fw Jefferson Scientists Find Calcium Is Key To Slowing Colorectal Cancer Growth

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Web Site:      ScienceDaily Magazine

Page URL:   http://www.sciencedaily.com/releases/2003/02/030211072542.htm

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Original Source:    Jefferson University

Date Posted:         2003-02-11

Jefferson Scientists Find Calcium Is Key To Slowing Colorectal Cancer Growth

Allowing calcium to get inside colorectal cancer cells may be one way to

stop their growth.

Researchers at Jefferson Medical College and the Kimmel Cancer Center at

Jefferson University in Philadelphia knew that the same bacterial

toxin that causes traveler's diarrhea can stem the growth of metastatic

colorectal cancer cells. Now, they may have found out how.

The scientists discovered that the toxin appears to open a cellular door,

permitting calcium into tumor cells, which in turn somehow slows cell

division. The discovery may lead to new methods of treating colorectal

cancer, perhaps by combining the toxin with chemotherapy drugs and other

agents.

Gian Pitari, M.D., Ph.D., assistant professor of medicine at Jefferson

Medical College of Jefferson University, Waldman, M.D., Ph.D.,

M.V. Hamilton Family Professor of Medicine and director of the

Division of Clinical Pharmacology at Jefferson Medical College, and their

co-workers report their findings February 10 in the Proceedings of the

National Academy of Sciences Online Edition.

Drs. Waldman and Pitari had previously shown that when the toxin, known as

ST, hooks up with a receptor, GCC, on the surface of metastatic colorectal

cancer cells, metastatic colorectal cancer cell growth slows considerably.

Treating the cells with ST didn't kill them, but rather lengthened the time

of the cell growth cycle, slowing the cells' growth and spread. The current

research takes this work one step further, providing one potential mechanism

for this growth inhibition.

" Dietary calcium is the mediator of this antiproliferative effect, " says Dr.

Pitari, who adds that dietary calcium has been believed to have a role in

preventing the formation of polyps and cancer in the colon. " Now, we show

that one of the mechanisms by which dietary calcium works is through this

pathway. The toxin activates the receptor, GCC, causing an opening of a

channel and an influx of calcium into the tumor cell. This influx causes a

reduction of cancer cell growth. Somehow there is an interaction between the

toxin and dietary calcium in blocking the growth of the tumor.

" The mechanism by which this occurs is very specific and a completely new

pathway, " he says. " No one has linked this pathway to antiproliferation and

inhibition of tumor DNA synthesis, " he notes.

In the laboratory, Drs. Pitari, Waldman and their co-workers, including

internationally renowned electrophysiologist Andre Terzic, M.D., Ph.D. at

the Mayo Clinic in Rochester, Minn., discovered that when ST binds to GCC on

the cancer cell surface, a molecule called cyclic GMP is produced. Cyclic

GMP, in turn, opens up a calcium channel in the cancer cell, permitting

calcium to flow in. The calcium then imparts a signal that slows cancer cell

division.

Drs. Pitari and Waldman see several implications from these results. " We

think you can use the toxin as an intravenous infusion to treat cancer

metastases, " says Dr. Pitari. " The toxin will not cross the intestinal

lumen, meaning there won't be the side effects of diarrhea. In this case,

you could have only the therapeutic effects of the toxin on a metastatic

tumor. We think it could be one way to treat patients who had surgery on the

primary tumor, to prevent the formation of metastases or to even treat

metastases. "

Dr. Waldman explains that when the toxin hooks up with the GCC receptor, it

causes two events in the intestine: diarrhea and cell growth inhibition,

each through a different pathway. One pathway leads to secretion of water

and electrolytes. The other leads to calcium entering the cancer cell and

blocking DNA synthesis. " We propose blocking the pathway leading to diarrhea

and leaving only the positive effect, " says Dr. Pitari. " This might provide

a great opportunity to treat the cancer locally. It might also work

synergistically with other anticancer drugs. "

Next, says Dr. Waldman, the scientists plan to create human colorectal

cancer models in so-called nude mice, animals without immune systems, to see

if ST can inhibit the growth of tumors in animals.

The technology involved in the research has been licensed from

Jefferson University to Targeted Diagnostics and Therapeutics, Inc. (TDT),

based in Exton, Pa. TDT has licensed the rights for the development of

therapeutics from the work to Millennium Pharmaceuticals, Inc. in Boston.

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Note: This story has been adapted from a news release issued for journalists

and other members of the public. If you wish to quote from any part of this

story, please credit Jefferson University as the original source.