Biomedical Engineering Reference
In-Depth Information
treatment. To date, a series of pre-clinical studies have been performed on
mouse and rat, reporting ecient neuroprotection during various neurological
disorders in these animal models.
In contrast, GCPII targeting in cancer diagnosis and therapy is based purely on
its advantageous localization and tracking. GCPII's role in the etiology of
prostate cancer and/or angiogenesis remains unclear. Nevertheless, one FDA-
approved anti-GCPII radioconjugate is already in use for prostate-cancer diag-
nosis, while others are under development. In addition, several anticancer ther-
apeutics targeting GCPII have reached clinical phase I/II stages, and more are in
pre-clinical trials, most employing mouse xenograft models of prostate cancer.
GCPII-based treatment strategies are based mostly on the availability of
high-anity GCPII ligands, antibodies and inhibitors. Detailed structural
studies of GCPII have provided a useful tool for generation of rationally
designed GCPII-specific ligands, contributing greatly to successful drug
development.
Both of the therapeutic approaches are, however, compromised by several
factors. In contrast to initial reports, some recent studies suggest a relatively
broad GCPII tissue distribution in humans. According to current knowledge,
GCPII is probably engaged in 'gene sharing,' meaning that its gene is used to
perform different molecular functions. Besides its enzymatic role, GCPII may
also function as a receptor for an unknown ligand. The biological relevance/
complexity of other GCPII functions and expression sites as well as their
potential interference in GCPII-based therapies represents potential draw-
backs. Pre-clinical testing of GCPII-based therapies has not revealed any sig-
nificant toxicity or major side-effects so far nor have the imaging studies, either
with Ab or ligand, demonstrated the broad GCPII expression pattern that
some authors have proposed. However, GCPII expression (and possibly site-
specific function) has been shown to be species-dependent, and the response of
GCPII-based anti-cancer treatment in the human physiological context
remains to be observed in advanced clinical studies.
In addition, the function and expression pattern of GCPII paralogs and
variants are mostly unknown. At the same time, a partial overlap of GCPII-
targeted treatment with close homologs/variants of GCPII may occur, repre-
senting a potential additional challenge in the field.
In conclusion, it is clear that in addition to generation of more powerful
GCPII-based therapies and their advancement into clinical phase testing,
research into the biological/functional repertoire of GCPII and its family
members will be essential for successful GCPII-based therapy development.
References
1. J. S. Horoszewicz, E. Kawinski and G. P. Murphy, Anticancer Res., 1987,
7, 927.
2. M. B. Robinson, R. D. Blakely, R. Couto and J. T. Coyle, J. Biol. Chem.,
1987, 262, 14498.
