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Plant-derived molecules, genetic manipulation point to future chemoprevention methods

14.11.2006
Scientists are using genetic studies and natural chemicals, such as plant-derived triterpenoids, to further our knowledge on how genetic and early molecular interactions can lead to cancer, and how those early interactions can be manipulated to stave off a variety of cancers. The latest studies with new and promising chemopreventive agents were presented at the American Association for Cancer Research's Frontiers in Cancer Prevention Research meeting today.

Trterpenoids and the rexinoid LG100268 prevent lung tumors induced by vinyl carbamate in strain A/J mice

New synthetic drugs called triterpenoids which owe their origins to plant molecules have demonstrated their effectiveness in slowing the growth of lung cancer tumors, a research team from Dartmouth University has found.

Following up on previous work showing strong links between inflammation and the development of cancer, Karen Liby, Ph.D., a postdoctoral fellow, and her colleagues found that the triterpenoid CDDO-MA, currently undergoing trails for leukemia and solid tumors (sponsored by Reata Pharmaceuticals), significantly reduced the number and sizes of tumors in mice. In addition, a chemically related drug developed by Ligand Pharmaceuticals called LG100268 was effective at preventing tumor growth.

"Lung cancer is the leading cause of cancer deaths in the United States," said Liby. "Since the mortality from this disease is significant, and prognoses are poor once a patient has been diagnosed, prevention may provide the only avenues to combat this particular cancer. We think this study shows a promising role for triterpenoids and the drug LG100268 in stopping lung tumor growth."

The scientists knew that the compounds had anti-inflammatory properties and that LG100268 in particular could stop certain types of breast cancer in animal models. The compounds inhibited inflammation in a number of ways: halting nitric oxide production, blocking cyclooxygenase and nitric oxide expression, curbing proliferation and inducing apoptosis in human lung cancer cells.

They tested CDDO-MA and LG100268 on mice for 20 weeks. CDDO-MA and 268 reduced the number of lung tumors to 9.1 in the group fed CDDO and to 7.4 in the 268-fed group, compared to 15.5 in the control group. These tumors were smaller, too: 43 percent of tumors in CDDO-fed mice and 28 percent of tumors in the 268-fed group were less than 0.5 mm in diameter, compared to only four percent in the control groups.

CDDO-ME and CDDO-EA, other synthetic forms of CDDO, also reduced tumors. After 15 weeks on a diet of the CDDO-ME triterpenoid, tumors numbered only 7.4, compared to 15.9 in the control mice. For mice on CDDO-EA, tumors were reduced to 7.8. No tumors in these groups were larger than 1 mm in diameter, while 20 percent of tumors in the control mice averaged more than this size. In fact, between 63 and 70 percent of tumors were less than 0.5 mm in diameter.

The research suggests the potential for these compounds in preventing lung cancer, and points to the need for clinical trials to test their effectiveness in humans.

The triterpenoid, CDDO-methyl ester, and the rexinoid, LG100268, synergize in the prevention of mammary tumors in a mouse model of estrogen receptor-negative breast cancer

Triterpenoids and the rexinoid experimental drug LG100268 were also effective in combination against breast cancer development more than either compound individually, the Dartmouth research team found.

Liby and her colleagues found that the synthetic triterpenoid CDDO-ME and the drug LG100268 eliminated tumors in mice that were fed the compounds. The work bolsters the potential for these drugs as a chemopreventive agent for an increasing range of cancers.

"We previously reported that the rexinoid LG100268 and another potential drug, Afzoxifene, which modulates the estrogen receptor, synergize in the prevention and treatment of certain mammary tumors in mice," said Liby. "This study takes our work further, establishing a relationship between CDDO-ME triterpenoids, which are also effective anti-inflammation and anti-cancer compounds, and LG100268."

The triterpenoid CDDO-ME had already been proven effective in inhibiting proliferation and inducing apoptosis (programmed cellular death, a process that's often disrupted in cancer) in breast cancer cells, and blocked the growth of breast cancer cells in mice. CDDO and its synthetic variant CDDO-ME are undergoing clinical trials for leukemia and solid tumors.

Beginning at 10 weeks of age, mice that were genetically altered to become susceptible to breast cancer were fed either a control diet, a dose of CDDO-ME, LG 100268, or a combination of the two. After 40 weeks, all the control mice developed tumors. However, only 12 percent of mice on the CDDO-ME diet and 29 percent of the mice fed with LG100268 developed tumors. Most significantly, no tumors were found in the group fed a combination of both drugs.

"The drugs that were fed in this experiment were apparently well tolerated, and the mice gained weight throughout the experiment," Liby said. "These studies indicate that CDDO-ME and LG100268, even as individual drugs, can delay tumor development in living organisms. But the combination of the triterpenoid and rexinoid compounds was particularly powerful. This synergy could hold the key to prevention of breast cancer and should be considered for future clinical trials."

Genetic reduction of circulating insulin-like growth factor (IGF)-1 inhibits azoxymethane-induced colon tumorigenesis in mice

Mice with a genetic alteration that reduced amounts of a key growth hormone had fewer carcinogen-induced tumors than mice with normal levels of the hormone, a research group from the National Cancer Institute (NCI), University of Texas-Austin and Mount Sinai School of Medicine found.

The research suggests that reducing levels of the growth hormone IGF-1 could prove to be a promising method for preventing colon cancer from developing. It is also the first known study to successfully develop a way to examine depleted IGF-1 function in living animals.

Susan Olivo-Marston, Ph.D., a postdoctoral fellow at the NCI, and her colleagues found that mice that lacked a gene that ultimately resulted in drastically reduced IGF-1 in the livers of mice had nearly half the number of tumors seen in mice with normal IGF-1 levels. Specifically, they found that mice with normal IGF-1 levels had an average of 13 colon tumors, but the IGF-deficient mice had only 7.2 tumors on average. In addition, the colon tumors in IGF-deficient mice were less likely to be found in the proximal colon; 25 percent of tumors were in the proximal colon of deficient mice, compared to 60 percent in the control mouse colons.

Since IGF-1--in addition to its role in controlling the maximal, final growth of a young adult animal--also inhibits programmed cell death and stimulates colon epithelial cells, the scientists tested IGF-deficient mice for these cancer-causing characteristics. In fact, deficient mice had a decrease in proliferation in colon cells and an increase in apoptosis.

The researchers were presented with a significant challenge, in that directly knocking out expression of IGF-1 in mice resulted in severe developmental abnormalities and very low survival rates. Therefore, the researchers found an existing type of mouse that lacked a gene called igf1 in the liver. These mice are IGF-1 deficient, but develop normally and have a 75 percent reduction in circulating levels of IGF-1.

"High levels of IGF-1 have been associated with significant increases in colon cancer risk" said Olivo-Marston. "Since IGF-1 inhibits apoptosis and stimulates colon epithelium proliferation, we hypothesized that reducing, if not eliminating, its function could prove an effective deterrent against colon cancer growth. This small pilot study will need more follow-ups to verify our findings that reductions in IGF-1 may prevent colon tumor formation."

Olivo-Marston's colleagues include Drs. Curt Harris and Jackie Lavigne at NCI, and Stephen Hursting at the University of Texas.

Warren Froelich | EurekAlert!
Further information:
http://www.aacr.org

Further reports about: CDDO-ME Genetic IGF-1 LG100268 apoptosis colon proliferation synthetic triterpenoid

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