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Scientific Background

   Cell death was once thought to be a passive non-specific event, but is now
   known to be an active biochemical process. Scientists have discovered that any
   cells have the ability to die by this process, called  programmed cell death or
   apoptosis. 

   A number of important human diseases are caused by abnormal apoptosis
   control mechanisms, which can result in either a pathological increase in the
   number of cells (e.g. cancer) or a damaging loss of cells (e.g. degenerative
   diseases). Recent data has shown that cells have a discrete cell death pathway
   defined by a specific set of genes. These genes encode proteins that form the
   biochemical process that ultimately invokes cell death. 

   The key genes that control the cell death process are the cell death effectors of
   the CED-3/ICE ("caspase") family and the cell death inhibitors of the Bcl-2
   family. The caspase gene family encodes a set of proteases responsible for
   carrying out the death process. In a living cell, these proteases are normally
   kept inactive by proteins encoded by the Bcl-2 family. 

Caspase Proteins
   The caspases are a family of proteases responsible for carrying out the cell death
   process. In a living cell, these proteases are kept inactive by proteins on the
   mitochondrial cell surface from the BcL-2 family. When a cell is exposed to cell death
   signals such as ischemia, chemotherapy or radiation, BcL-2 function is blocked and
   caspase activators initiate the cell death cascade. 

   Small molecule drugs, like CHML, are able to specifically modulate the activity
   of the caspase family, the Bcl-2 family, or other key points in the apoptotic
   pathway, and exert control over the cell death process and have utility in
   diseases characterized by either excessive or insufficient levels of apoptosis. 
BcL-2 Protein Blockage
CHML is able to specifically modulate key points in the apoptotic pathway. 

Specific Mechanism:
p53 protein, commonly referred to as "the tumor suppressor gene," is a key player 
in the cellular apoptosis process. Bio-therapeutic activation of this pathway, has 
been a popular target for recent drug discovery technology. 

Apoptosis

p53, Bax and p21 protein levels were measured by immunoblotting assay, in
MCF-7, ML-1, H1299 (human lung carcinoma) and RKO (human colon cancer,)
cell lines after treatment with CHML. p53 protein was found to be elevated in
the MCF-7, RKO and ML-1 cells. 

As the ability to induce apoptosis is not limited to p53 positive cell lines, it
appears that CHML is able to provoke apoptosis through both p53-dependant
and -independent pathways. 

Core Technologies: 
Supporting GLORY's drug discovery program, is a sophisticated new technology
for drug administration. Arterial Infusion using DSA*, is a fast developing
science performed by trained Interventional Radiologists. Formerly used in
the management of Cardiology related conditions, the technology is capable of
delivering concentrated drugs to a highly specific site (e.g. tumor) via the
arterial network. 

Download (Real Time DSA) movie of destruction of tumor feeding network.
CHML infusion via DSA -
CHML Arterial Infusion using Digital Subtraction Angiography.* 

Diagnostics:
DSA is capable of delivering concurrent imaging of the intricate vasculature of
the tumoral network. This is used to guide the delivery of CHML, as well as
measure the immediate effects on the tumors blood supply network. 

In recent studies, CHML was able to effect significant disruptions to the tumoral
vasculature network in a number of various malignancies. In virtually every
case, marked destruction of the tumor's feeding system could be observed in
less than 30 minutes. 

This information further corroborates CHML's ability to penetrate a number 
of difficult tumors. 

Marked reduction can be seen on the two angiogram sequences below.
DSA image - Visual Destruction of Tumor's Main Blood Supply