PHILADELPHIA -- A chemically altered form of vitamin E mixed into mouse chow dramatically reduced spread of aggressive mammary cancer in mice, suggesting that the compound in pill form could be used to treat human metastatic cancer, according to a report in the October 1 issue of the journal Cancer Research.
The study, by investigators at the University of Arizona, is the first to show that the synthetic compound has potent anti-cancer properties when given in the simplest way possible - as a dietary supplement.
"We tried other ways of delivering different forms of the synthetic vitamin, such as by force feeding and injections, but found that one form, á-TEA, was more effective when incorporated into food, and that makes it much more clinically useful," said the study's lead investigator, Emmanuel T. Akporiaye, Ph.D., professor in the Department of Immunobiology at the University of Arizona.
Mice eating the super chow had a 4.8-fold reduction in the number of tumors that spread to the lungs, compared to control mice, Akporiaye said. An even greater effect was seen when the animals began eating á-TEA-laced food as a cancer preventive, he said.
"These preliminary studies are very promising, and it could be that combining this synthetic vitamin E derivative with other anti-cancer treatments may offer the potential of both treating and preventing human breast cancer," Akporiaye said.
Although vitamin E (alpha tocopherol) is an anti-oxidant, it cannot destroy tumor cells by itself, he said. To improve the vitamin, derivatives have been created by swapping a hydroxyl chemical group with an acid. One is alpha-tocopheryl succinate (á-TOS), which used a succinic acid residue, and another is alpha-tocopheryloxyacetic acid (á-TEA), which used acetic acid.
Replacing the hydroxyl group in vitamin E helps force cancer cells to self destruct, Akporiaye said, because the compounds work to free up pro-apoptotic proteins that are normally held in check within cells. "Cell survival is maintained when pro-apoptotic proteins are confined, and these synthetic forms of vitamin E release them, pushing the cell into committing suicide," he said.
"Only a little part of vitamin E is changed in these synthetic derivatives, but they show amazing anticancer properties, and they selectively target tumor cells," Akporiaye said.
To make the synthetic vitamins water soluble (not fat soluble like natural vitamin E), researchers have added sodium hydroxide. In this way, these vesiculated forms, called Vá-TOS and Vá-TEA, can be delivered clinically through injection or oral gavage (feeding through a tube), and experiments have shown they can treat melanoma, lung and breast cancer in rodent models.
In this study, the Arizona researchers evaluated the anti-tumor effect of Vá-TOS and Vá-TEA on mice with an aggressive form of mammary cancer that is similar to human breast cancer that readily metastasizes. They also looked at how well á-TEA would affect tumor growth if incorporated into the food ("chow") that the mice ate.
They found that injecting Vá-TOS or Vá-TEA into the peritoneal cavity of the mice reduced the average volume of tumors by two fold, compared to control mice that did not receive the injections. Administering Vá-TOS daily through a feeding tube had the same effect on tumor size, but Vá-TOS was ineffective when delivered in this way, Akporiaye said. "We found that Vá-TOS wasn't stable, and returned to its natural vitamin E state," he said.
To gauge the effectiveness of a dietary treatment, the researchers had special rat chow manufactured that incorporated a fairly large quantity of á-TEA into the food. They then tested the chow as a cancer preventive and as a cancer treatment.
For the prevention study, the mice ate á-TEA chow starting on the same day that they were injected with rodent mammary tumor cells known to spread quickly to the lungs and bones. The mice were allowed to eat as much food as they wanted, and at the end of 29 days, the average tumor volume was reduced by 6.7-fold, compared to control mice who had not been fed á-TEA.
In the therapy experiment, mice started eating á-TEA chow 11 days after tumors were implanted, and in the experimental group, there was a 3.6-fold reduction in average tumor volume compared to control mice, Akporiaye said.
In both preventive and therapeutic studies, mice fed á-TEA chow had a 4.8-fold reduction in the number of tumors that had spread to the lungs, compared to control mice. "The results were very impressive," he said. "The chow was very effective in slowing down the growth rate of the tumor and significantly reducing metastases."
The á-TEA diet produced no visible adverse side effects, not even weight loss, Akporiaye said.
"The combined characteristics of ease of delivery, relevance of route of delivery and selectivity for killing tumor cells suggest that dietary á-TEA may be useful for treating metastatic breast cancer," he said.
The researchers are now testing the effect of reduced doses of á-TEA in the chow and plan to test the synthetic vitamin in combination with dendritic cell immunotherapy. "When you kill tumor cells, they release antigens that can be picked up by specialized cells that stimulate the immune system,, and this two-step process could provide a longer lasting outcome," Akporiaye said.
The mission of the American Association for Cancer Research is to prevent and cure cancer. Founded in 1907, AACR is the world's oldest and largest professional organization dedicated to advancing cancer research. The membership includes more than 24,000 basic, translational, and clinical researchers; health care professionals; and cancer survivors and advocates in the United States and more than 80 other countries. AACR marshals the full spectrum of expertise from the cancer community to accelerate progress in the prevention, diagnosis and treatment of cancer through high-quality scientific and educational programs. It funds innovative, meritorious research grants. The AACR Annual Meeting attracts over 17,000 participants who share the latest discoveries and developments in the field. Special Conferences throughout the year present novel data across a wide variety of topics in cancer research, diagnosis and treatment. AACR publishes five major peer-reviewed journals: Cancer Research; Clinical Cancer Research; Molecular Cancer Therapeutics; Molecular Cancer Research; and Cancer Epidemiology, Biomarkers & Prevention. Its most recent publication, CR, is a magazine for cancer survivors, patient advocates, their families, physicians, and scientists. It provides a forum for sharing essential, evidence-based information and perspectives on progress in cancer research, survivorship and advocacy.
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Cancer Research