MADISON, Wis.—The heart drug digitalis, derived from foxgloves, may someday soon add cancer treatment to its pharmaceutical repertoire. A technique used by researchers at the University of Wisconsin-Madison (UWM) to alter digitoxin, a component of digitalis, created new compounds that showed efficacy against cancer cells during in vitro studies. Mouse studies are underway.
Jon Thorson, professor of pharmaceutical sciences at UWM, says cardiac glycosides in digitalis "have long been known to be cytotoxic from in vitro and in vivo studies." Cancer chemotherapy studies, he adds, also demonstrated that patients who are taking cardiac glycosides often responded better to the chemotherapy than those who were not.
Thorson's work, funded by the National Cancer Institute (NCI), may be early-stage, but it has established a library of 78 derivatives of digitoxin by removing sugars and then installing a neoglycosylation "handle" of other sugars onto its backbone. "In the case of digitoxin, handle installation required three simple quantitative steps with only a single chromatography step and set the stage to construct a large neoglycorandomized library in a very short time frame," says Thorson.
The compounds were assessed using a high-throughput cytotoxicity assay on a variety of human cancer cell lines, including colon and breast carcinomas. Thorson says it's unclear exactly why some compounds were effective against cancer cells, but certain new compounds were also more specific and potent against the cells than natural digitoxin. Current mouse work is determining maximum tolerable doses and the stability of the compounds in vivo; work with colon cancer should begin this fall.
The glycorandomization and neoglycorandomization technologies developed by Thorson's lab were licensed by the company zuChem from the Wisconsin Alumni Research Foundation (WARF). Rajni Aneja, zuChem's vice president for corporate development, describes them as a "really powerful" set of technologies that can both aid in drug development and scaling up compound production.
Chicago-based zuChem is using glycorandomization and other technologies in its work with anti-infectives and cancer. The company licensed all commercial rights to these glycorandomization technologies, so it would play a key role in technology transfer if one of Thorson's compounds eventually proves efficacious through clinical trials. Aneja describes zuChem's relationship with WARF and Thorson as being very interactive.
The Developmental Thera-peutics Program of the NCI funds UWM's research under a five-year, $5.6 million award. NCI's Yali Hallock, who manages a portfolio of natural products under study at various institutions, calls the UWM work preliminary, but also exciting because of the ability to develop a diverse library of compounds through glycorandomization. "Not many programs are working on unnatural sugars," she adds.
Hallock also praised other efforts of UWM's National Cooperative Drug Discovery Group in studying additional anti-cancer drugs from natural products. Although Thorson declined to reveal what other natural products are under investigation at NCDDG, he says, "We are working toward both developing new natural products not yet established as cancer drugs as well as enhancing the properties of established anticancer drugs."
UWM professor Ben Shen is principal investigator for UWM's grant; professor Paul Lambert focuses on development and use of mouse models; and C. Richard Hutchinson, a former UWM professor who is now a research fellow at Kosan Biosciences, rounds out the team with advice on scientific and preclinical aspects of cancer drug development.
