Biology Reference
In-Depth Information
of Epo were administered to patients diagnosed with myocardial
function showed an increased risk of thrombosis (
176-179
).
Thrombotic events were also increased in critically ill patients
although Epo therapy significantly reduced mortality particularly
in trauma patients (
213
), and increased risk of venous thromboem-
bolism was also noted in cancer patients (
214
). Another trial pro-
vided evidence of a possible negative interaction between short-term
administration of Epo and aspirin due to its ability to modulate
endothelial activation and platelet reactivity, von Willebrand factor
antigen levels and factor VIII activity (
215, 216
). Although largely
shown to improve neurodevelopmental outcome for preterm
infants, Epo has been associated with a significant increase in the
rate of retinopathy and may increase hypertension, coagulation,
and even interfere with neuronal development in neonates
(reviewed by ref.
84
). Finally the therapeutic use of Epo in cancer
patients remains highly controversial. A number of trials have
shown that Epo treatment increases the risk for progressive disease
and death although this may be dependent on the type and stage
of the cancer (reviewed by ref.
217, 218
). Potentially Epo could
have a direct growth-promoting effect on cancer cells as they have
been shown to express EpoR.
Thus it is apparent that our knowledge of the Epo signaling
cascade needs to be significantly improved to be able to harness the
benefits of using Epo and its mimetics as treatment for injury and
disease. To a great extent its beneficial effects seem to be related to
timing (the so-called “therapeutic window of opportunity”), dose
and type of injury. A better understanding of these parameters
would bring us significantly forward in our quest.
10
Conclusions and Outlook: What Don't We Know?
A wealth of preclinical data shows that the Epo signaling cascade is
an important mediator of protection and cell survival in many dif-
ferent non-hematopoietic tissues as part of an innate response to
injury. Many similarities exist between the mechanisms underlying
its hematopoietic and non-hematopoietic functions but there are
also some key differences that functionally lead to distinct outcomes.
Not unexpectedly it was thought that Epo, a drug considered
clinically safe, would be a trump card in most injury paradigms,
however to date results from patient trials have been varied and
more recently tip the balance to being negative. However, the
pleiotropic and potentially beneficial biological effects of Epo sig-
naling in non-hematopoietic tissues warrants in depth investiga-
tions of new therapeutic protocols. Clearly the generation of Epo
mimetics such as asialo-Epo, CEPO, and others that are non-
erythropoietic derivatives (
75, 79, 149
) will be instrumental in
providing new options for treatment.
Search WWH ::
Custom Search