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CA News: Serpents & Scientists ... venom/anti-cancer agent

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Posted by W von Papineäu on April 22, 2003 at 11:51:57:

UNIVERSITY OF SOUTHERN CALIFORNIA NEWS (Los Angeles) 20 April 03 Serpents & Scientists - The bite of the Southern Copperhead snake packs a punch, but its venom may also contain a powerful anti-cancer agent. The key, according to USC researchers, is its ability to inhibit the growth of tumors. (Alicia Di Rado)
Francis S. Markland’s USC lab is garnering yet another patent – and he has Agkistrodon contortrix contortrix to thank.
That seeming gibberish is the scientific name for the southern copperhead snake, whose potent venom makes not only for a painful bite but, more importantly, also may contain an anti-cancer agent.
Any day now, Markland, a professor of biochemistry and molecular biology at the Keck School of Medicine of USC, will get word that the United States Patent and Trademark Office has issued its latest patent for his lab’s work on contortrostatin, a protein found in the venom.
The patent protects technology related to how contortrostatin interferes with tumor cells’ ability to move.
But how did Markland make the jump from snake venom to a drug that seems to fight cancer?
It was no accident.
Many scientists in search of new drugs start with compounds from organisms more likely to be seen on “Animal Planet” than under a microscope. Whether they come from Ecuadorian tree frogs or giant Israeli scorpions, poisons that animals secrete are powerful substances.
Markland first explored a snake venom compound called fibrolase, which breaks up blood clots. After receiving a handful of patents related to the substance, Markland and the USC Office of Technology Licensing transferred it to a company now called Nuvelo Inc. Today, the drug (called alfimeprase) is in phase II clinical trials -– including one at USC University Hospital.
With fibrolase propelled into the pharmaceutical world, Markland and his lab partners, such as senior research associate Stephen Swenson and research associates Steffi Schmitmeier and Vlad Golubkov, could turn their full attention to cancer and contortrostatin.
“Contortrostatin is in a class of compounds called disintegrins, which interact with proteins called integrins,” Markland explained. “These integrins are found on the surface of normal and cancerous cells.”
First, Markland and colleagues believed contortrostatin might fight cancer by blocking integrins on the surface of cancer cells and stunting cells’ ability to move into vessels and tissues.
Thus, cells would be unable to spread beyond the tumor.
That proved true in the lab, but it did not stop there.
The compound seems to interfere with angiogenesis, the process by which new blood vessels are born and develop to supply much-needed nutrients to cancerous tumors.
“Newly growing blood vessels express an integrin that disintegrins can target,” Markland said, “but mature blood vessels do not express this integrin, so they are not affected.”
Developing the compound further means getting answers to some key chemical questions.
Matt Ritter, now a scientist with the Scripps Research Institute, began looking at contortostatin’s mechanisms of action when he was a doctoral student in Markland’s lab. He found the molecule is made up of two polypeptide chains held together by two covalent bonds.
But this raised a question: do the chains parallel each other in the same direction, or do they run in opposing directions? Robert Bau, professor of chemistry at USC, is analyzing the molecule through X-ray crystallography to find out more.
The answer could help explain why contortrostatin confuses cancer in a completely unexpected way. Scientists know that integrins can carry signals from outside a cell to the cell’s interior, but “contortrostatin can substitute for that and alter the signal,” Markland said. It is as if a device popped into a telephone changed normal conversation to gibberish.
“It is this unique reactivity that enables it to disrupt cellular migration,” he said.
Although contortrostatin has been evaluated only in the lab, Markland is excited about its prospects. In vitro studies have shown action against a number of cancer cell types, including breast, ovarian, prostate and glioma. It also affects newly growing endothelial cells.
“In different cell types, it acts with different integrins,” Markland said.
As soon as the researchers get over two significant hurdles – developing a targeted delivery system and engineering the protein so they do not have to derive it directly from snake venom – they hope to put it to the ultimate test: clinical trials.

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