Biology Reference
In-Depth Information
A variety of anemias exist, many of which will respond well to rHuEPO
administration, but other cases exist where rHuEPO may not be a good thera-
peutic choice. In settings of anemia where endogenous EPO concentrations are
low or even normal, rHuEPO has a good chance of being effective. In other
conditions where EPO concentrations are supernormal, the administration of
rHuEPO can help. In these cases it might be reasoned that EPO is not the only
limiting factor in the development of anemia, but that supplementing EPO can
make up for the limitation elsewhere in erythropoiesis [45].
Nonanemic conditions
Given the relatively wide distribution of EPOR expression in the body, it
would be surprising if effects were not seen outside the erythroid machinery.
The central nervous system is known to be the site of both EPO and EPOR
expression in the fetus and adult [20, 78, 79] and has been widely discussed as
a therapeutic target for rHuEPO therapy [80]. It is not clear whether EPO pas-
sage across the blood/brain barrier is a process facilitated by a specific mech-
anism, but neural cells are stimulated to grow
in vitro
in response to EPO
[81-84]. EPOR is expressed in rodent capillaries at the blood/brain interface
[82]. These data have lead to much speculation that rHuEPO may offer a ther-
apeutic advantage in various neurological injury-speculation borne out by pre-
clinical experience [82, 85-88].
EPO and EPOR are expressed in peripheral nerves before injury and show
differential regulation after crush injury, which suggests EPO may have
peripheral effects in the nervous system [89]. Effects of EPO on vascular func-
tion, angiogenesis, fatigue, preadaptation to altitude, hemoglobin oxygen dis-
sociation, and cardiac performance have been documented (Tab. 2). Among
these areas, the effects of EPO on angiogenesis both in culture and in intact
endometrium have suggested a role in neovascularization [90, 91]. Whether
these studies have implications for vascularization of neoplastic tissues is
unknown. Direct effects upon the vascular tissues have been shown
in vitro
as
have changes in blood pressure after longer term rHuEPO administration
[91-94]. A direct effect of EPO on blood pressure has not been reported, how-
ever. Effects of EPO in fatigue separate from the changes mediated by hemo-
globin increase have been suggested but have proven difficult to substantiate.
Several of these areas may prove productive in future clinical research, but
may be confounded by the major effect of EPO, which is, almost inexorably,
to increase the hematocrit. It may prove somewhat difficult to separate the role
of endogenous EPO from that of rHuEPO in the non-anemic condition where
normal hematocrit is presumably maintained by an adequate endogenous pro-
duction of EPO.
