Diabetes Drug Dramatically Boosts Power Of Platinum Chemotherapy

Combining a platinum chemotherapy agent and the diabetes drug rosiglitazone halted or shrank mouse tumors as much as three times more effectively than either of the drugs given alone, according to the article in the May issue of Cancer Cell.

If pairing the drugs has the same synergistic effect in humans, the researchers say, it could improve control of ovarian, lung and other cancers routinely treated with platinum-based chemotherapy, to which tumors eventually become resistant. Moreover, the experiments suggest the combination might extend the use of platinum drugs to other cancers where they haven't previously been shown to be effective.

"There's still a huge gulf between these experiments and human cancers," said Bruce Spiegelman, PhD, senior author of the report. "But it's worked in every animal model of cancer we've looked at, and I think there's a fair chance it will help people."

Dana-Farber researchers are already drawing up plans for initial clinical trials, which could begin sometime this year. "We really see a way forward here to improve the chemotherapy's effectiveness for multiple forms of cancer," said George Demetri, MD, a Dana-Farber researcher who is preparing a proposal for a pilot study of rosizitaglone and platinum chemotherapy drugs in lung and ovarian cancer and sarcomas.

If a pilot study shows promising activity, the combination would need to be compared with standard chemotherapy in larger phase 2 and phase 3 trials involving many hundreds of patients.

Rosizitaglone, sold under the name Avandia, enhances insulin receptors' sensitivity in diabetics whose pancreas secretes too little insulin. It was approved in 1999 for use by patients with type 2 diabetes to help control blood sugar levels. An estimated 5 million people in the U.S. take Avandia or a similar drug, piozitaglone, which is sold as Actos.

Both drugs work by activating PPAR-gamma, a transcription factor that functions as a master regulator of fat development in the body, a function discovered in the Spiegelman lab in 1994. Spiegelman and others observed that certain PPAR-gamma-activating compounds, called PPAR-gamma ligands, caused cancer cells to stop growing and become more mature, or differentiated. Therefore, Spiegelman and others felt it was a logical step to try PPAR-gamma ligands as cancer treatment, but several small clinical trials found rosiglitazone alone was ineffective against several cancer types.

Despite this setback, and because rosizitaglone was well-tolerated by patients compared to standard cancer drugs, Dana-Farber researchers believed it was worthwhile to try it and similar PPAR-gamma ligands in a different context, said Geoffrey Girnun, PhD, a researcher in Spiegelman's laboratory and lead author of the Cancer Cell report. "After discussing it with other Dana-Farber researchers, we decided to try these agents in combination with platinum-based drugs, and in several different cell lines, we saw positive results," said Girnun.

In addition to rosizitaglone, the scientists tested pioglitazone and an experimental compound made by Glaxo Smith Kline, combining each of them with cisplatin, carboplatin and oxalyplatin -- all commonly used chemotherapy drugs that destroy cancer cells by damaging their DNA.

When non small-cell lung cancer cell lines were treated with rosizitaglone alone, there was no effect on growth. Carboplatin alone reduced growth of the cancer cells by about 60 percent. But when both drugs were administered, cell growth was reduced by 80 percent. The drugs were also tested individually and together on ovarian cancer cell lines that normally are resistant to chemotherapy -- and proved capable of reducing growth of the cancer cells by 90 percent. Even when applied to colon cancer cells, a type of cancer not usually treated with platinum drugs, rosiglitazone and carboplatin lowered the growth rate by 70 percent. (Rosizitaglone did not show the same positive effect when paired with oxalyplatin.)

The drug combination also had striking growth-suppressing results when given to mice with human lung and ovarian tumors implanted under their skin and in mice that had received a chemical that causes them to develop colon cancer, explained Spiegelman, who is also a professor of cell biology at Harvard Medical School.

The experiments showed that the PPAR-gamma ligands suppressed the activity of metallothioneine genes, which are believed to trigger the development of cancer cells' resistance to platinum chemotherapy.

"Our finding that PPAR-gamma activation dramatically increases the efficacy of carboplatin, potentially causing tumor stasis or even tumor shrinkage could represent a significant advance in chemotherapy," the researchers wrote.

The work was supported by the National Institutes of Health and the Madeline Franchi Ovarian Cancer Award.