23/07/2012 (The Star) - Not many people paid heed to tocotrienols 30 years ago, but of late, the scientific community just can’t seem to get enough of it.

Just in the last five years alone, dozens of papers had been published on this lesser known form of vitamin E, which can actually exist in four forms, or isomers.

The most well studied isomers would come under the tocopherol group, with its alpha, beta, delta and gamma isomers. Initial research on tocotrienols, which also comes in the alpha, beta, delta and gamma isomers, looked at its value in moderating cholesterol levels. In the 1990s, scientists started to look at how tocotrienols could be used against cancer.

A study is being carried out locally to assess whether tocotrienols might be able
to delay the progression of prostate cancer without any serious side effects

Tocotrienols are natural c ompounds found in rice bran, coconut oil, cocoa butter, barley, wheat germ, annatto, and palm oil. However, tocotrienols occur at very low levels in nature. As for vitamin E from palm oil, 75% of it consists of tocotrienols – alpha, delta, and gamma (the predominant form), while alpha tocopherol makes up the remaining quarter. Given its relative abundance, palm oil is arguably the most suitable feedstock to meet any global demand for tocotrienols.

Tocotrienol research has surged in the past four years, with over 50% of peer-reviewed articles published since 2008. The first-ever scientific compilation of tocotrienol research, Tocotrienols: Vitamin E Beyond Tocopherols, was published in 2008, while a second edition was published two months ago (May 2012). Going by absolute numbers, studies into tocotrienols still pale in comparison to that of tocopherols, accounting for only 1% of all research into vitamin E.

Past research found tocotrienols to be able to inhibit the growth of tumour cells in chemically-induced breast cancer in rodents. Other studies also supported the claim that tocotrienols, especially the delta and gamma tocotrienols, have inhibiting qualities on human breast cancer cells by inducing cell death through the initiation of apoptosis (the programmed death of cells).

The Journal of Biological Chemistry (April 2000) reported that researchers from the University of California, Berkeley, found tocotrienols, especially alpha-tocotrienol, to be effective in preventing age-related neuro-degenerative diseases and certain types of cancer, such as breast cancer.

Cognisant of the potential of tocotrienols, the Government, through the Malaysian Palm Oil Board (MPOB), has been pushing for more research on the medical applications of tocotrienols. The drive to add value to tocotrienols falls under the 8th Entry Point Project of the Palm Oil National Key Economic Area, whereby it aims to expedite growth in food and health-based segments of palm oil.

For Davos Life Science Pte Ltd (www.davoslife.com), the future lies in more experimentation using the more purified forms of tocotrienol isomers. Davos is fully owned by Malaysian plantation giant Kuala Lumpur Kepong Bhd, and is an established supplier of palm tocotrienol for supplements, functional food/beverages, as well as the cosmetic and skincare industry.

Davos recently received a grant from MPOB to embark on a clinical trial for prostate cancer, and it is working with Professor Azad Hassan Abdul Razack of Universiti Malaya Medical Centre (UMMC), and Dr Murali Sundram of the Kuala Lumpur General Hospital (KLGH), to find out if gamma-delta tocotrienols are able to delay the disease progression in men suffering from castration resistant prostate cancer (CRPC).

The prostate is a gland in the male reproductive system. In Malaysia it is the sixth most frequent cancer and it accounts for 5.7% of cancer cases in males. Most prostate cancers are slow growing, and are usually seen in men over 50.

Although it is one of the most common cancer in men, many never have any visible symptoms, and eventually die of other causes (including other unconnected cancers). Prostate cancer is a very long-drawn disease, and the patient can live for decades before dying (not necessarily from the prostate cancer itself).

In other cases, the cancer only becomes aggressive when the man reaches old age.

About 75% of vitamin E from palm oil consists of tocotrienols.

However, as our life expectancy increases, more prostate cancer patients are now suffering the debilitating effects of this cancer and dying from it, which makes the search for a more gentle or benign form of therapy important.

About 90% of the patients don’t resort to chemotherapy for prostate cancer because doctors don’t think there are any significant benefits. Chemotherapy (using chemodrugs like docetaxel) costs about RM30,000 for one full course (comprising eight cycles), and in most cases, prolongs life by an additional few months. Side effects can be a factor, and can include diarrhoea, vomiting, weight loss, muscle weakness, loss of appetite, and even paralysis.

Based on the promising animal studies using gamma-delta tocotrienols, the researchers are hoping to see similar effects in delaying the progression of CRPC, which will likely have lesser side effects than docetaxel. The two-year trial will involve 50 prostate cancer patients from UMMC and KLGH. Simultaneous trials at Australia’s Princess Alexandra Hospital (at Brisbane, Queensland) will also see participation of another 50 patients.

According to Dr Fong Chee Wai, head of research and development for Davos, while there has been a fair amount of research involving tocotrienols, many used a mixed form of tocotrienols (containing two or more isomers), and in some cases, tocopherols were also present in the mixture.

This is not ideal as high doses of alpha-tocopherol is known to reduce the bioavailability of tocotrienols, thereby reducing their efficacy. In addition, even though tocotrienols may be viewed as being members of the natural vitamin E family, it is difficult to attribute any particular effect, good or otherwise, to a mixture of isomers as no one can be certain which particular isomer is actually contributing to the observed effect.

“This makes it difficult for the scientific and medical community to have confidence in the results to the extent they can wholeheartedly promote their use to their patients,” said Dr Fong, a Singaporean who had worked with the natural product screening facility of Glaxo-Wellcome (a pharmaceutical company based in UK) in the early-90s when most drugs were discovered from natural sources.

He has also more than 10 years of experience working on aberrant cell signalling in cancer research with Singapore’s Agency for Science, Technology and Research (A*Star). He joined Davos last year after a three-year stint at Merck Millipore, a German pharmaceutical company.

Phase 1 of the study begins this month (July 2012), and will look at the safety and toxicity aspects of giving a higher than normal (compared to the usual diet) dose of tocotrienols to humans.

There is currently no Estimated Average Requirement, Recommended Dietary Allowance, or Adequate Intake and the Tolerable Upper Intake Level (UL) for tocotrienols (unlike for tocopherols ­– with the exception of ULs for infants).

The good news is that tocotrienols are rather well tolerated by humans. A recent clinical study on pancreatic cancer by Professor Mokenge Malafa at the H. Lee Moffitt Cancer Center & Research Institute of Florida, the United States, saw patients consuming daily doses up to 3,200mg without any observable adverse side effects.

Men who volunteer for this upcoming local tocotrienol study will have their medical history carefully screened to weed out those that had cancer in other parts of their body. “The cancer can be from the lung, and metastasised (spread) to the prostate. We do not want these cases in order to minimise the confounding factors,” said Dr Fong, who added that the second phase of the clinical study needs at least 100 patients,” said Dr Fong, who is nonetheless careful to add that all these should not be equated with claims of being able to cure cancer.

“We are hoping that tocotrienols might be able to delay the progression of prostate cancer without any serious side effects.”