Protecting the Intestinal Lining from Chemotherapy 8/24/05

In a recent study, researchers found that a human growth factor induced strong growth of the epithelial lining inside the intestines of mice, and helped protect the tissue of the intestine against damage caused by chemotherapy.

The study, [Kim, et al., Science, vol. 309, pp. 1256-1259 (2005)] conducted by researchers from Nuvelo Inc., Sunnyvale, Calif., and the pharmaceutical research division of Kirin Brewery, Tokyo, Japan, found that R-spondin1, a secreted protein, in preclinical development under the name NU206, acts as a specific and potent stimulator of the human epithelial cells that line the gastrointestinal tract and mouth.

The epithelial lining often undergoes significant damage during cancer-related treatments such as chemotherapy or radiation therapy, causing a potentially severe complication known as mucositis.

The results show that NU206 stimulates the growth and development of new epithelial cells and is proving highly efficacious in animal models of human gastrointestinal disease, said Walter Funk, PhD, vice president of research, Nuvelo. This study, he says, supports the direction of the company's clinical program for the compound as a supportive cancer treatment for chemotherapy- and radiation therapy-induced oral and gastrointestinal mucositis.

The researchers conducted the study using a transgenic mouse model and a recombinant version of the protein. The study also found that once the growth factor was withdrawn, the epithelium of the intestine reverted to its normal state and did not continue to proliferate.

The recombinant protein was then tested in a mouse model of a gut tumor with chemotherapy-induced mucositis, where the group saw an improvement in the cellular health of the epithelial tissues and a dramatic reduction in symptoms of mucositis, which include diarrhea and weight loss. They also found that the growth factor did not impact the anti-tumor efficacy of the chemotherapeutic agent 5-fluorouracil.

"Ascribing biological function for orphan secreted proteins remains a major challenge in the post-genomic era," the researchers write." The transgenic mouse system provided an unbiased in vivo screen, they say.

The researchers conclude that it will be very important to identify receptors for R-spondins to fully understand the biology of this important class of activating ligands.

By Elizabeth Tolchin