DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Hematopoietic Agents:
Growth Factors, Minerals,
and Vitamins
Kenneth Kaushansky
and Thomas J. Kipps
The finite life span of most mature blood cells requires
their continuous replacement, a process termed
hematopoiesis. New cell production must respond to
basal needs and states of increased demand. Red blood
cell production can increase >20-fold in response to anemia
or hypoxemia, white blood cell production increases
dramatically in response to a systemic infection, and
platelet production can increase 10- to 20-fold when
platelet consumption results in thrombocytopenia.
The regulation of blood cell production is complex.
Hematopoietic stem cells are rare bone marrow
cells that manifest self-renewal and lineage commitment,
resulting in cells destined to differentiate into the
nine distinct blood-cell lineages. For the most part, this
process occurs in the marrow cavities of the skull, vertebral
bodies, pelvis, and proximal long bones; it
involves interactions among hematopoietic stem and
progenitor cells and the cells and complex macromolecules
of the marrow stroma, and is influenced by a
number of soluble and membrane-bound hematopoietic
growth factors. A number of these hormones and
cytokines have been identified and cloned, permitting
their production in quantities sufficient for therapeutic
use. Clinical applications range from the treatment of
primary hematologic diseases to use as adjuncts in the
treatment of severe infections and in the management of
patients who are undergoing cancer chemotherapy or
marrow transplantation.
Hematopoiesis also requires an adequate supply
of minerals (e.g., iron, cobalt, and copper) and vitamins
(e.g., folic acid, vitamin B 12
, pyridoxine, ascorbic
acid, and riboflavin); deficiencies generally result in
characteristic anemias, or, less frequently, a general failure
of hematopoiesis (Hoffbrand and Herbert, 1999;
Wrighting and Andrews, 2008). Therapeutic correction
of a specific deficiency state depends on the accurate
diagnosis of the anemic state, knowledge about the correct
dose, the use of these agents in various combinations,
and the expected response. This chapter deals
with the growth factors, vitamins, minerals, and drugs
that affect the blood and blood-forming organs.
Hematopoietic Growth
Factors
History. Modern concepts of hematopoietic cell growth and differentiation
arose in the 1950s when cells from the spleen and marrow
were shown to play an important role in the restoration of
hematopoietic tissue in irradiated animals. In 1961, Till and
McCulloch demonstrated that individual hematopoietic cells could
form macroscopic hematopoietic colonies in the spleens of irradiated
mice. Their work established the concept of discrete hematopoietic
stem cells, which can be experimentally identified, albeit in
retrospect (i.e., the presence of a multilineage clonal splenic colony
appearing 11 days after transplantation implied that a single cell
lodged and expanded into several cell lineages). This concept now
has been expanded to include normal human marrow cells.
Moreover, such cells now can be prospectively identified.
The basis for identifying soluble growth factors was provided
by Sachs and independently by Metcalf, who developed clonal, in
vitro assays for hematopoietic progenitor cells. Initially, such
hematopoietic colonies developed only in the presence of conditioned
culture medium from leukocytes or tumor cell lines.