Chemical derived from vitamin-E shows early promise as cancer drug

09/29/04

AUSTIN, Texas By studying cancer in mice, researchers at The University of Texas at Austin have gained preliminary evidence that a novel compound that resembles vitamin E halves the size of tumors and the ability of cancer to spread to other body sites.

"We have clear evidence that this chemical is directly causing cancer cells to die," said Kimberly Kline, a nutrition professor in the Department of Human Ecology who directed the research in collaboration with Bob G. Sanders, a professor in the School of Biological Sciences.

The findings will be published in the October issue of Experimental Biology and Medicine. They result from studies involving treatment of genetically identical mice, which were given the novel vitamin E compound either orally or by aerosol.

Based on earlier, similar findings by Kline and colleagues, the National Cancer Institute is funding national efforts to investigate the ability of this novel compound, RRR-alpha-tocopherol ether acetic analog (alpha-TEA), to prevent colon and breast cancers in preclinical animal models.

Mice in the study were treated with alpha-TEA for 21 days after an injection of mouse-derived mammary cancer cells that normally would have formed a tumor mass and spread (metastasized) to the animals' lungs. Regardless of whether alpha-TEA was administered to the mice by mouth (orally) or via breathing (aerosol), the compound was capable of reducing the primary tumor mass by greater than half.

In addition, the compound was capable of reducing tumor lesions (metastases) in the lung that were big enough to see with the naked eye. For example, only one of 10 alpha-TEA aerosol-treated mice developed visible lung tumor lesions in comparison to five of 10 untreated control mice. None of the treated animals showed any type of general symptoms of toxicity to alpha-TEA, which Kline chose for further study in 1997 from 50 candidates.

Because cancer may result from just one normal cell going awry, Kline and former graduate student Karla Lawson also used special microscope equipment to identify smaller cancer lesions. The equipment could pinpoint the injected cancer cells in the animals because the cells had previously been genetically modified by co-author LuZhe Sun from the University of Texas Health Science Center in San Antonio to fluoresce bright green under proper exposure.

Using this fluorescent cue, Kline and colleagues determined that mice treated with aerosolized alpha-TEA had less than half the number of lung micrometastases as untreated mice (an average of 31 versus 73 detected cancer cells or small clusters of such cells). In addition, 48 percent of nearby lymph nodes of those mice lacked any microscopic signs of cancer, though these structures are where the cancer would likely spread. Only four percent of lung-related lymph nodes in controls were cancer-free. Treated mice that did develop microscopic signs of cancer in the lymph nodes had only one or two lesions, rather than the six or seven of untreated counterparts.

Kline, who holds the Julian C. Barton Professorship in Nutrition, also investigated how alpha-TEA impacts breast cancer cells, using cells grown in plastic containers. When exposed to alpha-TEA, the cancer cells showed only 20 percent of their normal ability to multiply and produce new cells. In addition to blocking the cancer cells' ability to divide, alpha-TEA caused the cancer cells to shrink and die through a process called apoptosis compared to untreated breast cancer cells.

"One reason that alpha-TEA is such a potent anti-cancer agent is that it impacts on numerous anti-growth and pro-death cellular processes in cancer cells but not normal cells," said Kline.

The researchers also investigated whether another derivative of vitamin E called RRR-alpha-tocopheryl succinate or VES, was as effective. VES was effective when administered by aerosol but was not effective when given orally, probably because it is broken down into an inactive chemical form by intestinal enzymes.

Kline will continue analyzing alpha-TEA activity and cellular effects in mice. Meanwhile, the chemical is going through more detailed toxicity evaluations and analyses for its preventive and treatment potential by researchers receiving support from the Rapid Access to Preventive Intervention Development (RAPID) program of the National Cancer Institute.

"Our research is promising at this stage, but there's a lot of further investigations that have to be conducted before alpha-TEA can be cleared by the Federal Drug Administration for testing in humans," Kline said.

Source: Eurekalert & others

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