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| Institute: |
Lab or Branch |
| NCI/SAIC Research Technology Program |
Analytical Chemistry Laboratory |
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| Title: |
| SELDI proteomic profiling of sera from
patients of FAP-celecoxib clinical trial |
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| Authors: |
| Z. Xiao, G. Izmirlian, A. Umar, H. J. Issaq,
T. P. Conrads, A. J. Atkinson, P. M. Lynch, E. T. Hawk,
P. Greenwald, T. D. Veenstra, I. U. Ali |
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| Abstract: |
| Individuals with familial adenomatous polyposis
(FAP) have a near 100% risk of developing colon cancer.
Celecoxib, a selective cyclooxygenase-2 inhibitor, was
shown to significantly reduce the number of colorectal
polyps when administered (100mg or 400mg twice daily)
to 77 FAP patients in a 6-month clinical trial (NEJM 2000;
342:1946). At the genomic level, FAP patients have mutations
in adenomatous polyposis coli (APC) tumor suppressor gene
that is also frequent in sporadic colorectal cancers.
Groups of FAP individuals showed striking heterogeneity
in their response to the chempreventive effects of celecoxib.
The objective of this study was to determine serum proteomic
changes in the FAP patients upon receiving celcoxib in
order to better understand the molecular mechanisms underlying
this heterogeneity. SELDI ProteinChip® technology
was applied to analyze the serum proteomic patterns in
different groups of patients. Protein profiles were resolved
on the Strong Anionic and Weak Cationic Exchange (SAX
and WCX) protein chip surfaces and detected by mass spectrometry.
Pre- and post-treatment serum protein profiles were compared
in 31 patients (Placebo, 6; 100 mg bid, 12; 400 mg bid,
13). A significant change (p<0.05) was identified in
multiple serum proteins in patients after treatment with
low and high dosage of celecoxib respectively. In particular,
the level of a protein at 5089/5093 Da was decreased post
treatment in both low and high dosage groups, but not
in the placebo group. Pre-treatment serum protein profiles
were also compared with respect to their treatment outcomes
(strong positive responders, 32; no/negative responders,
23). Protein patterns that differentiated the strong response
from no/negative response were built using a classification
algorithm. Preliminary results from SELDI analysis of
serum samples from patients in the FAP/celecoxib clinical
trial have identified a) differentially expressed protein
markers in response to treatment with celecoxib and b)
protein markers that may serve as predictors of clinical
response in patients if celecoxib were to be used as a
chemopreventive agent. Based on the mass information of
the protein markers, identification of these proteins
using multiple technologies is currently in progress.
The proteomic information obtained from the FAP patients
in this study will help facilitate the management of FAP
and in the development of better and targeted strategies
for prevention of colon cancer. |
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