ITHACA, N.Y. -- For nearly 20 years, a group of chemical biologists at Cornell University has been refining a technique for peering into the inner workings of cells to watch cancer-fighting drugs at work. Now, in three papers they report that their research has yielded critical insights into how the drug BPA, used as an experimental treatment for high-grade brain tumors, targets diseased cells.
In two separate studies of the uptake of BPA (boronophenylalanine) by cancerous brain cells, a group led by Subhash Chandra, a senior research associate with Cornell's Department of Chemistry and Chemical Biology, has found that the dose currently favored by medical researchers is not high enough to target cancer cells effectively. While the standard length of time that a patient spends being infused with BPA is one to two hours, the Cornell group found that an infusion time of six hours was required to ensure that cancer cells take up the drug in adequate levels. Chandra's Cornell collaborators on the studies included researchers Duane R. Smith and Daniel R. Lorey.
Remarkably, the results of the two studies were almost identical, even though one was performed on rats and one on human brain cancer cells cultured and grown in the laboratory on silicon chips. The human studies were published in the June 2002 issue of Radiation Research and the rat studies in the November 2001 issue of Cancer Research .
As a result of the Cornell-led research, Studsvik Medical, a research company in Nykoping, Sweden, has begun clinical trials of longer infusions of the drug in hopes of improving the success of the therapy.
"Different models showing the same thing -- I think this is what gives the strength to this study," says Chandra. The conclusions are strengthened by a third study, also led by Chandra, published in the August issue Clinical Cancer Research , that lends powerful support to a new method of observing BPA activity in the brains of living cancer patients.
To track BPA in brain cells, the Cornell scientists used an imaging technique known as subcellular secondary ion mass spectrometry (SIMS). The technique yields three-dimensional images of the electrically charged atoms, or ions, present in a sample, sorting the ions by mass and charge and producing separate images for each type of ion.
The sensitivity of the technique is so high that it can even distinguish between different isotopes -- atoms of the same element, but with different masses. It is extremely well suited to cancer research, since cancer-fighting drugs can be "tagged" with isotopes that serve as chemical markers, showing the location of the drug within tissues subjected to SIMS imaging.
Boronophenylalanine is used in an experimental treatment for glioblastoma, an especially virulent form of brain cancer that strikes about 17,000 people a year in the United States. The disease is always fatal, usually within a year or two of diagnosis.
What makes glioblastoma so difficult to treat -- and so deadly -- is its tendency to spread aggressively, forming clusters of malignant cells far from the main tumor. While the main tumor mass can be surgically removed, the small clusters of invading cancer cells eventually will grow and form new tumors. In order for treatment to be successful, not only the main tumor mass must be eradicated but also the tiny invading cell clusters.
In the treatment, called boron neutron capture therapy (BNCT), patients are given a drug (such as BPA) containing an isotope of boron attached to an amino acid, which is taken up into cancerous cells at a rate three to four times that of the uptake by normal brain tissue.
A beam of low-energy neutrons is then directed at the patient's brain. When a boron atom is hit by a neutron, it "captures" the neutron and undergoes nuclear fission, releasing two smaller particles. These particles travel 5 to 10 microns -- approximately the width of a cell -- before coming to rest, destroying the diseased tissues in their wake.
Although BNCT has been moderately successful at treating tumors in clinical trials, the invading cell clusters have proved resistant to treatment, taking up less BPA than their counterparts in the main tumor mass. The new research indicates that with a longer drug infusion time, the BPA levels in the invading cells could come closer to those in the main tumor mass.
Other authors of the Cancer Research paper are Rolf F. Barth and Weilian Yang, Department of Pathology, Ohio State University; and Darrel D. Joel and Jeffrey A. Coderre, Brookhaven National Laboratory. Coauthors of the Clinical Cancer Research paper are George W. Kabalka, Department of Chemistry, University of Tennessee; and Jeffrey A. Coderre, Department of Nuclear Engineering, Massachusetts Institute of Technology.
All three research projects were supported by the U.S. Department of Energy, which recently awarded the Cornell laboratory a three-year, $829,000 grant to continue the cancer research using ion microscopy.
This article was prepared by Cornell News Service science intern Lissa Harris