Biology Reference
In-Depth Information
itive-acting factors, the product of the mouse Steel locus, i.e., SCF, the func-
tional ligand for the c-kit cell-surface receptor, is one of the better understood
factors. In mice anemic because of defects in either SCF or c-kit, administra-
tion of exogenous EPO still increases hemoglobin concentration [45, 46],
although to a modest degree. This result would suggest that the few CFU-E
that survive functional SCF deficiency
in vivo
can still respond normally to
exogenous EPO, though their numbers are reduced by limitations imposed on
the cellular pathway at more primitive levels. The interaction of SCF and EPO,
which is of obvious significance in these earlier populations, has been ele-
gantly examined at the molecular level and shown to result from a subtle inter-
play of survival, proliferation, and differentiation signals [47].
These effects at the cellular level lead consistently to increases in hemoglo-
bin in response to increases in circulating EPO, whether exogenous rHuEPO
or endogenous EPO produced in response to hypoxia. The relationship
between serum concentrations of EPO is relatively straightforward (Fig. 2). A
significant temporal mismatch exists between the residence time of rHuEPO
(t
1/2
= approximately eight hours), the life-span of reticulocytes (approximate-
ly five days), and the life-span of erythrocytes (approximately 120 days). A
more thorough discussion of the pharmacokinetics of EPO is to be found in
Chapter 6, but in summary, an increased EPO serum concentration of relative-
ly short duration (measured in hours or days) can produce a very large number
of reticulocytes. The flux through the reticulocyte compartment is huge under
conditions of accelerated erythropoiesis and yields a large number of erythro-
cytes to the circulation. The erythrocytes formed, however, live a compara-
tively long time (on the order of three months). This process, in effect, leads to
a disproportion between the duration of accelerated erythropoiesis (sustained
by increased amounts of EPO and measured in hours) and the longevity of the
hemoglobin response (measured in months). This information is of little value
beyond curiosity until new therapeutic derivatives of EPO are considered (see
Chapter 15), where an increase in circulating half-life of an erythroid molecule
will have a large effect on hemoglobin - on a scale out-of-proportion to the
increased residence time of the EPO analog.
Overall, much of the machinery involved in translating an increase of either
endogenous or recombinant EPO into an increase in circulating hemoglobin
has been defined. At the opposite end of the response is the effect of EPO with-
drawal. In addition to the predictable cessation of erythropoiesis when EPO is
in short supply, the precipitous decrease in circulating EPO concentrations
associated with a return from altitude, the return from space flight, and, per-
haps, the end of a course of EPO treatment in the clinic, is associated with an
accelerated rate of hemoglobin loss from the blood. The seminal work in this
area of Rice and colleagues has led to the proposal of a mechanism of neocy-
tolysis, or the premature destruction of newly formed erythrocytes after inter-
action with endothelial cells or macrophages [48-50]. The precise role a
mechanism such as neocytolysis may play in therapeutic intervention with
rHuEPO has yet to be defined.
