the C-C bond. This STMC hexasaccharide is an effective inhibitor of P-selectin in vivo. We show that selective inhibition of heparanase attenuates metastasis in B16-BL6 melanoma cells, expressing high levels of this endoglycosidase, but has no effect on the metastasis of MC-38 carcinoma cells that express little or no heparanase activity. P-selectin-specific STMC attenuated metastasis in both animal models, indicating that inhibition of tumor cell interaction with the vascular endothelium is critical for cancer dissemination. Thus, the small size, the stability of the C-C bond, and the chemically defined structure of the newly generated STMCs make them superior to heparin derivatives and signify STMCs as valuable candidates for further evaluation.     

Pathological considerations in the treatment of Parkinson's disease: More than just a wiring diagram

Parkinson's disease (PD) represents a common but challenging condition in which an increasing number of therapeutic options have evolved over the course of the last 50 years. The introduction of dopaminergic therapies has dramatically improved outcomes but life expectancies remain significantly curtailed. Currently, all available treatment options are directed towards the amelioration of symptoms. However, it is hoped that a greater understanding of the distinctive pathology underlying PD might offer some novel therapeutic approaches.The identification of degeneration within the nigrostriatal tract as the most prominent pathological process in PD has led to the development of a number of therapies. However, despite initially good symptomatic control it has become clear that the longer-term use of these medications is associated with a number of debilitating motor complications. The management of these drug-related issues has necessitated a further tier of therapeutic options based largely on a greater understanding of the basal ganglia circuitry involved. Indeed, surgical interventions targeting these neural circuits have provided increased control of motor symptoms in patients with advanced disease, however, such techniques still fail to slow or reverse the disease. To this end, a number of novel approaches focussed on restoration or repair of the diseased brain have received increasing attention. Nevertheless, there are multiple symptoms that are unresponsive to any of these therapies, highlighting the involvement of other neurotransmitter systems and the complexities of the disease beyond the basal ganglia circuitry. An appreciation of the ongoing neurodegenerative processes at the core of PD and the burden of disease associated with them, emphasises the need for increased research into more effective and comprehensive treatment methodologies.     

In vitro screen of a small molecule inhibitor drug library identifies multiple compounds that synergize with oncolytic myxoma virus against human brain tumor-initiating cells

Background

Brain tumor-initiating cells (BTICs) are stem-like cells hypothesized to form a disease reservoir that mediates tumor recurrence in high-grade gliomas. Oncolytic virotherapy uses replication-competent viruses to target and kill malignant cells and has been evaluated in clinic for glioma therapy with limited results. Myxoma virus (MyxV) is a safe and highly effective oncolytic virus (OV) in conventional glioma models but, as seen with other OVs, is only modestly effective for patient-derived BTICs. The objective of this study was to determine whether MyxV treatment against human BTICs could be improved by combining chemotherapeutics and virotherapy.

Methods

A 73-compound library of drug candidates in clinical use or preclinical development was screened to identify compounds that sensitize human BTICs to MyxV treatment in vitro, and synergy was evaluated mathematically in lead compounds using Chou-Talalay analyses. The effects of combination therapy on viral gene expression and viral replication were also assessed.

Results

Eleven compounds that enhance MyxV efficacy were identified, and 6 were shown to synergize with the virus using Chou-Talalay analyses. Four of the synergistic compounds were shown to significantly increase viral gene expression, indicating a potential mechanism for synergy. Three highly synergistic compounds (axitinib, a VEGFR inhibitor; rofecoxib, a cyclooxygenase-2 inhibitor; and pemetrexed, a folate anti-metabolite) belong to classes of compounds that have not been previously shown to synergize with oncolytic viruses in vitro.

Conclusions

This study has identified multiple novel drug candidates that synergistically improve MyxV efficacy in a preclinical BTIC glioma model.