Drug Targeting Organ-Specific Strategies

250 9 Tumour Vasculature Targeting
ment of plasminogen, called angiostatin, was purified and found to replace the inhibitory activity
of the primary tumour completely [100]. Treatment of tumour-bearing mice with angiostatin
almost completely prevented metastasis formation in the lung. In theory, these inhibitor
proteins could serve as carrier molecules for drug targeting, provided they specifically
bind to tumour vasculature. They could then form the basis for dual targeting strategies, in
which the carrier itself exerts an effect in addition to the effect of the attached drug. Depending
on the mechanisms of action of both active components, synergistic effects might be
expected [101].The target for angiostatin on endothelial cells has recently been discovered to
be ATP synthase [102]. Whether this binding site is expressed in tumour vasculature and can
be exploited as a target epitope with angiostatin as a carrier molecule, needs to be investigated.
Using a similar strategy endostatin was discovered [103]. Although the exact identity of
the binding site for endostatin is not known, Chang et al. demonstrated that endostatin can
bind to blood vessels of different calibre in various organs. In breast carcinoma binding of endostatin
co-localized with FGF-2, but FGF-2 and heparin did not compete for endostatin
binding [104]. The lack of selectivity for tumour vasculature probably excludes this molecule
from being used as a carrier molecule in drug targeting strategies.
To summarize, some major steps forward have been made in the development of novel
drug targeting approaches aimed at selectively killing tumour endothelial cells.The extensive
‘from the bench to the bed’ experience with tumour cell-targeted immunotoxins [105] has
paved the way for further development of these tumour endothelial cell-targeted strategies.
In this context it is of primary importance that the handling of clinically relevant target epitopes
and their drug targeting ligands by endothelial cells, be established under pathological
conditions.
9.4 Tumour Vasculature Targeting Potentials: Extrapolation
of Animal Studies to the Human Situation
From the above, it is clear that tumour vasculature-directed drug targeting approaches to
blocking tumour blood flow can be potent strategies for the therapy of large solid tumours.
At present, however, only pre-clinical data are available in this area of research, and no sensible
extrapolation from pre-clinical experiments with human or animal tumours can be
made from the animal model to the clinical setting. One important difference between human
tumours and tumours grown in animals is the level of vascular permeability. Although
this parameter can vary significantly between the various animal tumours [106], it is believed
that the vasculature of animal tumours is in general more permeable. This may be a result of
the fact that the majority of animal tumours grow more rapidly than those developing in humans.Another
consequence of this rapid tumour growth, is that the majority of blood vessels
in animal tumours are in a pro-angiogenic state. As a result, anti-angiogenic therapy or angiogenesis-related
epitope-targeted therapy will affect a greater proportion of the blood vessels
in an animal tumour. In human tumours the vasculature is more heterogeneous. Therefore,
the selective targeting of drugs to different epitopes covering a broad range of angiogenesis-related
markers seems most appropriate strategy to gain access to the majority of tumour
blood vessels.