"STI571: A Tyrosine Kinase Inhibitor for the Treatment of CML — Validating the Promise of Molecular Targeted Therapy"
June 2000
Editor's Note: This is the brief report about STI571 written by Dr. Brian Druker and on which he based his recent presentation at the conference about chronic myelogenous leukemia in Bologna, Italy. According to officials at Oregon Health Sciences University, Druker has not yet published any peer-reviewed research papers on STI571 because it is still early in the clinical trials phase. However, he does now have one before a publication review committee. The brief report below, reprinted verbatim, is similar to the one he uses at various CML conferences, OHSU officials say.
By Brian J. Druker, M.D.
Oregon Health Sciences University
The Bcr-Abl fusion protein, resulting from a (9;22) chromosome
translocation, causes several types of leukemia. The 210 kDa form of Bcr-Abl
is present in virtually all patients with chronic myelogenous leukemia (CML)
and a 185 kDa variant is present in approximately 20 percent of acute
lymphoblastic leukemia patients. The transforming function of Bcr-Abl
requires tyrosine kinase activity of these Bcr-Abl fusion proteins, which is
elevated as compared to c-Abl. Thus, Bcr-Abl is an ideal candidate for a
molecularly targeted therapeutic agent and an inhibitor of the Bcr-Abl
kinase would be predicted to be an effective and selective therapeutic agent
for CML. STI571 (formerly CGP57184B) was synthesized by Novartis
Pharmaceuticals by identifying a lead in a high throughput in vitro screen
for tyrosine kinase inhibitors and optimizing its activity for specific
kinases. STI571 functions through competitive inhibition at the ATP binding
site and shows a high degree of specificity for the Abl, PDGER and Kit
tyrosine kinases. It induces either growth arrest or apoptosis specifically
in Bcr-Abl expressing hematopoietic cells with no obvious effects on normal
cells or in cells transformed by other tyrosine kinase oncogenes.
Based on anti-leukemic activity in several pre-clinical models and a lack of
significant toxicity in animals, a phase I clinical trial was conducted in
CML patients who had failed other treatment options. All patients in the
chronic phase (n=31) have achieved hematologic remissions once therapeutic
dose levels were achieved. With prolonged therapy (5 months or greater), a
growing fraction of these patients have cytogenetic responses, including
several individuals with complete disappearance of the Ph chromosome. STI571
also has remarkable activity as a single agent in CML blast crisis and Ph +
ALL patients. Although responses tend to not be durable, 20 percent of
myeloid blast crisis patients have ongoing responses between six months and
one year. As virtually all patients with CML express Bcr-Abl and the Bcr-Abl
protein is unique to tumor cells, this disease has provided an ideal
opportunity to test the concept that drugs targeted against a tumor-specific
abnormality will have therapeutic utility. Ongoing studies are directed at
optimizing the use of this agent.
Source: Oregon Health Sciences University
Give me a holler
This site was last updated on Feb. 10, 2001
Copyright © 2000-2001 CMLSupport.com. All rights reserved.
The fine print: These contents may not be reproduced in whole or in part without the express written permission of the author. Or she will beat you up and stuff. This site is best viewed with Internet Explorer, but we won't stop you from using another Web browser. Congratulations if you've read all of this! (But we're sorry to say, the person before you got our last cash prize!)
|
