Finding a Magic Bullet

CURE, Winter 2004, Volume 3, Issue 4

It was the mid-1960s and Barnett Rosenberg, PhD, was curious about cell division. The Michigan State University biophysicist had watched the process under a microscope and noted the cells looked much like the pattern created by iron filings as they wiggled and moved when placed near a magnet.

Would changing electrical conditions around the cell change this pattern the same way it did with the iron filings? To test his question, Dr. Rosenberg and colleagues Loretta VanCamp and Thomas Krigas, PhD, began experimenting with electricity and bacteria, stumbling upon the finding that when platinum electrodes were used to send an electrical charge through bacteria, it was not the electricity that caused cell division to stop, but some kind of electrochemical reaction. What they found upon further research was that the electric current had prompted a chemical reaction between the normally unreactive platinum in the electrodes and nutrients in the solution containing the bacteria, and, in this reaction, a compound was produced, a molecule centered on a platinum atom called cis-diamminedichloroplatinum—or C-DDP.

The compound was not new, having been discovered in 1845. Almost 50 years later, Alfred Werner, PhD, determined the structure of DDP and won a Nobel Prize in 1913 for this discovery. But Dr. Rosenberg and his team reasoned that if the compound inhibited cell division, it might be a useful cancer drug. They pursued the development of the new compound, which they called cisplatin (Platinol®).

While its exact mechanism for stopping cell division has never been fully understood, cisplatin appears to cause cell death by damaging the DNA (genetic material) of the cell. Cisplatin was soon credited with providing the first cure of an advanced solid tumor when Lawrence Einhorn, MD, proved its efficacy in testicular cancer. Ultimately, Dr. Rosenberg and his team created a sister drug called carboplatin (Paraplatin®) that was similar in molecular makeup but promised less severe side effects than cisplatin. Carboplatin is widely used in treatment of a number of cancers, including ovarian, lung and breast cancers.

When the Food and Drug Administration approved cisplatin in 1978, it had already been in use for more than four years by Dr. Einhorn and other oncologists for treating testicular cancer. Since then, cisplatin has been widely used against a number of other cancers, including head and neck, cervical, esophageal and ovarian cancers.

Frank Pasqualone, senior vice president of oncology for Bristol-Myers Squibb Company, watched the evolution of cisplatin as its product manager.

“The early story of cisplatin is a dramatic story of the collaboration of academia, industry and government,” he says. “There was no question that it was a good drug, but its tolerability was a major concern. (The side effects of cisplatin included severe nausea, kidney damage and nerve damage.)

The second chapter in the cisplatin story began when Zofran® (ondansetron) was introduced as the first in a new class of antiemetics. Zofran and the similar drugs that followed revolutionized cisplatin administration as patients had much less nausea and vomiting than before.”

The literature is replete with references of cisplatin and carboplatin use in esophageal, lung and gastric cancers, in addition to those mentioned above. But none proved to be the cure found for testicular. Today, Pasqualone says, research is moving away from the “shotgun strategies.”

“We know now how insidious cancer is and are investing in the new wave of targeted therapies that are easier on the patient. In addition, we are constantly learning more and more about predictive markers, which may be more indicative of who may benefit from a given therapy. Our collective goal as a cancer community is to find the same kind of cure for other solid tumors that was found for testicular with cisplatin.”