Drug Targeting Organ-Specific Strategies

A more selective inhibition of NFκB can be achieved by transfecting cells with DNA coding
for the natural inhibitor IκBα or a mutant IκB protein that lacks 36 N-terminal amino
acids, and consequently becomes proteolysis resistant. In this way expression of adhesion
molecules and monocyte adhesion and transmigration can be inhibited [87,88]. The potentials
and limitations of these latter types of therapy are however not fully understood as yet.
Different transfection systems (adenoviral, retroviral, non-viral) are available for gene delivery
purposes, all with their own potentials and restrictions.
Inhibitors of IκBα phosphorylation have been described which irreversibly inhibit cytokine-induced
phosphorylation without affecting constitutive phosphorylation. One such
compound (Bay 11-7083 ((E)3-[4-t-butylphenyl)-sulfonyl]-2-propenenitrile)) was found to
be effective in two animal models of inflammation after intraperitoneal administration [89].
In addition to the effect it has on the expression of adhesion molecules in pro-inflammatory
responses, inhibition of the transcription factor NFκB will also have an effect on angiogenesis.
Endothelial cells can produce growth factors and cytokines which have pro-angiogenic effects.
Some of these factors, e.g. IL-8,TNFα and MCP-1 are known to be produced via NFκBmediated
endothelial cell activation [90,91].The importance of NFκB-mediated responses in
pro-angiogenic endothelium was reflected in studies in which the NFκB inhibitor PDTC decreased
retinal neovascularization in the eye of mice [92].
Taking their central role in cytokine signalling into account, it seems evident that molecules
that inhibit JAK/STAT signalling are also interesting candidates for targeting to endothelial
cells in chronic inflammatory lesions. Endogenous factors such as suppressors of cytokine
signalling (SOCS), IL-4, STAT-induced STAT-inhibitor-1 (SSI-1) and JAK binding
protein (JAB), have been reported to intervene effectively at this level of cytokine signalling
in a variety of cell types [93–95]. In addition, a number of new chemical entities are under development
to fulfil this function [96–99]. Although at present most of these compounds have
been tested in oncology research, it seems likely that they can also affect JAK/STAT signalling
in other cells such as pro-inflammatory endothelium.
It is anticipated that elucidation of the fine tuning of the regulatory processes in endothelial
cells under pro-inflammatory conditions, will lead to the identification of additional novel
pharmacological targets in the near future.
7.4.3.2 Glucocorticoids, NSAIDs and Others
7.4 Targeting Drugs to the Endothelial Cell 183
Glucocorticoids are commonly used in inflammatory disorders owing to their broad anti-inflammatory
and immune suppressive effects in a wide variety of diseases. A major drawback
of these compounds is the serious side-effects associated with their use. They have at least a
partial inhibitory effect on the expression of adhesion molecules by the endothelium and
inhibit cytokine production [2]. For instance, the glucocorticoid dexamethasone impaired
the increase of E-selectin and ICAM-1 expression on HUVEC, at least partially by an inhibitory
effect on NFκB (Figure 7.4) [100–102]. In IBD patients, prednisolone, another glucocorticoid,
blocked NFκB activation thereby inducing healing of colonic inflammation
[103]. Barnes and Karin also underlined the beneficial effect of glucocorticoids in chronic
inflammatory diseases via NFκB-mediated mechanisms [90]. The anti-angiogenic effects
of glucocorticoids were demonstrated by the ability of dexamethasone to inhibit capillary