Growth factors - Pharmaceutical Biotechnology: Concepts and Aapplications - page 286

Normal skin appears to be devoid of PDGF receptors. Animal studies illustrate that rapid
expression of both α and β receptor subunits is induced upon generation of an experimental wound
(e.g. a surgical incision). Receptor expression is again switched off following re-epithelialization
and complete healing of the wound.
Initial human trials have found that daily topical application of PDGF (BB isoform) stimu-
lated higher healing rates of chronic pressure wounds, although the improvement recorded fell
just short of being statistically signifi cant. A second trial found that daily topical application of
PDGF (BB) did promote statistically signifi cant accelerated healing rates of chronic diabetic
ulcers. The product (tradename Regranex) was approved for general medical use in the late
1990s. Its active ingredient is manufactured by Chiron Corporation, in an engineered strain of
Saccharomycies cerevisiae harbouring the PDGF B chain gene. Regranex is notable in that it
is formulated as a non-sterile (low bioburden) gel, destined for topical administration. The fi nal
formulation contains methylparaben, propylparaben and m -cresol as preservatives. In addition,
as is the case with EGF, PDGF antagonists may also prove valuable in the treatment of some
cancer types in which inappropriately high generation of PDGF-like mitogenic signals leads to
the transformed state.

10.3.5 Fibroblast growth factors

FGFs constitute a family of about 20 proteins (numbered consecutively FGF-1 to FGF-20). Typi-
cally, they display a molecular mass in the region of 18-28 kDa and induce a range of mitogenic,
chemotactic and angiogenic responses. Classifi cation as an FGF is based upon structural
similarity. All display a 140 amino acid central core that is highly homologous between all family
members. All FGFs also tightly bind heparin and heparin-like glycosaminoglycans found in
the extracellular matrix. This property has been used to purify several such FGFs via heparin
affi nity chromatography. Although many of the original members of this family stimulate the
growth/development of fi broblasts (hence the name), several newer members have little/no effect
upon fi broblasts. Keratinocyte growth factor (FGF-7) is thus far the only member of the FGF
family to have gained approval for general medical use (Box 10.3).

10.3.6 Transforming growth factors

TGFs represent yet another family of polypeptide mitogens. The members of this family include
TGF-α, as well as several species of TGF-β. TGF-α is initially synthesized as an integral mem-
brane protein. Proteolytic cleavage releases the soluble growth factor, which is a 50 amino acid
polypeptide. This growth factor exhibits a high amino acid homology with EGF, and it induces its
biological effects by binding to the EGF receptor. It is synthesized by various body tissues, as well
as by monocytes and keratinocytes. It is also manufactured by many tumour cell types, for which
it can act as an autocrine growth factor.
TGF-β was fi rst described as a growth factor capable of inducing transformation of sev-
eral fi broblast cell lines (hence the name TGFs). It is now recognized that 'TGF- β ' actually