Disease model, dependence

Immunosuppression induced by sirolimus (36) appears to be mediated by a mechanism distincdy different from that of either cyclosporin or FK-506. Sirolimus markedly suppresses IL-2 or IL-4-driven T-ceU proliferation. The preclinical studies suggest that sirolimus is a potent immunosuppressive agent in transplantation and autoimmune disease models. The clinical potential of this agent depends on its toxicity profile (80). 

Human prion disease models have also been developed in mice [154,155]. Crossing the species barrier into an experimentally accessible animal system, the prions responsible for Creutzfeldt Jakob disease, new variant CJD, Gerstmann-Straussler-Scheinker disease, and fatal familial insomnia produce a reproducible time-dependent neuronal degeneration leading to death. 

While no in vivo activity has been reported in an Abl-dependent CML model, AZD0530 was active in a xenograft model using Src-transformed NIH 3T3 cells and in an orthotopic model of pancreatic cancer, two Src-dependent models. The results of a Phase I trial in normal volunteers have been disclosed and AZD0530 was tolerated when administered at doses of up to 250 mg [156,157]. While it appears that the initial efficacy trial for AZD0530 will be as an anti-invasive agent for the treatment of metastatic bone disease, this compound probably also has potential for use in CML. 

Although they remain less effective than inhaled corticosteroids, a 5-LOX inhibitor (zileuton) and selective antagonists of the CysLTl receptor for leukotrienes (zafirlukast, montelukast, and pranlukast see Chapter 20) are used clinically in mild to moderate asthma. Growing evidence for a role of the leukotrienes in cardiovascular disease has expanded the potential clinical applications of leukotriene modifiers. Conflicting data have been reported in animal studies depending on the disease model used and the molecular target (5-LOX versus FLAP). Human genetic studies have demonstrated a link between cardiovascular disease and polymorphisms in the leukotriene biosynthetic enzymes, in particular FLAP, in some populations. 

In the recent literature, many examples of A/BPs containing benzophenones can be found. A first example concerns the study of HDACs. These enzymes catalyze the hydrolysis of acetylated lysine amine side chains in histones and are thus involved in the regulation of gene expression. There are approximately 20 human HDACs, which are divided into three classes (I, II, and III). Class I and II HDACs are zinc-dependent metallohydrolases that do not form a covalent bond with their substrates during their catalytic process, which is similar to MMPs. It has been found that hydroxamate 65 (SAHA, see Fig. 5) is a potent reversible inhibitor of class I and II HDACs. In 2007, Cravatt and coworkers reported the transformation of SAHA into an A/BP by installment of a benzophenone and an alkyne moiety, which resulted in SAHA-BPyne (66) [73]. They showed that the probe can be used for the covalent modification and enrichment of several class I and class II HDACs from complex proteomes in an activity-dependent manner. In addition, they identified several HDAC-associated proteins, possibly arising from the tight interaction with HDACs. Also, the probe was used to measure differences in HDAC content in human disease models. Later they reported the construction of a library of related probes and studied the differences in HDAC labeling [74], Their most... 

The American disease model is especially important because of its u idespread prevalence and prominence in the United States. It also is the foundation of Alcoholics Anonymous and other self-help groups. In the American disease model (it is called American because it is not nearly so popular in otlier countries), alcohol and drug dependence is viewed as the product of a progressiv e, irreversible disease. The disease is described as a merging of physical, psychological, and spiritual causes. The treatment that follows from the disease model is to identify people who have the disease, confront them with it, help them to accept that they have it, and persuade them to abstain from alcohol and other drugs. 

Pristane (2,6,10,14-tetramethylpentadecane) is a mineral oil known to induce arthritis, also called pristane-induced arthritis, in an experimental disease model (Wooley Whalen, 1991). Pristane-induced arthritis is MHC-haplotype dependent. DBA/1 mice, but not DBA/2 mice, are susceptible. The disease is accompanied by a broad spectrum of autoantibodies (rheumatoid factor, anticollagen, antibodies to heat shock protein). Pristane-induced arthritis is clearly immune dependent, since it is not observed in nu/nu mice and irradiated mice (Wooley Whalen, 1991). CD4+ T cells and polyclonal T cell activation are involved in the disease process (Wooley et al., 1998), and disease can be prevented by CD4+ Th2 cells specific for 65-kilodalton heat shock protein (Beech et al., 1997). 

Kacher Y., Golan A., Pewzner-Jung Y., Futerman A.H., Changes in macrophage morphology in a Gaucher disease model are dependent on CTP phosphocholine cytidylyltransfer-ase alpha. Blood cells, molecules diseases 39 (2007) 124-129. 

Depending on the cells or tissues involved in the formation and site of action of these lipid mediators, a number of beneficial roles have been demonstrated in vivo. The various SPM acting on specific GPCRs and/or via other mechanisms are associated with particular cell types or tissues, resulting in additional localized actions that are relevant to specific diseases. A wide range of beneficial actions by SPM that are relevant to human disease have been identified in cell studies, disease models, as well as human studies [1,3,4]. Some representative examples are listed in Table 9.1. 

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