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BU chemist studies drug - protein interactions for clues to next-generation anticancer drugs

27.03.2003


The work of a Binghamton chemistry professor is altering conventional wisdom about the interactions of the anticancer drug Taxol ® and could lead to the development of even more effective, next-generation pharmaceuticals.



With $406,835 funding from the National Institute of Health, Susan Bane and her Binghamton research team are working in collaboration with David Kingston of Virginia Polytechnic Institute to learn more about the protein "tubulin."

"Tubulin is a target for a number of anticancer drugs," Bane said.


Found in all cells and in the highest concentrations in the nerve cells of the brain, tubulin is critical to cell growth and therefore affords a switch that can help control the spread of cancer, all forms of which are characterized by uncontrolled cell growth.

Bane has been studying tubulin for over a decade, and Taxol, an anti-cancer drug commonly used to treat many types of breast, ovarian and lung cancers, is key to her research. Until her work recently suggested otherwise, scientists had thought that the synthetic portion of Taxol was key to the drug’s effectiveness.

"The conventional wisdom was that it was the most important part of the molecule because it binds with the receptor," said Bane.

But Bane’s discovery, which was recently published in Biochemistry, is that the naturally occurring part of Taxol actually does most of the work.

Taxol is a major money-maker for Bristol-Meyers Squibb Company, earning the pharmaceutical giant around $1.5 billion a year in the United States alone. By figuring out how anticancer drugs like Taxol interact with tubulin at the molecular level, Bane and her research team hope to pave the way for the development of even more effective next-generation drugs.

The convoluted origins of Taxol help to make clear why producing it and understanding exactly how it works in the body is challenging. In the early 1960s, the National Cancer Institute initiated a program to screen biological extracts collected from a wide variety of natural sources. One of these extracts was found to exhibit significant anti-tumor activity against a broad range of rodent tumors. But it was another five years before two researchers isolated the active compound from the bark of the Pacific yew tree, Taxus brevifolia, and identified that compound as paclitaxel. It was then close to 20 years more before phase I clinical trials of the substance began, and not until 1992 that Bristol-Meyers Squibb’s drug Taxol received conditional FDA approval for use in the treatment of metastatic ovarian cancer.

Much of that time, scientists were struggling not only to understand and maximize the therapeutic effects of paclitaxel, but also to figure out how to make it in a cost-effective manner and an easy-to-administer form. The Pacific Yew, one of the slowest growing trees in the world, is also an environmentally protected species. And because only very small amounts of the compound can be isolated from the bark, it would take six 100-year-old trees to provide enough Taxol to treat just one patient. Since removing the bark kills the tree, the costs of producing sufficient quantities of the drug remained a major limiting factor for years.

Fortunately, a closely related analogue of paclitaxel, which is the generic name for Taxol, was discovered in the leaves of a European species of ornamental shrub Taxus baccata. Although the extraction and subsequent chemical elaboration of the substance remained labor intensive, the source was at least renewable, and sufficient quantities were obtained to carry out clinical trials.

In spite of all the issues involved in its manufacture, by the latter 1990s, the relatively non-toxic properties of Taxol had made it a shining star in the treatment of cancer. By then, too, synthetic organic chemists had teamed up to assist Mother Nature, and the drug was finally made available in sufficient quantity to provide an effective, non-intrusive alternative to the more radical techniques of radiation therapy and surgery. As for its efficacy, Taxol is today primarily used to treat solid tumors, which are notoriously hard to combat, Bane said.

In its commercially available form, Taxol is a semi-synthetic- that is, the drug consists of two parts: one natural and one man-made.

"Plants make natural products for their own purposes, not to be anticancer drugs," Bane said. "Taxol is a very big and complicated molecule," she said. "The complicated core part of the molecule can be isolated from the needles of the Yew, which is a sustainable source. The less complicated part can be made synthetically," Bane said.

Taxol binds to protein polymers known as microtubules, which are part of the cell’s structure, and disrupts mitosis, the process of cell division that is the root of cell growth.

"When a cell divides, it makes the microtubules longer," said Bane. "Taxol binds to the microtubules and prevents them from disassembling. The net result is that the cell dies."

Using natural products in the war against cancer is big business. "More than half of the drugs we use that are commercially available have natural products as their origin," said Bane.

"The next ’big thing’ will fight cancer as well as Taxol but will be easier to administer and will not produce resistance," Bane said.

In order to speed that discovery, Bane and her team are trying to determine what Taxol is doing to tubulin, the main protein in microtubules.

"Is there a part that’s important? Is there a part that’s not essential" Bane asks, flipping through slides of analogs of the chemical, "What’s the shape of the molecule when it’s interacting with the protein?"

These are the questions that drive her research, which progresses through the study and analysis of Taxol derivatives, each containing some but not all of the atoms in Taxol. These analogs are created by Kingston at his lab at VPI. His group then labels the molecules with fluorescent dyes to make them more visible and sends them to Binghamton for analysis.

From there, Bane and her team study how the derivatives interact with tubulin, measuring how tightly each part binds, how easily each part can separate from the tubulin, and how quickly the reactions occur.

Learning more about how Taxol works on tubulin is certain to benefit scientists working to discover more effective anti-cancer drugs. But even so, research to find Taxol’s next-generation replacement is likely to be subject to many fits and starts, Bane said. New drugs might easily turn out to have low "therapeutic windows," the margin between toxic and effective doses. They could also have adverse side effects or be difficult to administer. Still, Bane knows her work is an important step toward more effective cancer treatment.

"If you want to build a new drug based on an old one, you have to know how the original one works," Bane said, "We are laying that foundation."

Ingrid Husisian | Binghamton University
Further information:
http://research.binghamton.edu/Discovere/march2003/TopStories/Chemist.htm

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