Fluorescent Macromolecular Sensors of Enzymatic Activity for In Vivo Imaging - Progress in Molecular Biology and Translational Science - page 350

activities play a role in the etiology and/or progression of cancer, atheroscle-
rosis, stroke and heart disease, diabetes, arthritis, multiple sclerosis,
Alzheimer's disease, 1 HIV, and other infections. For example, a number
of proteases have been implicated in cancer, including urokinase-type plas-
minogen activator (uPA), 2 matrix metalloproteinases (MMPs), 3 and cysteine
proteinases. 4 These enzymes are believed to facilitate extracellular matrix
breakdown, allowing cancer cells as well as activated stroma cells to invade
neighboring tissue. 5 MMPs are expressed in higher levels in some forms of
cancer, and their expression level correlates to tumor stage, 6 invasiveness, 7,8
metastasis, 9 and degree of tumor vascularization. 10 Increased expression and
activity of cysteine cathepsins and uPA have also been found in some
tumors, 11-14 and elevated levels of cathepsin B, D, and L are found in
mammary adenocarcinomas and are prognostic of poor outcome. 15-18
More recently, major roles have been identified for cyclooxygenases,
lipoxygenases, integrin-linked kinase 1, and glutaminase in the progression
of various malignancies. 19-21
Atherosclerosis is another clinically prevalent disease that is now thought
to arise, in part, from damage incurred though the activation of inflamma-
tory pathways and associated enzymes. Lipoprotein-associated phospholi-
pase A2 (Lp-PLA2) activity generates proinflammatory lipids that
participate in the formation of atherosclerotic necrotic cores, 22 which in
turn recruit macrophages and granulocytes that release myeloperoxidase
(MPO). The resultant MPO-mediated generation of hypochlorite anion
leads to matrilysin (MMP7) activation and contributes to plaque rupture
as a result of fibrous cap degradation. 23 Increases in Lp-PLA2 have been
linked to an increased risk of cardiac death, myocardial infarction, acute cor-
onary syndromes, and ischemic stroke. 24
The critical role of enzyme activity in many different diseases has also
been deduced from beneficial clinical outcomes obtained following thera-
peutic interventions that alter specific enzyme activities. Examples include
the use of angiotensin converting enzyme inhibitors for the treatment of hy-
pertension, 25 elastase inhibitors for the treatment of cardiovascular disease, 26
HIV aspartyl protease inhibitors to prevent development of AIDS, 27
proteasome inhibitors for the treatment of multiple myeloma, 28 and
leukoprotease inhibitors for the treatment of cystic fibrosis. 29 Development
of enzyme inhibitors for the treatment of cancer is currently an intensive area
of research, and therapeutic benefit has been shown for inhibitors of AMP-
activated protein kinase, 30 MMP9 and MMP14, 31,32 cathepsin S, 33 , and

cathepsins B, L, and S. 34