by Alison Davis
April 16, 2004

Nearly half a century ago, a stroke of luck led scientists to discover the cancer drug cisplatin. Researchers investigating the effect of electrical fields on bacterial growth discovered that a metal-containing chemical solution used to conduct current, not the electrical fields themselves, stopped the bacteria from dividing. Further tests proved that cisplatin , a platinum-containing substance produced when the metal electrodes reacted with the chemical solution, could also halt the growth of cancer cells. Today, cisplatin is an important component of the treatment for many advanced testicular and ovarian cancers. However, tumor cells can "learn" how to reject cisplatin and other chemotherapy drugs, allowing the cells to multiply and spread. Doctors cannot simply give more cisplatin to remedy this drug resistance problem because of the risk of serious ear and kidney toxicities caused by higher doses of the drug.

Basic researchers studying the role of metals in biology have made another surprise discovery about cisplatin. An interdisciplinary team of scientists found what is likely to be a main cause cisplatin resistance, and it has to do with how the body handles another metal: copper. Biochemist Dennis Thiele, Ph.D., of the University of Michigan Medical School in Ann Arbor and the late geneticist Ira Herskowitz, Ph.D., of the University of California, San Francisco, joined forces to discover that the Ctr1 protein, which transports metals into cells, takes in not only copper, but also cisplatin. The researchers found that yeast cells that lacked the metal transporter protein were highly resistant to cisplatin, suggesting that the cells had no way to absorb the drug. The scientists next created experimental cell lines using mice that lack the equivalent copper-intake protein. Mouse cells that did not contain any Ctr1 protein were eight times more resistant to cisplatin than their normal counterparts.

Since human Ctr1 is 92 percent identical to mouse Ctr1, it is highly likely that the metal transport protein works the same way in mice as it does in humans. The researchers reasoned that a defective or missing copy of the gene that codes for Ctr1 in some tumor cells may explain why certain people stop responding to cisplatin. The findings have important medical implications: If researchers can figure out a way to increase the amount or activity of Ctr1 in tumor cells, they may be able to extend the use of this effective chemotherapy drug. Future pharmacogenetic studies, in which scientists search for connections between genes and drug response, may help identify who will respond well or poorly to cisplatin treatment.