Biomedical Engineering Reference
In-Depth Information
stem/progenitor cells in patients with coronary artery disease. This cytokine is
used routinely in the treatment of humans, e.g., to help in harvesting cells for bone
marrow transplantation. Although results from these first small trials do not permit
any conclusion of efficacy, the safety of G-CSF in AMI has already come into
question [
26
]. The observed increase in restenosis may be partially explained by
the study design (which precluded the standard clinical practice of promptly stent-
ing the obstructed vessel), but the rise in leukocyte number to leukemic levels may
be directly responsible, via plaque growth or destabilization. Adverse vascular
events have also been attributed to G-CSF in patients with intractable angina who
were not candidates for revascularization and even in patients without cardiac dis-
ease. In the future, it may be preferable to use strategies that augment circulating
progenitor cells (EPC) without causing massive inflammation. A second opened
question regarding systemic mobilization is whether enough progenitor cells will
home where needed, to the sites of cardiac injury [
95
] . Systemically administered
human progenitor cells were predominantly trapped by the spleen when given to
athymic nude rats [
96
], and cardiac regeneration elicited by the treatment with
G-CSF plus SCF was documented only for animals lacking a spleen [
26
] . The use
of leukocyte-mobilizing cytokines might be most worthwhile combined with
selective enhancements of progenitor cell homing or as a prelude to isolating cells
for local delivery [
95
] .
The potential use of AMD3100 as a mobilization factor for the treatment of AMI.
In a mouse model of cardiac infarct caused by ligation of coronary artery, trans-
planted bone marrow-derived cells were shown to protect against MI by regenerat-
ing new myocardial tissue [
27
]. Subsequent studies in the same model showed that
treatment with stem-cell mobilizing cytokines stem cell factor (CSF) and G-CSF
resulted in significant tissue regeneration and improvement in cardiac function fol-
lowing cardiac infarct [
26
]. Though the exact mechanism by which stem cells exert
a protective effect resulting in observed tissue repair and improved heart function is
a matter of debate and still has to be defined, the evidence is conclusive that mobi-
lized bone marrow-derived adult stem cells are responsible for this tissue regenera-
tion and protection in these disease models. By extrapolation it seems reasonable to
assume that AMD3100 (AnorMed) mobilized cells may have similar properties to
G-CSF mobilized cells. A number of in vitro pharmacological studies have shown
that AMD3100 is a potent and selective antagonist of the CXR4 receptor. The CXR4
receptor-SDF-1 axis functions in homing HSCs and EPCs to the bone marrow
microenvironment, while by employing hemotactic isolation to SDF-1 gradient,
these cells can be mobilized. Hence, AMD3100 is a potent and selective antagonist
of the CXCR4 chemokine receptor that blocks binding of its cognate ligand, stromal
cell-derived factor 1 alpha (SDF-1 alpha). It is currently under investigation in the
treatment of multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and other
hematopoietic malignancies, prior to the high dose chemotherapy. Concurrently,
AMD3100 is under investigation for the mobilization of stem cells in the treatment
of AMI [
97,
98
] .
