Page 345 - Basic _ Clinical Pharmacology ( PDFDrive )

CHAPTER 18 The Eicosanoids: Prostaglandins, Thromboxanes, Leukotrienes, & Related Compounds 331

EP receptor deletion in mice results in an imbalance between mPGES-1 is evident in tumors, and preclinical studies support the
4
bone resorption and formation, leading to a negative balance potential use of mPGES-1 inhibitors in chemoprevention or treat-
of bone mass and density in older animals. Prostaglandins may ment. In tumors, reduced levels of OATP2A1 and 15-PGDH,
mediate the effects of mechanical forces on bones and changes which mediate cellular uptake and metabolic inactivation of
in bone during inflammation. EP -receptor deletion and inhibi- PGE , respectively, likely contribute to sustained PGE activity.
4
2
2
tion of prostaglandin biosynthesis have both been associated with The pro- and anti-oncogenic roles of other prostanoids remain
impaired fracture healing in animal models. COX inhibitors can under investigation, with TXA emerging as another likely procar-
2
also slow skeletal muscle healing by interfering with prostaglandin cinogenic mediator, deriving either from macrophage COX-2 or
effects on myocyte proliferation, differentiation, and fibrosis in platelet COX-1. Studies in mice lacking EP , EP , or EP recep-
2
4
1
response to injury. Prostaglandins may contribute to the bone loss tors confirm reduced disease in multiple carcinogenesis models.
that occurs at menopause; it has been speculated that NSAIDs EP , in contrast, plays no role or may even play a protective role
3
may be of therapeutic value in osteoporosis and bone loss pre- in some cancers. Transactivation of epidermal growth factor recep-
vention in older women. However, controlled evaluation of such tor (EGFR) has been linked with the oncogenic activity of PGE .
2
therapeutic interventions has not been carried out. NSAIDs, espe- PGD , acting on the DP receptor, may reduce angiogenesis,
2
1
cially those specific for inhibition of COX-2, delay bone healing thereby reducing tumor progression.
in experimental models of fracture.
Effects of Lipoxygenase & Cytochrome
H. Eye P450-Derived Metabolites
PGE, PGF, and PGD derivatives lower intraocular pressure. The
mechanism of this action is unclear but probably involves increased Lipoxygenases generate compounds that can regulate specific cel-
outflow of aqueous humor from the anterior chamber via the uveo- lular responses that are important in inflammation and immunity.
scleral pathway (see Clinical Pharmacology of Eicosanoids). Cytochrome P450-derived metabolites affect nephron transport
functions either directly or via metabolism to active compounds
I. Cancer (see below). The biologic functions of the various forms of
There has been considerable interest in the role of prostaglandins, hydroxy- and hydroperoxyeicosaenoic acids are largely unknown,
and in particular the COX-2 pathway, in the development of malig- but their pharmacologic potency is impressive.
nancies. Pharmacologic inhibition or genetic deletion of COX-2
restrains tumor formation in models of colon, breast, lung, and A. Blood Cells and Inflammation
other cancers. Large human epidemiologic studies have found that LTB , acting at the BLT receptor, is a potent chemoattractant
1
4
the incidental use of NSAIDs is associated with significant reduc- for T lymphocytes, neutrophils, eosinophils, monocytes, and pos-
tions in relative risk for developing these and other cancers. Chronic sibly mast cells. LTB also contributes to activation of neutrophils
4
low-dose aspirin does not appear to have a substantial impact on and eosinophils, and to monocyte-endothelial adhesion. The
cancer incidence; however, it is associated with reduced cancer death cysteinyl leukotrienes are potent chemoattractants for eosinophils
in a number of studies. The anticancer efficacy of aspirin in humans and T lymphocytes. Cysteinyl leukotrienes may also generate dis-
may be related to hyperactivity of the PI3 kinase/Akt pathway in tinct sets of cytokines through activation of mast cell cysLT and
1
tumor cells. In patients with familial polyposis coli, COX inhibitors cysLT . At higher concentrations, these leukotrienes also promote
2
significantly decrease polyp formation. Polymorphisms in COX-2 eosinophil adherence, degranulation, cytokine or chemokine
have been associated with increased risk of some cancers. Several release, and oxygen radical formation. Cysteinyl leukotrienes also
studies have suggested that COX-2 expression is associated with contribute to inflammation by increasing endothelial permeabil-
markers of tumor progression in breast cancer. In mouse mammary ity, thus promoting migration of inflammatory cells to the site of
tissue, COX-2 is oncogenic whereas NSAID use is associated with inflammation. The leukotrienes have been strongly implicated in
a reduced risk of breast cancer in women, especially for hormone the pathogenesis of inflammation, especially in chronic diseases
receptor-positive tumors. Despite the support for COX-2 as the such as asthma and inflammatory bowel disease.
predominant source of oncogenic prostaglandins, randomized clini- Lipoxins have diverse effects on leukocytes, including activa-
cal trials have not been performed to determine whether superior tion of monocytes and macrophages and inhibition of neutrophil,
anti-oncogenic effects occur with selective inhibition of COX-2, eosinophil, and lymphocyte activation. Both lipoxin A and lipoxin
compared with nonselective NSAIDs. Indeed data from animal B inhibit natural killer cell cytotoxicity.
models and epidemiologic studies in humans are consistent with a
role for COX-1 as well as COX-2 in the production of oncogenic B. Heart and Smooth Muscle
prostanoids. 1. Cardiovascular—12(S)-HETE promotes vascular smooth
, which is considered the principal oncogenic prostanoid, muscle cell proliferation and migration at low concentrations; it
PGE 2
facilitates tumor initiation, progression, and metastasis through may play a role in myointimal proliferation that occurs after vas-
multiple biologic effects, increasing proliferation and angio- cular injury such as that caused by angioplasty. Its stereoisomer,
genesis, inhibiting apoptosis, augmenting cellular invasiveness, 12(R)-HETE, is not a chemoattractant, but is a potent inhibitor
+
+
and modulating immunosuppression. Augmented expression of of the Na /K -ATPase in the cornea. In vascular smooth muscle