SU professor presents new findings on chemotherapy drug, plans studies to further development of drugs with fewer side effects

SU professor presents new findings on chemotherapy drug, plans studies to further development of drugs with fewer side effectsMarch 28, 2006Carol K. Masiclatclkim@syr.edu

For millions of people battling cancer, chemotherapy is a necessary fact of life. The powerful drugs used slow the abnormal, unregulated growth of cells (cancer) by attacking cells undergoing the division process. One such drug, cisplatin, has become one of the most widely used chemotherapy drugs in the world.

When it was approved by the Food and Drug Administration in 1978, platinum-based cisplatin revolutionized the treatment of various types of cancers, including testicular, ovarian, lung, esophagus (gullet), stomach and bladder cancers. Cisplatin, and another platinum drug, carboplatin, account for more than $2 billion in annual sales worldwide. But while the treatments with these drugs have been effective, they also often bring with them side effects that can range from mild to life threatening. One of cisplatin’s most common side effects is its high renal toxicity, which can lead to severe and permanent damage to the kidneys.

Recent discoveries by James Dabrowiak, Syracuse University professor of chemistry, and his collaborators at SU and at SUNY Upstate Medical University, may revolutionize how cancer is treated with cisplatin and related drugs. Using a highly sensitive form of nuclear magnetic resonance spectroscopy (NMR), Dabrowiak and his team discovered that platinum drugs react with carbonate present in the blood and cells. The result is the formation of adducts, called carbonato complexes, which may be the main chemical components responsible for cell death.

While carbonato complexes are very important for uptake, antitumor properties and toxicity, only small amounts of these compounds are naturally produced in the blood of patients receiving these drugs. For this reason, it is critical to make these compounds chemically and study their effects on normal and cancer cells.

“Our findings have turned over a number of existing concepts and beliefs on the molecular mechanism of action of cisplatin,” says Dabrowiak. “When the findings are fully appreciated and implemented, they will lead to the synthesis of new and more effective platinum drugs for treating cancer.”

Reducing the toxicity of cisplatin and carboplatin is an important priority in Dabrowiak’s work. The research may lead to modified versions of these drugs that enable patients to stay on treatments for longer periods of time without the risk of damage to important organs.

Says Dabrowiak: “That is a critical thing for the patient, reducing toxicity. It makes their lives easier and more comfortable, and their therapies are more effective.”

The research team has published two papers to share their findings, “Cisplatin Carbonato Complexes. Implications for Uptake, Antitumor Properties and Toxicity” in the October 2005 issue of the Journal of the American Chemical Society, and “Activation of Carboplatin by Carbonate” in the January 2006 issue of the ACS journal Chemical Research in Toxicology.

The next move for Dabrowiak and his collaborators is carrying out animal studies with platinum drugs that have been modified with carbonate. The team will continue to investigate the efficacy of carbonato complexes for treating tumors and minimizing drug-induced side effects.