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'Wrapping' Gleevec fights drug-resistant cancer
Source: (cancerfacts.com)
Friday, May 04, 2007
HOUSTON– May 4, 2007 – The anti-cancer drug Gleevec® is far more effective against a drug-resistant strain of cancer when it wraps the target with a molecular bandage that seals out water from a critical area on the cancer cell, say researchers.
The study, highlighted on the cover of this week's issue of Cancer Research, could usher in a more effective version of the already highly effective "leukemia pill" as well as aid in the design of the next generation of targeted therapies.
Led by Dr. Ariel Fernandez, professor of bioengineering at Rice University, who designed the modified drug, a trio of research teams from Rice, and the University of Texas M.D. Anderson Cancer Center, found that the new version of imatinib Gleevec®, called WBZ, is more effective in binding to a protein, called KIT, which is mutated in leukemia and other cancers.
"The re-engineered version of imatinib accomplishes three things," said Fernandez in a prepared statement. "It binds with KIT. It binds with the most effective imatinib-resistant version of KIT. And finally, it binds in a way that ensures that any further version of KIT that becomes resistant to WBZ-7 will no longer be effective as a catalyst for cell reproduction."
Imatinib is one of the most effective of a new generation of cancer drugs that are designed to attack cancer cells and leave healthy cells unharmed. Imatinib targets KIT, which plays a role in cell reproduction. In healthy cells, KIT is active only on rare occasions, but in some cancers the protein is always "on," acting as a biochemical catalyst that spurs cancer cells to constantly reproduce.
Gleevec binds to KIT and effectively blocks the cell signal that tells the cell to reproduce. While Gleevec was hailed as a major advance in the treatment of leukemia, it later turned out that in some patients the cancer cells would become resistant to the drug.
The wrapping version of the drug, known as WBZ-7, was created, produced and tested by three research teams, one headed by Fernandez and the other two headed respectively by William Bornmann and Dr. Gabriel Lopez-Berestein from the University of Texas M. D. Anderson Cancer Center in Houston.
In laboratory studies, WBZ-7 was found to be effective against a form of gastrointestinal cancer that has developed a resistance to imatinib. Fernandez and his colleagues developed the WBZ-7 to form a molecular bandage that seals out water molecules near the "active site" of KIT – the part of the protein that imatinib binds.
"Like virtually all proteins, KIT has packing defects that leave some hydrogen bonds poorly shielded from water attack," Fernandez said. "These bonds, which are called dehydrons, are in the twilight zone between order and disorder."
In KIT, there is a dehydron near the active site that plays a key role in drug resistance. Fernandez said WBZ-7 is identical to imatinib, save for the addition of four atoms – a carbon and three hydrogens – at a key point.
Although the change appears to be minimal at first glance, finding a method to synthesize the compound was complex and challenging, Fernandez said. The task fell on Bornmann, a director of the Center for Targeted Therapy's Translational Chemistry Service, and his colleagues Shimei Wang and Zhenghong Peng – who dubbed the compound WBZ-7 based on their initials and the fact that it was the seventh compound they'd made together.
Following the drug's synthesis, a second team of M. D. Anderson researchers, led by Lopez-Berestein, a professor in the Department of Experimental Therapeutics began a comprehensive testing program. In the first stage, WBZ-7's effects were tested against more than 250 catalytic proteins called kinases, which are in the same class of proteins as KIT, to make sure the drug would not have unintended consequences. Finally, a range of tests were conducted that confirmed that WBZ-7 was just as effective against both non-resistant and drug-resistant strains of gastrointestinal cancer cells.
The research was funded by the National Institutes of Health, the National Science Foundation, Eli Lilly and Company, and by Rice's John and Anne Doerr Fund for Computational Biomedicine.
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