The new agent is called taxoid IDN-5109.

Ralph J. Bernacki, PhD, Michael R. Vrendenburg and others from the Department of Pharmacology & Therapeutics at RPCI, Iwao Ojima, PhD, State University of New York at Stony Brook, and Fernando Cabral, University of Texas Medical School, Houston, reported their findings in today's edition of the Journal of the National Cancer Institute.

Tumor resistance mediated by Pgp often limits the effectiveness of many clinically-useful chemotherapeutic agents, including paclitaxel. IDN-5109 may increase the spectrum of therapeutic benefit of taxoids now used against breast, ovarian and lung cancers to include other tumor types such as colon tumors, against which paclitaxel and docetaxel have been relatively ineffective.

"The taxoid paclitaxel has proven to be a valuable chemotherapeutic agent against a wide variety of solid tumors," said Dr. Bernacki. "However, tumor resistance, such as that caused by overexpression of Pgp in certain tumors, has imposed limits on its responsiveness observed in the clinical setting."

To overcome tumor resistance to paclitaxel, Bernacki's laboratory has taken a two-pronged approach.

First, they have developed active agents, such as IDN-5109, which inherently overcomes multidrug-resistance in Pgp-positive tumors.

Secondly, they have developed drug resistance reversal agents, such as tRA96023, which have no direct impact on chemotherapeutic activity, but enhance the effectiveness of other drugs.

The hypothesis is that combining agents such as IDN-5109 and tRA96023 will provide the best avenue for treating traditionally non-responsive tumors.

The researchers found that IDN-5109's activity in Pgp-expressing cells is due to its ability to inhibit Pgp action, thereby increasing cellular retention of the drug in the tumor. Also, by combining IDN-5109 and tRA96023, IDN-5109's effectiveness was further increased against the paclitaxel-resistant DLD1 colon tumor.

"Additionally, an exciting find was the discovery that IDN-5109 was active following oral administration," notes Bernacki. Presently, both paclitaxel and docetaxel must be administered intravenously.

"IDN-5109's effectiveness in preclinical testing, as well as a preclinical toxicology profile similar to other clinically-useful agents, have facilitated its entry into clinical trial, where it may prove to be more effective than paclitaxel and docetaxel against a variety of tumors, especially those exhibiting a multidrug-resistance phenotype," continued Dr. Bernacki.

"Further," he added, "since current options for colorectal cancer are severely limited, IDN-5109 may broaden the spectrum of taxoid use to include colon tumors, thus providing an alternative to the current regimen of treatments."

Roswell Park Cancer Institute, founded in 1898, is the nation's first cancer research, treatment and education center and is the only National Cancer Institute-designated comprehensive cancer center in Western New York.

16-Aug-2001