600
(Wang et al. 2006 ). A number of small molecules were isolated that activate p53
reporter activity, increase expression of p53 target genes such as p21(WAF1) or
death receptor 5 (KILLER/DR5) of TNF-related apoptosis-inducing ligand
(TRAIL), and induce apoptosis in p53-defi cient cells. Some of the compounds acti-
vate a p53 response by increasing p73 expression, and knockdown of transactivat-
ing isoforms of p73 by siRNA reduces their induction of p53-responsive
transcriptional activity. Some compounds do not induce signifi cant p73 expression
but induce a high p53-responsive transcriptional activity in the absence of p53.
In vivo experiments demonstrate potent antitumor effects of selected compounds.
The results establish the feasibility of a cell-based drug screening strategy targeting
the p53 transcription factor family of importance in human cancer and provide lead
compounds for further development in cancer therapy. These fi ndings emphasize
the growing role of imaging technology in aiding researchers in the development of
personalized cancer treatments. The therapeutic effects of the small molecule com-
pounds will be explored in different types of cancer and the potential toxicities of
these compounds will be evaluated.
Molecular imaging can provide pharmacokinetic (PK) and pharmacodynamic
(PD) information. Use of the technique in early clinical trials can:
- Provide information on optimum biological dose and PK/PD relationships
- Identify tumors containing specifi c molecular targets
- Provide in vivo pharmacodynamic evaluation of compounds.
Further efforts are needed in this area and pharmaceutical industry need to get
involved besides the academic investigators and the companies providing the equip-
ment and other materials. The major challenge for drug development is to overcome
the lack of specifi c tracers and ligands available for in vivo imaging. Here, the
problem is often not one of specifi city for the molecular interaction or pathway, but
rather of background owing to non-specifi c binding in vivo, peripheral metabolism
and/or poor penetration across endothelial barriers. In vivo assays of molecular
interactions and pathways should be suffi ciently cancer-specifi c to be of use as ther-
apeutic targets. Such probes could provide therapeutically relevant functional mea-
sures of disease status and, hence, assays of potential responsiveness. They would
also provide endpoints of pharmacodynamic responses. Systems already in place
for cancer include the imaging of proliferation and its relevance to anti-proliferative
agents, blood fl ow and its relevance to antiangiogenic agents, and gene expression
with relevance to gene therapy. If an in vivo diagnostic is available to monitor the
effects of numerous available antiangiogenesis agents on tumors, it can help us to
defi ne responder and non-responders.
CellPoint LLC is optimizing its novel diagnostic imaging agent on Philips’
SKYLight® gantry-free gamma camera in collaboration with Philips Medical
Systems. CellPoint’s ethylenedicysteine (EC) drug conjugate technology is a unique
delivery system that functions as a chemical bridge linking tissue specifi c ligands,
such as hormones, proteins, peptides, glucose analogues, or pharmaceutical com-
pounds to radioisotopes for cancer diagnosis and treatment. The companies will
collaborate on the molecular imaging agent, Tc-99 m-EC-deoxyglucose based on
20 Development of Personalized Medicine