Messenger - Vol. 2, No. 3, Page 13 Summer 1993 On Research Controlling the body's environmental vigilantes Inside the human body, members of one enzyme gang act like environmental vigilantes, constantly prowling the cell's corridors, always ready to zap cancer-causing intruders. Dubbed "glutathione S-transferases," these vigilante enzymes quickly knock out toxic compounds that invade the body. Unfortunately, in their zeal to get the bad guys, the body's defenders also knock out cancer-fighting drugs. This is because anti-cancer drugs must be structurally similar to toxic compounds in order to destroy tumors. Vigilante enzymes try hard, but they aren't too smart: They can't tell the difference between dangerous toxic compounds and the drugs sent to kill intruders. If Roberta F. Colman can prove exactly how glutathione S-transferases work, the information could lead to new drugs that arrest these enzymes in cancer patients. "Common anti-cancer drugs like Melphalan and Chlorambucil are toxic compounds that destroy tumors," explains Colman, professor of chemistry and biochemistry. "However, these drugs are, in turn, decomposed by the vigilante enzymes, causing them to lose their anti-tumor activity." Like all enzymes, glutathione S-transferases act as catalysts, increasing the rate of chemical reactions within the body. Specifically, these vigilante enzymes stimulate a particular region of the glutathione molecule (found in the liver tissue of mammals) to combine with various non-soluble foreign substances such as carcinogenic food preservatives and aflatoxin, which comes from mold. After reacting with glutathione, these non-soluble, cancer-causing intruders are transformed into water-soluble substances that can be safely flushed from the body. Sadly, the vigilante enzymes also enhance the reaction of glutathione with drugs used for chemotherapy, rendering them ineffective. To develop new drugs that temporarily inhibit the enzymes, scientists need a precise map of the enzymes' "binding pocket." So, Colman is tagging portions of vigilante enzymes extracted from rat livers, to determine how the enzymes' behavior changes when a particular binding site is blocked. Already, her research has defined several key regions of activity within the enzymes. "A major problem in the treatment of many types of cancer is the fact that these enzymes cause resistance to chemotherapy drugs," Colman notes. "If we could develop inhibitors to specifically target glutathione S-transferases, these inhibitors could be used to increase the effectiveness of currently used cancer drugs and so prolong the life of oncology patients." -Ginger Pinholster