Toxicology is getting a facelift with an infusion of genomics and proteomics-and powerful computing-that will help researchers predict adverse effects to chemicals in the environment, as well as the effectiveness of drugs used to treat breast cancer patients.

Knowing how a person's body would allow a toxic effect to occur at the gene and protein level, may someday make it easier for doctors to decide what treatment is more appropriate. Such information also would lead to the development of better biomarkers to detect toxicity earlier during medical treatment, researchers said at the annual meeting of the American Association for the Advancement of Science (AAAS).

Like a wad of gum stuck in a child's hair, a small breast cancer cell from a tissue mass requires delicate unraveling and extraction. Traditionally, researchers have studied the genetics of the whole tumor mass because of the difficulty faced when trying to excise the cell of interest. Now, Emanuel Petricoin of the Food and Drug Administration has been working with a special video-game like microscope that pulls selected cells out, like a tractor beam. When combined with new protein array technologies that he and his colleague Lance Liotta (National Cancer Institute) have also been developing, the new microscope technology has allowed him to study toxicity and the cancer-associated "miswiring" of the cellular circuitry in breast cancer patients receiving different kinds of drugs or combination of drugs.

After the cell is isolated from the tumor mass, it is ready to have its proteome (the protein complement encoded by a person's genome) analyzed. To do this, Petricoin has also developed protein array tests to detect subtle changes in protein phosphorylation along many key "nodes" within the cellular circuitry.

Phosphorylation occurs when a phosphate group is removed from ATP, a component in many cellular circuits. While it is possible to know of the existence of a gene product in a cell, Petricoin takes it a step further to find out what it is doing; he is concerned not just with the receptor of a molecular drug, but whether or not there is a continuous energy cascade or a plug, for a given cellular activity. As a result, he is able to look at a cell-signaling pathway globally.

"This protein array is able to look at signal pathway profiling, cellular circuitry, and protein-protein interactions on a chip, to look at toxic and cancer related signaling events," Petricoin said.

"We're also using this to monitor toxicity simultaneously. In clinical trials, we're going to use this to target the patient's response and change drugs to fit the profile. The promise of proteomics is that while DNA is the information archive, proteins actually do the work. They are the targets, the biomarkers, or the molecular machines that cause the cell to die, grow, or differentiate," Petricoin said.

By profiling these tumors and assigning them with a computer-system tool to their proteomic mass spectroscopy, to generate a complex protein "barcode" serum, the computer can datamine between different known toxicities for patients, and have a better basis upon which to assign a drug treatment.

SOURCE:
Annual Meeting of the American Association for the Advancement of Science, February 14, 2003 (http://www.aaas.org)