October 31, 1997

Novel colorectal cancer therapy shows promise

Novel colorectal cancer therapy shows promise

Vanderbilt University Medical Center investigators have found that adding antioxidants such as Vitamin E to the standard chemotherapy regimen used to treat colorectal cancer helps kill more cancer cells, both in tissue culture and in mice.

The research team's findings, published today in the journal Nature Medicine, could lead to novel treatments of colorectal cancer, the second-leading cause of cancer deaths in the United States, said Dr. Robert J. Coffey Jr., professor of Medicine and Cell Biology and senior author of the study.

"The results that we have seen in mice and in vitro are very encouraging," Coffey said. "Traditionally, antioxidants like vitamin E. and B-carotene have been touted as agents that prevent cancers from forming. While a chemopreventive effect has not yet been proven, we have found intriguing evidence that antioxidants may help treat established cancers."

The current standard treatments of colorectal cancer ‹ the drugs 5-fluorouracil (5FU) and leucovorin ‹ are effective in only approximately 20 percent of advanced tumors. A major reason the remaining 80 percent of advanced tumors are resistant to chemotherapy is that these tumors harbor a disabled p53 gene.

In those few tumors with normal p53, chemotherapy alone increases p53 levels, which then induce a set of genes, notably p21, that leads to tumor shrinkage via cell growth arrest and programmed cell death, or apoptosis.

Antioxidants such as those used in this study ‹ a water-soluble form of Vitamin E trolox and a dithiocarbanate, PDTC ‹ appear to bypass a disabled p53 gene to induce p21, which, in combination with chemotherapy, leads to arrested tumor growth and apoptosis of tumor cells, but not normal cells.

"This latter finding points to an added benefit of the combined treatment," Coffey said. "These antioxidants protect rapidly dividing normal tissues, such as the gut, from the injurious side effects of chemotherapy."

While results in the lab and in animal models are very encouraging, Coffey said that clinical trials are necessary to determine whether the combination of antioxidants and chemotherapy will be as effective in humans. Since the dose of Vitamin E tested was only three-to-four times higher than the daily recommended dose for normal individuals ‹ and well below a toxic dose ‹ human clinical trials are not only feasible, but promising, Coffey said.

"These results offer the hope of a new strategy to circumvent a disabled p53 protein by addition of antioxidants to restore chemotherapeutic responsiveness to certain types of cancers."

Co-authors of the study were Rebecca Chinery, Ph.D., research instructor in Medicine and Cell Biology; Jeffrey Brockman, Ph.D., research fellow in Medicine; Dr. Mark Peeler, Surgical Resident; Yu Shyr, Ph.D., assistant professor of Preventive Medicine; and Dr. R. Daniel Beauchamp, professor of Surgery and Cell Biology and chief of the division of Surgical Oncology.

Coffey emphasized that Rebecca Chinery spearheaded these studies. The work was made possible by the financial support of the Joseph and Mary Keller Foundation and the Peter Powell Memorial Fund.