Biology Reference
In-Depth Information
Table 2. The rationale for rHuEPO use in various nonanemic conditions
Neural effects
Stroke, subarachnoid
Controversy over whether EPO
[132]
hemorrhage
crosses the blood/brain barrier.
Mechanism of action may be
anti-apoptotic or mitogenic.
Cognitive effects
Secondary to hemo-
[133, 134]
dynamic changes?
Oxygenation?
Vascular effects
Changes in blood pressure
[135]
often parallel hemoglobin,
however,direct effect of
EPO alone is unclear.
Angiogenesis
Demonstrated effects in
[91]
endometrium, other setting
less well documented.
Blood donation
Autologous donation
[136, 137]
before surgery.
Oxygen dissociation
Modulation of erythrocyte
[138]
2,6 DPG (and oxygen
dissociation) directly by EPO.
Effects on tumors
Receptor shown in some
[139, 140]
breast and renal tumor cells.
Proliferation shown in renal
carcinoma.
Effects on fatigue
Difficult to deconvolute from
[141]
anemia, cognitive function etc.
DPG, diphosphoglyceric acid.
Control of rHuEPO response rates
The administration of rHuEPO in a situation where every other constituent of
the biologic response is in excess and EPO is the only limiting factor in ery-
thropoiesis will yield the most marked response. Such a situation is extremely
rare. Even in the case of renal disease where compromised endogenous EPO
production is an obvious feature, other factors such as uremia, general inflam-
mation, or iron deficiency can limit the effectiveness of injected rHuEPO by
placing other constraints on the response [95]. These constraints may be the
demonstrated inhibition of erythropoiesis by tumor necrosis factor (TNF),
IL-1, and interferon (IFN), the pro-inflammatory cytokines [96], or by limited
supply of iron for hemoglobin synthesis. Recognizing that such a clear-cut sit-
uation is not likely to present itself, the effectiveness of administered rHuEPO
will depend on a milieu of negative influences including those above in addi-
tion to anti-EPO antibodies and soluble EPOR. The latter two factors have
direct consequences for rHuEPO therapy. Antibodies to EPO have been noted
in diseases such as systemic lupus erythematosus and HIV and are capable of
neutralizing the action of administered rHuEPO [97-99]. Antibodies may be
