Biomedical Engineering Reference
In-Depth Information
calcium influx, defined as
F
TOT
= F
AA
+ F
NO
:
Each decrement is the model counterpart of a treatment with an increas-
ing concentration of carboxyamidotriazole (CAI) drug. CAI is in fact an
anti-invasive and anti-angiogenic agent, which alters calcium-mediated signal
transduction in ECs by blocking agonist-activated calcium entry in a dose-
dependent manner [26, 213, 277]. In particular, it is currently under investiga-
tion as an orally administered tumoristatic agent in Phase II and III clinical
trials for different tumors, as explained in [214, 284].
Decrements in F
TOT
result in marked decrements in the cell directional
velocity v
x
, which are followed by the relative decrements in the final cell
displacement (x
CM
(t = 6 h) = 150 m for F
TOT
=2 and x
CM
(t = 6 h) =
70 m for F
TOT
=4), as shown in Figure 6.8. Furthermore, an approximately
complete inhibition of the mitogen-induced calcium responses, F
TOT
! 0,
causes the cell to remain in its unpolarized stationary state, dramatically
stopping its directional locomotion, as for F
TOT
=8, v
x
is almost a constant
4 m/h and x
CM
(t = 6 h) < 20 m.
The cell behavior is explained by the fact that partial inhibitions of F
TOT
cause decrements in the intensity of calcium responses: in fact both the max-
imal peaks and the overall accumulation of the ion decrease (i.e., c
(t = 6
h) 1.4 for F
TOT
=2, c
(t = 6 h) 0.6 for F
TOT
=4, and c
(t = 6 h) 0.2
for F
TOT
=8); see Figure 6.8(E). The consequence is a downregulation of the
biophysical properties of the EC, such as the intrinsic motility, elasticity and
chemotactic strength, involved in its migratory capacity. However, the inter-
ferences in the influx distributions do not affect the spatial propagation of the
ion, as represented in Figure 6.8(B-C).
Disruptions in the second messenger machinery are of high biological in-
terest as well. In particular, we exclude the production of arachidonic acid
(similarly nitric oxide) by imposing k
a
= v
c
= 0 in Equation (6.7) (similarly
k
n
= v
ca
= 0 in Equation (6.8)). It is the model counterpart of the activ-
ity of PLA2 (eNOS) inhibitor (such as AACOCF3 or, respectively, L-NAME
drugs, which are well studied anti-angiogenic compounds both in vitro and
in vivo, see again the excellent medical review [284]). Both exclusions result
in an incomplete transition of the TEC toward the motile phenotype, and in
the consequent decrement of its directional velocity and final displacement
(x
CM
(t = 6 h) = 110 m in the case of AA inhibition, and x
CM
(t = 6 h) =
180 m in the case of NO inhibition), as shown in Figure 6.9(A-D). The expla-
nation is that the disruption in the biosynthesis of each of the two molecules
extinguishes its intracellular presence and, consequently, abolishes the rela-
tive calcium influx, as also provided by the experimental system in [274].
Indeed, the final outcome of both proposed treatments is a downregulation of
the VEGF-induced calcium signals similar to those obtained from the direct
block of the influxes of the ion (reproduced in Figure 6.8) which, as seen, have
caused partial inhibitions of the cell migratory capacity. In particular, also
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