Biomedical Engineering Reference
In-Depth Information
model of amyotrophic lateral sclerosis (ALS). 14 GCPII inhibition has also been
suggested as a novel therapeutic approach for the treatment of schizophrenia,
diabetic neuropathy and neurodegenerative disorders. 100,122,123
Pre-clinical studies on animal models have employed two main classes
of inhibitors: (1) 2-PMPA and its phospinate (GPI 5232) and thiol analogs
(2-MPPA) and (2) urea-based substrate analogs (ZJ11, ZJ17,
ZJ43). 89,92,98,99,124,125 The first single-dose administration of the orally bioa-
vailable GCPII inhibitor 2-MPPA in humans was announced in 2005. 124,126
However, the compound was later withdrawn from further clinical tests due to
reported immunotoxicity.
3.8.2 Cancer
Targeted therapies of prostate cancer are being sought to complement surgery,
radiation, and chemotherapy, especially in advanced/aggressive forms of the
disease. GCPII is considered one of the most promising molecules for prostate-
cancer imaging and therapy for a combination of reasons. GCPII is present in
all stages of the disease, and its expression levels have been shown to be
upregulated in advanced disease. 127,128 Several features of GCPII make it a
promising molecular address for specific anticancer drug delivery: it has a well-
characterized enzymatic activity, is membrane-bound and blood-accessible,
and undergoes constitutive and antibody-induced internalization. 61 On the
other hand, recent studies have reported that GCPII is expressed in many non-
cancerous tissues. 29,42,43 Moreover, cytoplasmic localization of GCPII has been
reported in a number of non-prostatic tissues (see Section 3.3.2) which might
limit its pharmaceutical applications.
In addition to prostate cancer, GCPII expression in the neovasculature
of most non-prostatic solid tumors raises the possibility that GCPII could
be viewed as a specific anti-angiogenic drug target for cancer treatment (see
Section 3.3.1.1.3).
3.8.2.1 Imaging
Current (and future) imaging techniques for prostate cancer, including ultra-
sound, MRI, and CT, have been expertly summarized in several recent reviews
(and references therein) and are not detailed here. 129-131 Instead, we focus on
clinical and experimental imaging procedures exploiting GCPII as a specific
prostate cancer marker.
At present, 111 In-capromab pendetide (ProstaScint or CYT356), a radio-
conjugate of the 7E11-C5 antibody, is the only FDA-approved GCPII-specific
reagent for imaging soft-tissue sites of metastatic prostate cancer. The some-
what low sensitivity of the scans apparently stems from the fact that 7E11-C5
recognizes an intracellular epitope that is not accessible to the circulating
antibody. As a result, ProstaScint images only the necrotic/apoptotic cells.
The second-generation antibodies target the extracellular part of the enzyme.
Imaging (and therapeutic) reagents based on the J591 antibody are the most
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